By Iris Krishna, M.D., MPH

One of the more commonly encountered medical complications in pregnancy is diabetes mellitus. Diabetes mellitus in pregnancy is characterized as pregestational or gestational diabetes.

Pregestational diabetes is diagnosed prior to pregnancy and affects approximately 1 percent of pregnancies, while gestational diabetes is diagnosed during pregnancy and affects approximately 6 percent to 9 percent of pregnancies.

Non-obstetric surgery occurs in approximately 1 in 600 pregnancies and can be uniquely complicated by poorly controlled diabetes mellitus, which is associated with adverse perinatal, obstetric and neonatal outcomes. Operative procedure, anesthesia, disrupted meal schedules and altered nutritional intake can lead to labile blood glucose levels, and good glycemic control is key to ensuring a successful maternal and fetal outcome for the pregnant woman undergoing non-obstetric surgery.

Pathophysiology
Pregestational diabetes is a metabolic abnormality characterized by elevated circulating glucose outside of pregnancy. The exact etiology of diabetes mellitus (DM) varies and can include a primary insulin production defect, insulin receptor abnormalities, end-organ insulin resistance, diabetes secondary to another disease process (e.g. cystic fibrosis) or drug induced diabetes (e.g. steroid use).

For example, Type 1 DM occurs secondary to an autoimmune destruction of the pancreatic islet beta-cells and is an insulin-deficient state.3 This disease process typically occurs early in life, requiring insulin therapy for treatment and is more susceptible to ketoacidosis if no therapy is initiated.

In contrast, Type 2 DM is more common than Type 1 DM and is characterized by onset later in life, peripheral insulin resistance, relative insulin defficiency and obesity. In gestational diabetes mellitus (GDM), hyperglycemia results from carbohydrate intolerance first recognized or diagnosed during pregnancy.

Throughout pregnancy, insulin resistance increases due to a mixture of placental hormones, specifically, human placental lactogen, progesterone, prolactin, placental growth hormone, cortisol, tumor necrosis factor and leptin. In surgery requiring anesthesia, a neuroendocrine stress response is triggered, releasing hormones such as epinephrine, glucagon, cortisol, inflammatory cytokines and growth hormone.

This stress response can result in further metabolic abnormalities in the pregnant woman as this leads to insulin resistance, decreased peripheral glucose utilization and impaired insulin secretion, resulting in hyperglycemia or even ketosis. Due to physiologic changes in pregnancy, there is a greater tendency towards ketosis, and diabetic ketoacidosis (DKA) can occur at lower glucose levels and often progress more rapidly as compared with the non-pregnant patient.

Antepartum Management
Management of DM consists of dietary modifications, exercise and pharmacologic therapy. Capillary blood glucose monitoring should be performed four times a day: fasting and 1 or 2 hours postprandial with the goal to maintain a fasting glucose level <95mg/dL and 1-hour level <140mg/ dL or 2-hour level <120mg/dL. Dietary therapy consists of caloric intake of approximately 30 kcal/kg/day divided into three meals and three snacks. Calories should be divided as 40-50 percent carbohydrates, 20 percent protein, and 30- 40 percent unsaturated fat to help maintain a low glycemic index. If unable to be achieve goal target values through diet and exercise, then pharmacologic therapy with insulin or an oral hypoglycemic such as metformin or glyburide is initiated.

All subcutaneous insulin types used for treatment of DM have been approved for use in pregnancy as they do not cross the placenta. Insulin requirements increase with gestational age and insulin should be adjusted accordingly throughout pregnancy. In general, insulin needs in the first trimester range from 0.7-0.8 U/kg/d, second trimester from 0.8-1 U/kg/d, and third trimester from 0.9-1.2 U/kg/d.

To achieve target glucose levels, a combination of short-acting and longer-acting insulins are administered. Generally, short-acting insulins (insulin lispro, insulin aspart, insulin regular) are administered before meals to reduce glucose elevations associated with eating, and longer-acting insulins (insulin NPH, insulin detemir, insulin glargine) are used to restrain hepatic glucose production between meals and in the fasting state. Longer-acting insulins are usually administered before breakfast and/or bedtime. Table 1 describes the pharmacokinetics of commonly used insulin agents.

Oral hypoglycemic agents typically used in pregnancy are metformin or glyburide. Metformin is a biguanide that inhibits hepatic gluconeogenesis and glucose absorption and stimulates glucose uptake in peripheral tissues. Metformin does cross the placenta, and dosing usually starts at 500 mg nightly for a week then increasing to 500 mg twice daily due to common adverse side effects of abdominal pain and diarrhea. The maximum dose of metformin is 2,500-3,000 mg per day in two to three divided doses.

Glyburide is another suggested oral hypoglycemic agent and is a sulfonylurea that binds to pancreatic beta-cells to increase insulin secretion and insulin sensitivity of peripheral tissues. Glyburide crosses the placenta, and the common dosage of glyburide is 2.5-20mg daily in divided doses, but doses up to 30 mg may be necessary to achieve adequate glucose control.

Surgical Considerations
In general, well controlled blood glucose prior to surgery is associated with fewer complications, and decisions regarding management depend on the patient’s current regimen, which may include insulin, oral medications or diet alone. The goal of perioperative diabetes management is to avoid hypoglycemia, avoid marked hyperglycemia and prevent ketoacidosis. The optimal perioperative glucose targets are unclear, and there is little evidence to support specific targets.

Based on expert opinion, perioperative targets for the non-pregnant patient are between 110 and 180 mg/dL. For the pregnant patient, it is recommended to maintain glucose levels within target ranges of fasting <95 mg/dL and 1-hour <140 mg/dL or 2-hour postprandial <120mg/ dL, if possible, keeping in mind to avoid hypoglycemia, which can be reduced by frequent glucose monitoring, and to avoid marked hyperglycemia as there is a tendency towards ketosis in pregnancy with DKA observed with glucose levels as low as 180 mg/dL.

Ideally, surgery should be performed early in the day to avoid prolonged fasting. The patient should take a full dose of insulin the night before surgery and take no insulin the morning of surgery. Even on a nothing by mouth (NPO) regimen post operatively, the patient should be advised to take one-half to two-thirds of their basal insulin regimen.

While inpatient, blood glucose levels can be drawn every 4-6 hours, and corrective insulin given using a sliding scale administered to maintain blood glucose levels at target ranges. Once home or eating, regular insulin regimen can be restarted. For a diabetic on oral medication, the perioperative management depends on the length of the surgical case. If surgery is short or an anticipated same-day discharge, minimal change in medication is needed. Table 2 provides a guide to management of oral agents in the perioperative period.

A special consideration during pregnancy is glucocorticoid therapy. Administration of antenatal corticosteroids for fetal bene t is recommended for non-obstetric surgery performed at viability. Antenatal corticosteroids will result in a transient hyperglycemia in diabetic patients, which may require inpatient admission for blood glucose monitoring. Hyperglycemia may occur 3 to 8 hours after administration of antenatal corticosteroids,and pregnant women on insulin require a 20 percent increase in the dose of insulin after administration. Pregestational or gestational diabetics may require a doubling of their insulin dosing on days of administration. Blood glucose levels generally return to normal approximately 3 days after the second dose of antenatal corticosteroids.

Prevention of ketoacidosis is one of the main goals of perioperative diabetes management, as this is an acute life-threatening complication for the mother and her fetus. Pregnancies complicated by DKA are associated with increased rates of maternal and fetal morbidity and mortality, with rates of fetal loss estimated to range as high as 10-25 percent. DKA in pregnancy can occur in lower glucose levels and often progresses more rapidly as com- pared with the non-pregnant patient. A discussion on diagnosis and management of DKA is beyond scope of this article, but it is imperative to have a low threshold for evaluating the pregnant patient for DKA in the perioperative setting. Pregnant women may present with abdominal pain, nausea and vomiting, lethargy and altered mental status, and laboratory evaluation will demonstrate acidosis with a low arterial pH <7.3, anion gap >12 mEq/L, serum bicarbonate level <15mEq/L, and serum ketones. Suspected DKA is a medical emergency and requires multidisciplinary management by a maternal-fetal medicine specialist and endocrinologist.

Non-obstetric surgery for the diabetic pregnant patient can pose a significant risk. The key to perioperative management is to avoid hypoglycemia, avoid marked hyperglycemia and prevent ketoacidosis. Multidisciplinary management with maternal-fetal medicine and endocrinology should be considered.

Suggested Readings
Ceana Nezhat (ed), Kavic MS, Lanzafame RJ, Lindsay MK, Polk TM (assoc eds). Non-Obstetric Surgery during Pregnancy: A Comprehensive Guide. New York: Springer. In Press.

Lawrence JM, Contreras R, Chen W, Sacks DA. Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999-2005. Diabetes care. 2008;31(5):899-904. Classification and Diagnosis of Diabetes. Diabetes care. 2017;40(Supplement 1):S11-S24.

ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 60, March 2005. Pregestational diabetes mellitus. Obstetrics and gynecology. 2005;105(3):675-85.

Practice Bulletin No. 180: Gestational Diabetes Mellitus. Obstetrics and gynecology. 2017;130(1):e17-e37.

Johnson BE, Porter J. Preoperative evaluation of the gynecologic patient: considerations for improved outcomes. Obstet Gynecol. 2008;111(5):1183-94.

Sibai BM, Viteri OA. Diabetic ketoacidosis in pregnancy. Obstetrics and gynecology. 2014;123(1):167-78

By Helen K. Kelley

Genomic medicine, a discipline that involves using an individual’s genomic information as part of their clinical care, is true personalized medicine. Physicians and researchers in this field are working diligently to find new treatments that customize a patient’s medical care based on their unique genetic makeup.

William R. Wilcox, M.D., Ph.D.

Rapid Advances in Genetic Disease Research
“This is an exciting time in the field of genetic disease research,” says William R. Wilcox, M.D., Ph.D., professor of human genetics and pediatrics at Emory University School of Medicine. “There’s no question, we’re advancing quickly.”

Wilcox says there are three specific areas in genomic medicine that are making rapid progress and are poised to make a significant impact on certain populations:

1 Newborn screening. “In Georgia, we are conducting pilot screening for different disorders with National Institutes of Health (NIH) funding. These screens are for rare disorders that often are missed by healthcare providers or are only diagnosed after permanent damage has occurred,” Wilcox explains.

One example is spinal muscular atrophy (Werdnig-Hoffman disease). “There is a treatment available now that can prevent this disorder from developing if you identify it at the newborn stage,” he says.“These pilot screening programs are a joint effort between Emory University and the Georgia Public Health Laboratory. I’m proud that Georgia is one of the national leaders in this effort.”

2 Diagnostics. “We’re increasingly able to provide the answer as to why a child or an adult with an often bizarre group of symptoms has them – we can come to a specific diagnosis. For example, we are becoming more successful in identifying what causes significant learning disabilities or autism,” Wilcox says.

“We can figure out why it happened from a genetic perspective because of advances in molecular testing that have occurred over the last few years,” he adds. “In the not too distant future, I think we will be moving from the research we’re currently doing to full genome sequencing at a more reasonable cost.”

3 Treatment. Dr. Wilcox says that his colleagues at Emory, Children’s Healthcare of Atlanta (CHOA) and across the country are participating in a significant amount of research to provide new treatments for various genetic diseases.

“We’re learning how to treat disorders like sickle cell disease and hemophilia through clinical trials that involve processes like removing hematopoietic stem cells from the patient, making modifications and then putting them back in. Or we can give an intravenous infusion that can be targeted to help a specific organ, such as delivering a missing enzyme that isn’t being produced,” he says. “There is now even a drug to treat spinal muscular atrophy that can be delivered through a peripheral IV infusion that is able to cross the blood-brain barrier and provide a functional gene to the motor nerve cells. We are advancing rapidly in our knowledge of treatments for genetic diseases.”

When asked what he predicts for the future of genomics, Wilcox says he thinks research will continue to evolve, providing increased efficiency of treatments at lower costs.

“For genetic screening, the sequencing technologies are getting cheaper and more organized,” he says. “It may be that one day, we all have our genome sequencing done and then carry it around with us on a flash drive. You’ll know what genes you carry and what treatments you need.”

In the News: Researchers Discover Roles and Teamwork of CRISPR-Cas Proteins
Recently published research from the University of Georgia and UConn Health provides new insight about the basic biological mechanisms of the RNA-based viral immune system known as CRISPR-Cas.

CRISPR-Cas, short for Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated, is a defense mechanism that has evolved in bacteria and archaea that these single-celled organisms use to ward off attacks from viruses and other invaders. When a bacterium is attacked by a virus, it makes a record of the virus’s DNA by chopping it up into pieces and incorporating a small segment of the invader’s DNA into its own genome. It then uses this DNA to make RNAs that bind with a bacterial protein that then kills the viral DNA.

The system has been studied world- wide in hopes that it can be used to edit genes that predispose humans to countless diseases, such as diabetes and cancer. However, to reach this end goal, scientists must gain further understanding of the basic biological process that leads to successful immunity against the invading virus.

Michael Terns, distinguished research professor of biochemistry and molecular biology in UGA’s Franklin College of Arts and Sciences, is principal investigator for the project.

“This research is more fundamental and basic than studies that are trying to determine how to use CRISPR for therapeutic or biomedical application,” says Michael Terns, principal investigator for the project. “Our study is about the unique first step in the process, known as adaptation, where fragments of DNA are recognized and integrated into the host genome and provide immunity for future generations.”

Previously, it was not understood how the cell recognized the virus as an invader, nor which bacterial proteins were necessary for successful integration and immunity. Through this study, researchers were able to determine how the bacterial immune system creates a molecular memory to remove harmful viral DNA sequences and how this is passed down to the bacterial progeny.

By looking at patterns in the data, the researchers discovered several new findings about how two previously poorly characterized Cas4 proteins function in tandem with Cas1 and Cas2 proteins found in all CRISPR-Cas systems.

In this initial adaptation phase, one of two different Cas4 proteins recognizes a signaling placeholder in the sequence that occurs adjacent to the snippet of DNA that is excised.

When the Cas1 and Cas2 proteins are present in the cell with either of two Cas4 protein nucleases, Cas4-1 and Cas4-2, they act like the generals of this army-based immune system, communicating uniform-sized clipped DNA fragments, directions on where to go next and ultimately instructions that destroy the lethal DNA fragment.

For a cell to successfully recognize and excise strands of DNA, incorporate them into its own genome and achieve immunity, the Cas4 proteins must be present in conjunction with the Cas1 and Cas2 proteins.

To achieve these findings, the research team from the University of Georgia created strains of archaeal organisms with key genetic deletions. Hundreds of millions of DNA fragments captured in the CRISPR loci were sent to the Graveley lab in Farmington, Conn., where they were sequenced with the Illumina MiSeq system. The researchers then used supercomputing for bioinformatics analysis and data interpretation.

While there is still much to learn about the biological mechanisms involved in CRISPR-Cas systems, this research tells scientists more about the way these proteins work together to save the cell and achieve immunity.

Growing cancer cells (in purple) are surrounded by healthy cells (in pink), illustrating a primary tumor spreading to other parts of the body through the circulatory system.

In the News: NIH Completes In-depth Genomic Analysis of 33 Cancer Types
Researchers funded by the National Institutes of Health have completed a detailed genomic analysis, known as the PanCancer Atlas, on a data set of molecular and clinical information from more than 10,000 tumors representing 33 types of cancer.

“This project is the culmination of more than a decade of groundbreaking work,” says NIH Director Francis S. Collins, M.D., Ph.D. “This analysis provides cancer researchers with unprecedented understanding of how, where and why tumors arise in humans, enabling better informed clinical trials and future treatments.”

The PanCancer Atlas, published as a collection of 27 papers across a suite of Cell journals, sums up the work accomplished by The Cancer Genome Atlas (TCGA), a multi-institution collaboration initiated and supported by the National Human Genome Research Institute (NHGRI) and the National Cancer Institute (NCI), both part of NIH. The program, with more than $300 million in total funding, involved upwards of 150 researchers at more than two dozen institutions across North America.

The project focused not only on cancer genome sequencing, but also on different types of data analyses, such as investigating gene and protein expression profiles, and associating them with clinical and imaging data.

The PanCancer Atlas is divided into three main categories, each anchored by a summary paper that recaps the core findings for the topic. The main topics include cell of origin, oncogenic processes and oncogenic pathways. Multiple companion papers report in-depth explorations of individual topics within these categories.

The entire collection of papers comprising the PanCancer Atlas is available through a portal on cell.com. Additionally, as the decade-long TCGA effort wraps up, there will be a three-day symposium, TCGA Legacy: Multi-Omic Studies in Cancer, in Washington, D.C., September 27-29, 2018, that will discuss the future of large-scale cancer studies, with a session focusing on the PanCancer Atlas. The meeting will feature the latest advances on the genomic architecture of cancer and showcase recent progress toward therapeutic targeting.

By Laura E Gilbertson, M.D., Milad Sharifpour, M.D., and Grant C Lynde, M.D.

More than 75,000 pregnant patients undergo non-obstetric surgery in the United States each year. Fortunately, good preparation and planning can lead to good outcomes for both mother and child.

Finding physicians and hospitals with experience in caring for parturients with comorbid conditions is one of the most important considerations. Secondarily, attempting to schedule the surgery for the second trimester –when most organogenesis has been completed, but before the risk of preterm delivery increases –is the second-most important consideration.

It’s important for all physicians referring pregnant patients for surgery to be able to accurately educate their patients on the anesthetic considerations. There is a lot of inaccurate information that patients are presented in the mass media, and even more so, on the internet. With a better understanding of the maternal-fetal dyad, all practitioners should be able to help expecting parents find medically sound answers to their questions regarding the effects of anesthetic agents on their unborn child, what their surgical options are and how to best prepare.

Of utmost concern to any expecting mother is the possibility that surgery will cause harm to their baby. One of the most common questions involves teratogenicity caused by prenatal treatments. While it remains that maternal issues such as severe maternal hypoxia and hypotension pose the greatest risk to the fetus, there has now been considerable attention placed on the role of anesthetic agents on development.

There are several key factors that may influence teratogenicity, such as susceptibility, dose of the teratogenic substance, duration and timing of the exposure as well as genetic predisposition. Due to the substantial concern about the teratogenicity seen in animal models exposed to anesthetics, the U.S. Food and Drug Administration (FDA) issued an extensive statement to the public in December 2016 warning about the potential dangers of general anesthetics to the fetus. As this statement is now in the public realm, it is even more important for physicians to stay knowledgeable on the most recent literature.

Anesthetics primarily work by interfering with normal GABAa and NMDA receptor mediated activity to produce effective amnesia and unconsciousness. These same receptors are also believed to be involved in fetal central nervous system development. The most widely studied deleterious consequence of exposure to sedatives or anesthetics in immature animals is apoptosis (programmed cell death). Frequently used medications in anesthesia such as benzodiazepines and propofol as well as inhalational anesthetics have demonstrated varying degrees of apoptosis after exposure in animal models, however these apoptotic events have yet to show any correlation with future developmental abnormalities.

While concern about the effects of general anesthetics on the developing brain originates from animal observations, human studies have shown that a short duration of general anesthesia in the neonatal period has no profound developmental effects. Although no single anesthetic agent or medication has been shown to be neurotoxic to humans, a risk benefit ratio should always be implemented prior to administration of any anesthetic.

Another common question expecting mothers have is, “Can I have laparoscopic surgery?” Benefits of laparoscopic surgery include reduced surgical pain, decreased postoperative opioid consumption, decreased incidence of post-operative ileus and shorter length of hospital stay. Benefits unique to pregnant patients include decreased risk of fetal respiratory depression, as well as decreased postoperative maternal hypoventilation secondary to decreased opioid consumption, lower risk of wound complications and decreased risk of thromboembolic events. During pregnancy, insufflation pressures of 10-15 mmHg can be safely used for laparoscopy, however the pressure should be adjusted to the patient’s physiology.

A multidisciplinary team including surgeons, anesthesiologists, obstetricians and perinatologists should be involved in the decision to proceed with surgery. Urgent and emergent surgery should proceed without delay to minimize risk to the patient and the fetus. However, semi-elective procedures should be scheduled during the second trimester, when organogenesis is completed, and the risk of preterm labor is not as high as that during the third trimester.

Pregnant patients should undergo the same pre-operative evaluation as non-pregnant patients, and laboratories and other testing should be performed as indicated by the patient’s overall health and condition. In addition, the following risks should be taken into consideration:

1. Aspiration Prophylaxis: While gastric emptying is shown to be normal until active labor, pregnant women may be at a higher risk of aspiration. Aspiration prophylaxis should include a non-particulate antacid (bicitra) and H2-receptor blockers.

2. Difficult Intubation: Due to airway changes during pregnancy, pregnant patients are at increased risk of difficult intubation. Regional and neuraxial anesthesia should be considered when appropriate.

3. Thromboembolism: All pregnant patients undergoing surgery require mechanical and pharmacologic thromboembolic prophylaxis as pregnancy is a hypercoagulable state.

4. Patient Positioning: Depending on gestational age, the gravid uterus may apply pressure over major intra-abdominal vessels specifically in a supine position.

The final consideration for surgical procedures on the pregnant patient involves preparations for emergent delivery of the fetus. There is conflicting guidance for intraoperative fetal heart rate monitoring. Practices vary on whether to perform continuous versus intermittent monitoring, and whether to monitor any time during the pregnancy or only after fetal viability. What is not in question, however, is the need to have obstetrical support for women undergoing surgery once the fetus reaches 24 weeks’ gestation.

In conclusion, with good preparation, surgery may be performed successfully and with minimal risk to the pregnant patient. While some women may have misconceptions about the risks and future effects on their baby, they should be reassured that surgery during pregnancy occurs rather frequently, without significant complication.

Referring physicians should recommend specialists and hospitals that are experienced and are able to manage any possible complications, such as preterm delivery. While occurring infrequently, the fact that thousands of women do successfully undergo surgical procedures every year while pregnant should provide reassurance to our patients.

Suggested Reading:
Ceana Nezhat (ed), Kavic MS, Lanzafame RJ, Lindsay MK, Polk TM (assoc eds). Non-Obstetric Surgery during Pregnancy: A Comprehensive Guide. New York: Springer. In Press.

By Helen K. Kelley

In recent years, immunotherapy – a range of cancer therapies that use the body’s own immune system to attack cancer cells – has gained ground as a weapon for fighting many different forms of the disease. We recently spoke with two Atlanta physicians about the promise and the reality of some immunotherapies.

Targeted Therapies Block Growth and Spread of Cancer
Kenneth Braunstein, M.D., an Atlanta hematologist affiliated with Northside and Saint Joseph’s hospitals, says that precision medicine – predicting more accurately which treatment and prevention strategies for a particular disease will work based on individual genes, environment and lifestyle – is a hot topic right now in the field of hematology and cancer treatment.

“What precision medicine means for immunotherapy is that we’re looking for the driver genes of cancer. The problem is that there are different types of driver genes for various diseases. While some of those driver genes are well characterized and understood, such as for sickle cell and Parkinson’s diseases, the driver genes in cancer cells are not so well defined,” he explains. “And the big question about driver genes is, if you eliminate a particular gene, will that cure the cancer?”

There is some evidence to support this elimination theory. For example, tyrosine kinase inhibitors are being used to successfully block cell reproduction in T-cell non-Hodgkin lymphoma.

“We’re seeing that these patients show no evidence of disease after 10 years. They’ve stopped therapy, and, so far, they are not coming back,” Braunstein says. “So, in this case, the evidence points to the idea that if you can block the reproduction of cells, you can cure the disease.”

Another therapy, CAR T, has shown promise but has produced mixed results in patients who have received it. CAR T attempts to remove all cancer cells by attaching a virus that binds to T-cells and programming those cells to attack a particular target. When it works, Braunstein says the results are dramatic.

“It’s like an atom bomb; it just clears everything,” he says. “But the problem with CAR T is that we now have patients who can show us long-term follow-up. About half of them have a recurrence at about two years. It’s not clear whether CAR T can become the magic bullet we had hoped it would be. It can be the atom bomb, but to get to zero cancer cells, we may need the hydrogen bomb.”

Braunstein encourages physicians to learn more about targeted therapies and be aggressive in referring their patients to specialists who may know of clinical trials that would be appropriate.

“For the right patients, a targeted therapy may well be the best way of getting them to the point of zero minimal residual disease or close to it,” he says.

Aaron Alizadeh, M.D.

Checkpoint Inhibitor Therapy for Effective Immune System Response
“We are truly at a historic juncture with the addition of immunotherapy as a weapon in fighting cancer,” says Aaron Alizadeh, M.D., a hematology/oncology specialist and researcher with Georgia Cancer Specialists.

“Over the last several years, there has been an enormous increase in the understanding of and research into the immunologic underpinnings of cancer – how the immune system detects cancer and vice versa, and how cancers are able to evade the immune system.”

Alizadeh says that checkpoint inhibitor therapy, one of the newer immunotherapies, has proven to be a very effective form of treatment for certain tumors. The therapy employs two main classes of drugs – those that target the CTLA-4 receptor (ipilimumab), and those that target PD-1 antibodies (pembrolizumab). It plays into the natural checks-and-balances scheme of the immune system, enabling it to recognize the tumor and mount an effective immune response to kill the tumor.

Checkpoint inhibitor therapy was first successfully used in the melanoma arena.
“The reason melanoma was chosen as the first type of cancer to be treated with checkpoint inhibitor therapy is that it is a very immune-responsive disease,” Alizadeh says. “Recent data shows that melanoma has a proclivity to go to the brain, and when it does, the results are devastating and deadly. Recent clinical trials showed that checkpoint inhibitor therapy is effective at penetrating the central nervous system for tumor involvement there.

He adds that the treatment is now being used on other types of tumors.

Drs. Esteban Celis (L) and Hussein Sultan (R) in the Georgia Cancer Center at Augusta University laboratory.

“As a result of checkpoint inhibitor therapy’s success in treating melanoma, many other tumor types have been identified that are also responsive. It works on lung, kidney, bladder, liver and Hodgkin lymphoma, and some forms of colon cancer also respond readily,” he says. “It’s been a matter of identifying the right kind of treatment for the right kind of cancer.”

Clinical trials hold the key to a better understanding of how checkpoint inhibitor therapy can be used in treating different forms of cancer, including duration of treatment, side effects and more.

“Although we’re just in the infancy of this form of therapy, the future is bright,” Alizadeh says. “However, there is much more to understand and to be tested, … and there are a lot of questions that need to be answered.”

Novel Cancer Vaccine Strategy Blocks Death of Tumor-specific Cytotoxic T cells
New research published in Cancer Immunology Research by Drs. Esteban Celis and Hussein Sultan of the Georgia Cancer Center at Augusta University could serve as the stepping- stone in constructing vaccines with a greater likelihood of finding and attacking tumors in the human body.

According to Celis and Sultan, the key in this vaccine strategy is increasing the amount of time a cytokine called interleukin 2 (IL-2) stays in the body. IL-2 is a molecule in the immune system responsible for regulating the activity of some white blood cells known as killer T cells.

“After administering peptide-based vaccines in mouse models of cancer, we saw that sustained IL-2 signaling dramatically increased the number of tumor-specific cancer-killing Tcells (CD8+),” says Dr. Sultan, a postdoctoral fellow in the laboratory of Celis, leader of the Center’s Cancer Immunology, Inflammation and Tolerance Program.

During their experiments, Celis and Sultan noticed there was also an increase in the T cells’ ability to resist cancer immune evasion caused by a protein called programmed deathligand 1 (PD-L1). It is well known that the PD-L1 protein can be produced by tumor cells, allowing them to evade destruction by the killer T cells.

“Together, these results substantially improved the anti- tumor efficacy of peptide-based vaccines in tumor-bearing mice,” Sultan says.

“To be effective, IL-2 needed to be administered either as a complex of IL-2 and anti-IL-2 antibody, or in the form of polyethylene glycol-modified IL2 (PEG-IL-2),” Celis adds. “These formulations prolonged the half-life of IL-2, allowing sustained activation of the IL-2 receptor on vaccine-generated T cells, allowing them to survive longer in the body and attack the tumor.”

According to Celis, it is difficult for vaccines to induce antibodies against tumors because most of the tumor antigens are not foreign proteins, as is the case with viruses. On the other hand, T cells have the capacity to recognize other types of antigens.

“As we know, cancer cells are created when normal cells undergo certain mutations,” Celis says. “So, they don’t al- ways look foreign to our immune system.”

Both Celis and Sultan hope their observations in mouse models of cancer can find their way into clinical studies with human cancer patients.

By Stephen M. Anderson, M.D.

Regional anesthesia plays an important role in patient recovery. Opioid-sparing techniques show benefits including decreased length of stay (LOS), improved postoperative pulmonary function and decreased overall morbidity and mortality. This article will discuss indications for regional anesthesia for abdominal surgery, the techniques by which they are used, and the risks and benefits of each, as well as thoracic epidural analgesia (TEA), transversus abdominis plane (TAP) blocks and rectus sheath blocks.

Comparison of sensory block achieved by rectus sheath block (large black circle over abdominal midline), bilateral standard TAP block (grey semi-circle over lower abdomen), and unilateral oblique subcostal TAP block (which can vary but approximately covers the area shaded in grey in the upper abdominal quadrant)⁷

Thoracic Epidural Analgesia (TEA)
Open abdominal surgery is associated with significant pain that typically requires a substantial opioid regimen to control. The benefits of TEA have long been recognized, such as improved pulmonary function with decreased incidence of postoperative respiratory depression and pneumonia, increased coronary perfusion and decreased incidence of postoperative ileus. In addition to organ system-specific benefits, TEA is associated with improved pain scores, decreased opioid requirements, shortened LOS and improved mortality.¹

Risks and limitations are also associated with TEA. Organ-specific risks include vasodilation and hypotension, paresthesias with placement, post dural puncture headache (PDPH), subarachnoid placement, limitations associated with anticoagulation regimens and coagulopathy, and epidural abscess and/or hematoma formation. In addition, adequate nurse education, cost of placement and management teams and time constraints must be taken into account.¹ When there are significant limitations or for patients for whom TEA would be contraindicated, multimodal analgesia regimens have also been shown to have benefits.^2,3

Transversus Abdominis Plane (TAP) blocks
As mentioned earlier, abdominal surgery is often associated with significant pain, and most of this pain originates from the anterior abdominal wall. Traditionally, this pain has been relieved with an opioid regimen or a combination of multimodal analgesia, which may or may not have included neuraxial analgesia. While effective at treating pain, opioids have significant side effects including nausea, sedation, urinary retention and inhibition of gastrointestinal function.⁴

Even thoracic epidurals, which have long been considered the gold standard of regional analgesia for abdominal surgery, are not without limitations and complications. Coagulopathy, infection at the insertion site, prior spine surgery or trauma, hypovolemia, sepsis, hemodynamic instability and patient refusal are just a few of the contraindications.⁵ Limitations of epidurals are also significant and include hypotension, splanchnic hypoperfusion, patient immobility and cost.⁴

A good multimodal analgesia regimen that adequately controls pain and minimizes the side effects of opioids is essential to an ERAS protocol for abdominal surgery. TAP blocks have been shown to decrease pain scores, decrease opioid requirements and shorten hospital length of stay in patients following laparoscopic abdominal surgery.⁴ However, compared to trocar site infiltration by the surgeon, TAP blocks showed no analgesic or opioid-sparing benefits.⁵

Limitations of TAP blocks include cost of equipment (specifically ultrasound), training of block nursing staff, accidental peritoneal puncture, accidental intravascular injection causing local anesthetic toxicity and preoperative time limitations.

Target for Local Anesthetic Infiltration during a rectus sheath block (RAM = Rectus Abdominis Muscle)

The introduction of ultrasound has greatly improved the anesthesia provider’s ability to provide regional anesthesia in general and TAP blocks specifically. The direct visualization of vessels, muscles and other structures has not only aided in the placement of local anesthesia in the correct fascial plane, but it has allowed us to minimize the complication rate of intravascular injection and peritoneal puncture.

The ultrasound probe is placed in a transverse fashion between the lower costal margin and iliac crest on the lateral abdominal wall at the midaxillary line. The abdominal muscle layers are then identified from shallow to deepest: external oblique (EO), internal oblique (IO) and transversus abdominis (TA). Deep to those are the peritoneum and bowel contents.

The needle is inserted in plane, and local anesthetic is deposited in the plane between the IO and TA. With this posterior approach, it is reasonable to expect analgesia between T10 and L1.⁶

If a higher level of analgesia is desired, the posterior TAP may need to be supplemented with a subcostal TAP to achieve a level up to T7. In this approach, the ultrasound probe is placed just beneath the costal margin. The needle is introduced into the fascial layer separating the rectus abdominis and the transversus abdominis.⁶

Rectus Sheath Block
The aim of this technique is to block the terminal branches of the T7-12 nerves, which run in the plane between the internal oblique and transversus abdominis muscles to penetrate the posterior wall of the rectus abdominis muscle (RAM) and end in an anterior cutaneous branch supplying the skin of the umbilical area. Like TAP blocks, rectus sheath blocks relieve somatic pain of the anterior abdomen and not the visceral structures. This block is more clinically useful for umbilical hernia repairs and more midline surgeries.

Like TAP blocks, care must be taken to avoid accidental peritoneal puncture. In addition, with epigastric arteries running in the midline, ultrasound with or without Doppler is recommended to avoid vascular puncture and intravascular local anesthetic injection. Local anesthetic toxicity is also a concern since this block may be combined with TAP blocks, which are high-volume blocks.

The patient is placed in the supine position, and the transducer placed in the transverse position immediately lateral to the umbilicus. Color Doppler can be used to identify the epigastric arteries. The oval shaped RAM is identified, and the needle is inserted in-plane in a medial to lateral orientation through the anterior rectus sheath. The needle is further advanced through the body of the muscle until the tip rests in the posterior rectus sheath. In an adult patient, 10 mL of local anesthetic (e.g., 0.5 percent ropivacaine) per side is usually sufficient for successful blockade.8 Since this paired muscle is separated in the midline by the linea alba, the block will need to be repeated on the other side to achieve bilateral analgesia.

References
1. Gan, TJ; et al. Enhanced Recovery for Major Abdominal Surgery. First Edition. Professional Communications, Inc. 2016. 165-168.
2. Ahmed, Aliya; Latif, Naveed; Khan, Robyna. Posteroperatiev analgesia for abdominal surgery and it’s effeectiveness in a tertiary care hospital. J Anaesthesiol Clin Pharmacol. 2013 Oct-Dec; 29(4): 472–477.
3. Rigg, John; et al. Epidural anaesthesia and analgesia and outcome of major surgery: a randomised trial. The Lancet. Volume 359: 9314. 1276–1282. April 2002 4. Ris, F; Findlay, JM; Hompes, R; Warwick; Cunningham, C; Jones, O; Crabtree,N; Lindsey, I. Addition of transversus abdominis plane block to patient controlled analgesia for laparoscopic high anterior resection improves analgesia, reduces opiod requirement and expedites recover of bowel function. Ann R Coll Surg Engl. 2014; 96: 579-585
5. Chawla, J; Schraga, E. Epidural Nerve Block. Medscape; 2015
6. Mukhtar, K. Transversus Abdominis Plane (TAP) Block. The Journal of NYSORA. 2009. 12: 28-33.
7. Webster, Katrina. Ultrasound guided rectus sheath block – analgesia for abdominal surgery. Update in Anesthesia. 2010. 12-16
8. Truncal and Cutaneous Blocks. The New York School of Regional Anesthesia. 2013. http://www.nysora.com/techniques/ultrasound-guided-techniques/3253- truncal-and-cutaneous-blocks.html

By Mark B. Wilkiemeyer, M.D., FACS

Abdominal wall hernia, simply defined as a space or gap in the abdominal wall, is one of the most common complaints seen by the practicing general surgeon. Literature tends to focus on management of hernia once it is identified and classified, but this ignores the necessary diagnostic steps to correctly classify the location of the hernia. The history and physical examination provides many of the clues necessary for proper hernia identification and subsequent classification and management.

History: Use the OLD CARTS Mnemonic
Onset can provide context for hernia identification and management. The sudden appearance of a bulge or the gradual “coming and going” of vague pain will help guide the physician towards an accurate diagnosis and help triage the patient. Sudden unrelenting painful bulges would prompt much more rapid assessment and surgical treatment than the slow, gradual onset of discomfort.

Location is an important component for hernia management. The patient’s subjective reporting of location of pain and/or a bulge provides the starting point for hernia identification. Incisional, umbilical and inguinal/groin hernias can be quickly localized by patient complaint.

Duration is less specific for hernia identification. As hernias can have long durations and gradually become more symptomatic, the duration of the hernia rarely is the most important factor in classification or management strategies.

Character of the pain can give clues to the hernia contents (bowel more crampy, preperitoneal fat sharp localized pain, omentum sharp but more generalized in location). As hernias can be painless but still bothersome, the character of the hernia symptoms should be noted but are not essential to initial diagnosis. It may prompt further diagnostic workup or more urgent management.

Aggravating factors and relieving factors will generally be related to abdominal wall musculature utilization and rest. Increases in intra-abdominal pressure through coughing, sneezing or exercise will commonly exacerbate discomfort.

Radiation of pain can provide additional clues as to the contents of the hernia.

Timing or temporal factors will sometimes help with hernia diagnosis and management but are often associated with aggravating factors and won’t often distinguish hernias alone.

Severity of symptoms will prompt urgent or elective management but rarely give additional information about the hernia itself. However, severe unrelenting crampy pain can point to a strangulated hernia containing ischemic or compromised bowel.

Physical Exam: Experience Counts
The comprehensive physical exam remains critical to assessment and management of the patient with a hernia complaint. Experience with examination improves diagnostic accuracy and likely reduces the use of imaging.

Generally, the hernia should be classified as “reducible” or “incarcerated”; this will assist in determining timing of repair if needed. Incarcerated hernias, or hernias thought to contain compromised viscera, will generally be explored and repaired as a surgical emergency. Conversely, the reducible hernia is often managed on an elective basis. Chronically incarcerated but minimally symptomatic umbilical or incisional hernias are exceptions to this rule, where severity of symptoms will help us make recommendations for urgency of surgical treatment.

Examination will include multiple positions (standing and supine) along with multiple degrees of intra-abdominal pressure. A relaxed abdominal wall can allow the physician to palpate the fascial edges of the hernia defect; a Valsalva maneuver provides “proof” of hernia bulge and possibly clues as to the contents.

Thorough inspection of overlying skin incisions and anatomic landmarks help improve accuracy of diagnosis and management; for example, umbilical hernias and incisional hernias at the umbilicus can provide vastly different challenges during surgical management.

Partial thickness abdominal wall hernias can provide diagnostic confusion; if no “hole” is present in the most superficial fascial layer, then a vague bulge may be identified but a focal fascial defect may be absent. We see this with lateral trocar site incisional hernias and lower lateral abdominal wall Spigelian hernias; generally, hernias in or near the midline will not cause this confusion.

One common point of confusion is the presence of rectus diastasis. This is not a true hernia but is the separation of the rectus muscles due to chronic abdominal distention. This separation is commonly secondary to truncal obesity or multiple pregnancies. This presents as a vertical abdominal bulge above the umbilicus which appears when doing a sit up. This does not represent a true hernia and therefore does not require repair unless there are cosmetic concerns.

Imaging When Necessary
Cross-sectional imaging of the abdomen and pelvis can provide assistance when history and physical examination are not sufficient to confirm diagnosis and accurate localization of an abdominal wall hernia. They are not necessary to make a diagnosis or recommendation for surgery, and can sometimes cloud the issue if there is no obvious hernia seen but history and physical are clearly pointing towards surgical management.

Cross-sectional imaging of the abdomen and pelvis can incidentally identify abdominal wall defects. When identified these should be evaluated by an experienced surgeon.

Surgical Management of Abdominal Wall Hernias
In general, symptomatic hernias will be repaired in suitable surgical candidates. Regional anesthesia is available to reduce anesthesia risk, but care should be given to prioritize the ability of the surgeon to produce a durable repair. If regional anesthesia alone is insufficient for reduction and proper repair of the hernia, then the surgical risk outweighs benefit and the procedure should be carefully reconsidered.

The main surgical principals of hernia repair are reduction of the hernia contents, clear identification of the borders of the defect, followed by closure of the defect with as little tension as possible. Mesh is commonly used to reinforce and add durability to the repair. The location of the mesh reinforcement has changed over the years. Current trends in hernia repair place the mesh within the layers of the abdominal wall as opposed to inside the peritoneal cavity or above the fascia.

Minimally invasive surgical techniques for abdominal wall hernias include laparoscopic and robotic approaches. Traditional repairs are done with open incisions. Each of these has benefits and drawbacks; nonetheless, the patient is well served by meeting with surgeons who can offer a wide variety of treatment options.

Mesh is used to reduce the risk of recurrence. In some cases mesh is required to “bridge” a defect that cannot be closed with suture, although this is less than ideal. The use of mesh can increase the risk of complications, but its value in adding durability to the repair generally outweighs these concerns.

Common materials used to manufacture synthetic mesh include polypropylene and polyester. In recent years biologic meshes have become common with porcine- and bovine-derived materials being used in certain complicated and high-risk situations. Generally these biologic materials are thought to carry less risk of chronic infection but are much more expensive than synthetic mesh and are commonly perceived as a less durable over the long term.

The ideal hernia repair continues to be an evolving science. Advances in technique and options for abdominal reinforcement create an exciting and changing landscape for patients and general surgeons.

Mark Wilkiemeyer, M.D., FACS

Dr. Wilkiemeyer grew up in Atlanta and attended Vanderbilt University, then went on to attend Tulane University School of Medicine in New Orleans, where he graduated Alpha Omega Alpha in 1998 as a Doctor of Medicine. He trained in General Surgery at University of Texas Southwestern, subsequently completing a fellowship in laparoscopic surgery at the Duke University Medical Center. He lives in
Atlanta with his wife, Claire Dudley Wilkiemeyer, M.D., and their two children.

By Kathryn Calhoun, M.D.

Chronic anovulation is a hallmark of Polycystic Ovary Syndrome (PCOS), so the vast majority of women with PCOS will require fertility treatment to conceive.

In a young PCOS patient with no obvious barriers to conception (other than anovulation), it is reasonable to start ovulation induction medicines before evaluating her uterus/tubes or her partner’s semen analysis. If the woman/ couple has not conceived after three successful ovulations, then a hysterosalpingogram (HSG) and semen analysis should be performed.

In contrast, an older woman (> 35 years) or a couple with risk factors for pelvic disease or sperm problems should have an HSG and a semen analysis before proceeding with ovulation induction therapy. Examples of risk factors for pelvic disease include a prior history of infections, surgery, pain, broids, endometriosis or pregnancy loss. Examples of risk factors for an abnormal semen analysis include changes in strength/libido, erectile dysfunction, obesity, sleep apnea, diabetes or cardiovascular disease.

Until recently, the first-line medication for ovulation induction in women with PCOS was clomiphene citrate (Clomid). Clomid is a selective estrogen receptor modulator (SERM) that blocks estrogen feedback on receptors throughout the body. At the brain (hypothalamic-pituitary) level, this perceived low estrogen state results in altered hormone (FSH/LH) signaling to the ovaries.

In 80 percent of PCOS women, this change in FSH/LH levels will result in ovulation.1 Side effects of Clomid are due to this reduced estrogen signaling and include headaches, hot ashes, mood changes, decreased cervical mucus, vaginal dryness and a temporary thinning of the uterine lining. Rarely, women may experience changes in vision, and this is a reason to discontinue Clomid use. The risk of twins is ~8 percent per cycle, the risk of triplets is < 1 percent. No causal relationship has been established between ovulation induction medicines and birth defects, miscarriage or ovarian cancer.¹

A recent study followed women with PCOS for up to five treatment cycles and reported better rates of ovulation (61.7 percent vs 48.3 percent) and live birth (27.5 percent vs 19.1 percent) with Letrozole (Femara) rather than Clomid.² Thus, Femara is now the first choice for ovulation induction in PCOS patients. Femara is an aromatase inhibitor that blocks the conversion of androgens to estrogens, thereby actually lowering estrogen levels in the body. The effect on the brain is similar to Clomid, though the side effects (hot ashes, headaches, thinning of uterine lining) are often less. Though it was underpowered to detect a significant difference, the risk of twins in this study was lower with Femara (3.9 percent) than Clomid (6.9 percent).²

Both Femara and Clomid are taken daily for 5 days at the start of a menstrual cycle. Progesterone may be used to induce a menstrual period, if necessary. Ovulation most often occurs 5-12 days after the last pill, and the patient should begin ovulation predictor kits (“OPKs”) and regular intercourse (if possible) during this interval.¹ An ultrasound is performed to check ovarian response, to evaluate the uterine lining and to help the couple plan further intercourse and/or intrauterine insemination (IUI). If the ovaries are not responding, dosing can be immediately adjusted at this visit.

If Femara is unsuccessful at inducing ovulation, the dose can be increased, the duration may be extended or the patient can then try Clomid. Adjunct medications are sometimes used, such as low-dose Dexamethasone or Metformin, though these may yield minimal additional benefit.

Using Metformin alone has demonstrated lower rates of ovulation, live birth and twin pregnancy than Clomid.³ If the patient demonstrates continued resistance to oral medications, the importance of lifestyle modification (weight loss, if applicable) is reinforced and ovarian drilling (surgery to reduce the androgen-producing stromal portion of the ovary) may be considered. After six months of therapy, the chance of pregnancy drops significantly despite ovulation.¹

If oral medications are unsuccessful, the next step may be injectable gonadotropins (FSH/LH.) Women with PCOS have a very high follicular/egg count, so these medicines may be risky if combined with intercourse or IUI. The chance of over-response, ovarian hyperstimulation syndrome (OHSS) or higher-order multiple gestations (triplets+) can lead to canceled cycles, treatment delays and disappointment.

For PCOS patients who do not succeed with lesser therapies, in vitro fertilization (IVF) represents a safe and effective next step. For the youngest PCOS patients, per cycle pregnancy rates can approach 70 percent. In an IVF cycle, a woman administers injectable gonadotropins (FSH/LH) for 9-12 days in order to mature a high percentage of her monthly egg group. The eggs are then retrieved with a short outpatient surgical procedure, then fertilization and early embryo development occur in the laboratory. An embryo is replaced in the uterus to begin the pregnancy.

Women with PCOS require special IVF care due to their robust egg count. The focus of treatment is to safely recruit a moderate-size group of eggs without significant OHSS. OHSS causes fluid shifts and third-spacing that can lead to symptomatic ascites and intravascular depletion. In addition to illness, OHSS can also result in lower-quality eggs/embryos. PCOS IVF protocols should employ lower doses and different combinations of medicines, as well as adjunctive therapies (i.e Metformin), to ensure an optimal and safe response.⁴ Even with appropriate treatment, at the end of the stimulation, most PCOS patients will have hormone levels that are too high for ideal implantation. To ensure the highest pregnancy rates, and a safe and healthy pregnancy overall, embryos are often frozen and transferred in the next cycle as a frozen embryo transfer (FET).

The good news is that most PCOS patients will conceive and enjoy a low-risk pregnancy. This is especially true for those patients with singleton gestations and no other comorbidities (i.e. obesity, insulin resistance/diabetes, hypertension). It is possible that the observed increased risks of pregnancy loss and late pregnancy complications in PCOS are most common in women with those additional risk factors.

REFERENCES
1. Fritz, Marc A.; Speroff, Leon. Clinical gynecologic endocrinology and infertility. 8th ed. Philadelphia: Lippincott Williams & Wilkins; c2010.

2. Legro RS, Kunselman AR, Brzyski RG, Casson PR, Diamond MP, Schlaff WD, Christman GM, Coutifaris C, Taylor HS, Eisenberg E, Santoro N, Zhang H; NICHD Reproductive Medicine Network. The Pregnancy in Polycystic Ovary Syndrome II (PP- COS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome. Contemp Clin Trials. 2012 May;33(3):470-81. doi: 10.1016/j.cct.2011.12.005. Epub 2012 Jan 13.

3. Legro RS, Barnhart KH, Schlaff WD, etc al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007; 356: 551-566.

4. Practice Committee of the American Society for Reproductive Medicine. Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril. 2016; 106: 1634-1647.

by Jennifer F. Kawwass, MD and Heather S. Hipp, MD

Polycystic Ovary Syndrome, or PCOS, the enigmatic syndrome ascribed to infertile, overweight females with irregular menstrual cycles, may be simpler to understand than it seems. The syndrome can be confusing: no clear linear causal pathway has been elucidated, and many endocrine axes interact to accentuate the classical physical manifestations. In addition, it is a broad diagnosis, and many women with PCOS do not fit the stereotypical PCOS mold.

Despite the heterogeneity of women that can meet criteria for PCOS, understanding the diagnostic basics can make the syndrome much easier to recognize.

Importantly, the diagnosis is independent of body mass index (BMI) or weight. In fact, 10-15 percent of women with PCOS are lean with a normal BMI. According to the 2003 NIH Rotterdam criteria, a diagnosis of PCOS requires two of the following three characteristics:

1. Oligoovulation and/or anovulation (i.e. irregular menstrual cycles)
Can be determined by patient history: menstrual cycles occurring in an unpredictable pattern or greater than 42 days apart are suggestive of anovulation.

2. Elevated androgens (clinical and/or biochemical)
Can be determined by laboratory value of testosterone above the female reference range or by clinical signs of hirsutism/ acne that exceed ethnic norms.

3. Polycystic appearing ovaries on transvaginal ultrasound
Can be determined by ultrasound assessment of the ovaries having a “PCOS” appearance. A formal antral follicle count (12 or more follicles measuring 2-9mm in diameter) on each ovary can also be done.

Although AMH is not part of the diagnostic criteria, an elevated AMH (e.g. over 4 ng/mL) in combination with the other diagnostic criteria is suggestive of PCOS.

Given that the criteria only requires two of the three above characteristics, women may have PCOS without hyperandrogenism or irregular cycles. There is a sub-category of women with PCOS who are lean (aka “lean PCOS”). These women often do not have hyperandrogenism and present with infertility due to anovulation. Due to their BMI, they are sometimes diagnosed with functional hypothalamic amenorrhea (see below), which is treated in a different fashion.

The primary tenet in diagnosing PCOS is appreciation that it is a diagnosis of exclusion. One can only clearly diagnose a woman as having PCOS after ruling out all potential masqueraders. As women with PCOS often present with irregular or absent menstrual cycles, excluding other causes of amenorrhea or oligomenorrhea is usually a good place to start. Common masqueraders include pregnancy, thyroid disease and hyperprolactinemia, which can be assessed with a laboratory evaluation including bHCG, a TSH a prolactin. A more rare cause is delayed onset congenital adrenal hyperplasia (CAH), which is screened for with 17-hydroxyprogesterone.

On a patient-specific basis, one can also screen for other rare causes of oligomenorrhea: Cushing’s syndrome in someone with rapid weight gain and new-onset hypertension, an ovarian or adrenal testosterone-secreting tumor in an individual with rapid-onset severe virilization, or acromegaly in someone with increasing glove, shoe or hat size. Most often, however, ruling out pregnancy, pituitary and thyroid disease, and CAH is a reasonable place to start.

Particularly in a lean woman with absent cycles, functional hypothalamic amenorrhea (FHA) may cause absent periods and may even be present in addition to underlying PCOS. Women with FHA typically present with a low BMI and a history consistent with excessive exercise or calorie restriction. If the FSH, LH, and estradiol are all low or in the low range of normal, referral to a reproductive endocrinologist for help with treatment of FHA would be reasonable.

Lastly, severe diminished ovarian reserve can cause irregular cycles. It can be very helpful to ascertain ovarian reserve and hypothalamic-pituitary-ovarian function. An overweight patient with irregular cycles may actually have diminished ovarian reserve and not PCOS. Obesity and irregular cycles are not synonymous with PCOS. An FSH and estradiol in the early follicular phase or after a progesterone-induced bleed may help clarify ovarian reserve in a patient that is not on oral contraceptives. An FSH over 10 would suggest diminished ovarian reserve and not PCOS. An anti-mullerian hormone (AMH) or transvaginal ultrasound with antral follicle count (AFC) may also help in the differentiation.

Figure 1. Simplified Approach to Diagnosing PCOS

Adolescents are a unique population. Because of young age and resultant robust ovarian reserve, polycystic ovarian morphology may not necessarily represent PCOS. Moreover, oligomenorrhea is normal around the time of menarche. Some researchers argue that to give a diagnosis of PCOS to an adolescent, she must have all three of the Rotterdam criteria.

Lifestyle counseling is warranted in women with a diagnosis of PCOS. For women who are overweight, a 5-10 percent weight loss has been associated with improvement in menstrual regularity and resumption of menses. Counseling regarding heightened risk of insulin resistance compared to women without PCOS may also help guide dietary and exercise choices for patients with the syndrome. Finally, when not trying to conceive, the importance of uterine lining protection with some form of hormonal contraception, including intrauterine devices, is worth discussing.

The next step is to determine fertility intentions. The treatment course diverges based on desire for either fertility or contraception. For those who are not currently interested in conceiving, oral contraceptive pills (OCPs) are often the first line of treatment. OCPs offer endometrial lining protection and can also improve symptoms of hyperandrogenism.

For those who desire pregnancy, the first line agent for ovulation induction is letrozole. Referral to an REI is reasonable before attempt at ovulation induction or after one to three cycles of failed attempts at pregnancy with the use of ovulation induction.

Women who have PCOS are at a higher lifetime risk of diabetes and, when pregnant, gestational diabetes, even if they are lean. Screening for diabetes should be strongly considered in any women with PCOS; this can be done with a hemoglobin A1c or a 2-hour oral glucose tolerance test. If pre-diabetes is diagnosed, Metformin can be offered to aid in insulin resistance and, in some women, weight loss.

It is also possible that someone on the PCOS-spectrum may develop more overt symptoms with weight gain. As such, a female with mild PCOS may benefit from counseling regarding the avoidance of weight gain.

PCOS affects 10-15 percent of reproductive-age women. As a result, it warrants the attention of not only obstetrician gynecologists, but also physicians in other specialties. The associated cardiovascular, endocrine and fertility sequelae can impact all aspects of a PCOS female’s medical care.

References
Carmina, E, Oberfield, SE, Lobo, RA. “The diagnosis of polycystic ovary syndrome in adolescents.” Am J Obstet Gynecol; 2010; 03 (3): 201. E1-5.

Good C, Tulchinsky M, et al. “Bone Mineral density and body composition in lean women with polcystic ovary syndrome.” Fertility and Sterility 1999; 72: 21-25.

Goodman NF, Cobin RH, et al. “American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society Disease State Clinical Review: Guide to the Best practices in the Evaluation and Treatment of Polycystic Ovary Syndrome- Part 2.” Endocr Pract 2015; 21: 1415-1426

Goyal, M, Dawood, AS. “Debates regarding lean patients with polycystic ovary syndrome: A narrative review.” J Hum Reprod Sci. 2017; 10 (3): 154-161.

Alexis P. Calloway, M.D.

By Alexis P. Calloway, M.D.

Much focus is given to the long- and short-term impact of commonly tested sexually transmitted infections such as HIV, chlamydia, gonorrhea and HPV on reproductive health. As the medical landscape of diagnosis and therapeutic options for infertility evolve, it is just as important to focus on viral hepatitis as well, with particular emphasis on Hepatitis B and C.

Viral Hepatitis in the United States
According to the Centers for Disease Control and Prevention (CDC), there were an estimated 33,900 new Hepatitis C virus ( HCV) infections in 2015, representing a 2.9-fold increase since 2010 with 75 percent to 85 percent of infections becoming chronic. The estimated number of new Hepatitis B virus (HBV) infections in 2015 was 21,900, however these rates are decreasing.

HCV is generally acquired through IV drug use and blood transfusions until changes in screening regulation for donations in the early 1990s. HCV can rarely also be acquired through sexual transmission. Alternatively, HBV is commonly acquired through sexual transmission, particularly in heterosexuals with multiple partners and unvaccinated men who have sex with men. Other common sources of transmission for HBV include mother-to- child transmission (MTCT), intravenous drug abuse and rarely through paternal transmission. (Iqbal et al., 2015) Chronic viral hepatitis, with HCV accounting for the majority of cases, is one of the most common causes of cirrhosis in the U.S. and carries a significant burden on the healthcare system. Given the multifaceted impact to the body, it is unknown what the specific burden to reproductive health may be.

Viral Hepatitis and Male Fertility
It is already known that many chronic viruses have the ability to infect sperm and adversely impact male fertility. Specifically in the last decade, it has been found that HCV causes a statistically significant decrease in semen volume, sperm count and progressive sperm motility and an increase in abnormal sperm morphology compared with healthy controls. Furthermore, the duration of HCV infection has been negatively correlated with semen volume and sperm motility where the HCV RNA viral load was negatively correlated with sperm count and sperm motility. (Hofny et al., 2011) In a study published in 2011, it was found that couples whose male partner was infected with HBV had a higher risk of low fertility rates after IVF, a risk which was independent from the initial sperm motility. (Oger et al., 2011)

As viral hepatitis may be asymptomatic until the onset of advanced disease, these barriers may not be identified as a potential etiology for infertility in younger populations. Targeted screening in this at-risk group may be of benefit in reproductive counseling, though no clear guidelines have been established. Some literature does attempt to address the issue of disparity of screening asymptomatic men in comparison to their heterosexual partners.

In a study of 1,243 male partners of 2,400 women who attended ultrasound examinations between 2010 and 2011, 430 accepted HIV and STI testing. It was ultimately found this is an acceptable time to feasibly engage the heterosexual male partner for screening. (Dhairyawan, Creighton, Sivyour, & Anderson, 2012) Other opportunities may arise to address screening and should be pursued on an individual basis by the patient’s healthcare provider.

Kurmanova, A.M., et al. (2016). “Reproductive dysfunctions in viral hepatitis.” Gynecol Endocrinol 32(sup2): 37-40.

Viral Hepatitis and Female Fertility
Menstrual disorders serve as the predominant cause of reproductive barriers in a patient affected with HBV and HCV due to intra- and extrahepatic pathology (as displayed in Table 1). (Kurmanova, Kurmanova, & Lokshin, 2016) Premenopausal women who are HCV positive or have chronic liver disease are at risk for premature ovarian failure impacting their lifelong fertility.

A study published in 2017 found that most new cases of HCV infection are among people who inject drugs, including reproductive-age females. Reproductive-age women who are HCV positive display markers of ovarian failure. This is associated with infertility and adverse pregnancy outcomes such as stillbirth, miscarriage, fewer live births and gestational diabetes. (Karampatou et al., 2017)

There is not much research surrounding the impact of HBV on reproduction in women specifically. One small study measuring pregnancy rates and implantation rates of HBV-sero- positive women and their partners found a higher rate of tubal blockage, often leading to signficantly higher rates of IVF and embryo transfer cycles if at least one partner was positive when compared to seronegative control couples. (Lam et al., 2010)

No matter the etiology, there are overarching impacts of cirrhosis on the reproductive health of women. Cirrhosis leading to generalized infertility and pregnancy is rare, but when it does occur specialized care is required.

Viral Hepatitis and the Pregnant Patient
Mother-to-child transmission is responsible for more than one third to one half of chronic HBV infections worldwide and can occur during pregnancy, delivery or after birth if not treated. Acute HBV infection during pregnancy is usually mild and not associated with increased mortality or teratogenicity. However, transmission rates significantly increase if acute infection occurs in the perinatal period, with rates as high as 60 percent reported. (Sookoian, 2006)

Chronic hepatitis B serves as a larger medical management consideration with emphasis on decision to treat during pregnancy with anti-retroviral therapy. This decision is generally influenced by ALT elevation greater than two times the upper limit of normal, HBV DNA levels, detection of Hepatitis B Surface Antigen (HBSAg) and anti-Hepatitis B e antibody (anti-HBe), and the presence or absence of cirrhosis.

Women with high viral loads (HBV DNA) in the third trimester should be treated even in the setting of normal ALT to decrease the vertical transmission risk to the infant. Furthermore, neonates of HBSAg-positive mothers should receive monovalent hepatitis B vaccine and HBIG 0.5ml as soon after delivery as possible (preferably within 12-24 hours) regardless of birth weight. (Committee On Infectious, Committee On, & Newborn, 2017) As perinatal transmission of HCV is unlikely, decision to treat can be deferred until after delivery. Subspecialist assistance may serve valuable in determining patient candidacy and timing for treatment.

Though HCV can be detected in maternal colostrum, this is not considered a factor associated with vertical transmission. In a study of 76 samples of breast milk from 73 chronically HCV-infected mothers, none of the samples contained HCV RNA and only one of the breastfed infants had evidence of HCV one month after birth without clear correlation to breastfeeding itself. (Polywka, Schroter, Feucht, Zollner, & Laufs, 1999) It is accepted by multiple organizations that breastfeeding is considered generally safe in asymptomatic HCV-positive mothers.

Reproductive Planning
Though initially targeted for the baby boomer population, emerging and highly effective therapies for HCV may prove beneficial to improving infertility in reproductive-age individuals burdened with this disease as well. Rates of sustained virologic response (SVR) have been found to be in the high 90th percentile for patients with common genotypes of the virus undergoing eight or 12 weeks of treatment. (Terrault et al., 2016)

Additionally, treatment is beneficial as early menopause in patients with chronic HCV was associated with low likelihood of SVR likely due to inflammatory factors and physiologic variations in estrogen that change at menopause. (Villa et al., 2011) Vaccination should also be pursued in household and sexual contacts for those with HBV.

As providers, viral hepatitis should be a part of the reproductive health discussion, with appropriate screening and treatment as indicated in this special and occasionally missed population.

References
Committee On Infectious, D., Committee On, F., & Newborn. (2017). Elimination of Perinatal Hepatitis B: Providing the First Vaccine Dose Within 24 Hours of Birth. Pediatrics, 140(3). doi:10.1542/peds.2017-1870
Dhairyawan, R., Creighton, S., Sivyour, L., & Anderson, J. (2012). Testing the fathers: carrying out HIV and STI tests on partners of pregnant women. Sex Transm Infect, 88(3), 184-186. doi:10.1136/sextrans-2011-050232

Hofny, E. R., Ali, M. E., Taha, E. A., Nafeh, H. M., Sayed, D. S., Abdel-Azeem, H. G., . . . Mostafa, T. (2011). Semen and hormonal parameters in men with chronic hepatitis C infection. Fertil Steril, 95(8), 2557-2559. doi:10.1016/j.fertnstert.2011.05.014

Iqbal, K., Klevens, R. M., Kainer, M. A., Baumgartner, J., Gerard, K., Poissant, T., . . . Teshale, E. (2015). Epidemiology of Acute Hepatitis B in the United States From Population-Based Surveillance, 2006-2011. Clin Infect Dis, 61(4), 584-592. doi:10.1093/ cid/civ332

Karampatou, A., Han, X., Kondili, L. A., Taliani, G., Ciancio, A., Morisco, F., . . . Investigators, P. (2017). Premature ovarian senescence and a high miscarriage rate impair fertility in women with HCV. J Hepatol. doi:10.1016/j.jhep.2017.08.019

Kurmanova, A. M., Kurmanova, G. M., & Lokshin, V. N. (2016). Reproductive dysfunctions in viral hepatitis. Gynecol Endocrinol, 32(sup2), 37-40. doi:10.1080/0951 3590.2016.1232780

Lam, P. M., Suen, S. H., Lao, T. T., Cheung, L. P., Leung, T. Y., & Haines, C. (2010). Hepatitis B infection and outcomes of in vitro fertilization and embryo transfer treatment. Fertil Steril, 93(2), 480-485. doi:10.1016/j.fertnstert.2009.01.137

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By Helen K. Kelley

Melanoma, typically a malignant tumor associated with skin cancer and the cause of the vast majority of skin cancer deaths, can also occur in the eye or any mucous membrane of the body. While the risk of melanoma increases with age, it is one of the most common cancers found in young adults, particularly young women.

Georgia is one of the states with the highest incidence of melanoma in the U.S. To learn more about why this number is rising and how doctors are treating the disease, Atlanta Medicine recently spoke with two physicians who are specialists in melanoma.

B. Scott Davidson, M.D.

Multidisciplinary approach to treatment; physicians should know signs
“I think a multidisciplinary team approach is crucial in the successful treatment of melanoma,” says B. Scott Davidson, M.D., a surgical oncologist with Northside Hospital Cancer Institute’s Melanoma and Sarcoma Program.

“It’s important to have close collaboration between surgical, medical and radiation oncologists who share their ideas about treating individual patients.”

He adds that since there are many variations in patient care, having input from a team of practitioners with different knowledge and skills can create a more effective treatment for each individual.

“There are a lot of components to treating melanoma, all of them important. It’s best to review those options during a multidisciplinary conference,” he says. “During these meetings, we form a game plan. We determine the best treatment options – immunotherapy, radiation and/or surgery – and the sequence of their delivery for the individual patient.”

Davidson adds that all physicians can play a role in the early detection of melanoma in their patients.
“It can be tricky to identify a melanoma just on gross examination. Certainly, any changing mole should be suspicious and the patient referred to a dermatologist for biopsy,” he says. “It’s good for every doctor to know the signs of skin cancer.”

He recommends following the guidelines set forth by The American Academy of Dermatology (AAD), known as the ABCDEs of melanoma:
• Asymmetry: Is one half of a mole unlike the other half?
• Border: Does a mole have an irregular, scalloped or poorly defined border?
• Color: It there more than one color in a mole, such as shades of tan and brown, black, white, red or blue?
• Diameter: Is a mole bigger than 6 mm (the size of a pencil eraser)? Melanomas are usually bigger than 6 mm when diagnosed, but they can be smaller.
• Evolving: Does a mole or another spot on the skin that look different from the rest? Is a mole or another spot changing in size, shape or color?

“The majority of melanoma occurs on sun-exposed areas, although there are certainly exceptions. And it is still a disease of all age groups,” Davidson adds. “The changing of a mole from benign to malignant probably calls into question the genetics that a person may harbor.”

Andrew Page, M.D.

Stimulating the immune system; rising numbers of skin cancer in younger people
According to Andrew Page, M.D., director of pancreas, liver and cancer surgery at Piedmont Hospital, the landscape in melanoma treatment has made phenomenal progress, particularly for patients with metastatic melanoma.

“Up until about seven years ago, the medications available to treat metastatic melanoma were not very good. Patient responses were not durable, and side-effects were not tolerable,” he says. “But starting in 2011, many groups began publishing remarkable outcomes for patients using novel treatments that were previously not available. Specifically, researchers had identified medications that target both the molecular pathogenesis of melanoma and the patient’s own immune system – and the results have revolutionized the treatment landscape for melanoma. Effectively, we now have medications to treat patients better with durable responses, without as severe toxic side effects.”

Newer drugs like Opdivo (nivolumab), used in the past couple of years for patients who have advanced (stage IV) melanoma, are now approved for people with stage III disease.

“In the past, if a person had comorbidities, the treatment itself – Interleukin-2 – could have killed them,” Page says. “But today, we have immunotherapeutic agents like Opdivo that are used, with some success, to treat advanced-stage melanoma. That’s amazing progress.”

Page warns that even though treatment of the disease is improving, the incidence of melanoma continues to rise.

“We have medications that work so much better today, yet melanoma is on the rise, about 90,000 incidences in the U.S. annually. While certainly many factors contribute to melanoma, young people, even children, are still getting too much sun exposure,” he says. “I’m seeing younger patients coming in with melanoma. Almost every single one of my young female patients admits to using tanning beds throughout high school.”

Study finds timing of diagnosis, treatment critical to survival
A new Cleveland Clinic study underscores the importance of early detection and treatment of melanoma, the deadliest form of skin cancer. The research, recently published in the Journal of the American Academy of Dermatology, indicates that the sooner patients were treated, the better their survival, particularly for stage I melanoma.

Using the National Cancer Database, researchers from Cleveland Clinic’s Dermatology & Plastic Surgery Institute studied 153,218 adult patients diagnosed with stage I-III melanoma from 2004 to 2012 and found that overall survival decreased in patients who waited longer than 90 days for surgical treatment, regardless of stage. In addition, the delay of surgery beyond the first 29 days negatively impacted overall survival for stage I melanoma, though not for stage II or III.

Compared to patients who were treated within 30 days, patients with stage I melanoma were 5 percent more likely to die when treated between 30 and 59 days; 16 percent more likely to die when treated between 60 and 89 days; 29 percent more likely to die when treated between 91 and 120 days; and 41 percent more likely to die when treated after 120 days. Patients with a longer time to treatment initiation tended to be older and male, and have more co-morbidities.

According to the authors, it is likely that more advanced cases represent delays in diagnosis, and these delays overwhelm the impact of a speedier treatment. However, in early-stage cases, early diagnosis allows for the opportunity to improve the chances of survival with a prompt surgery. Although many physicians follow a rule-of-thumb to treat melanoma surgically three to four weeks after diagnosis, there is no official recommendation on time to treatment.

The study is a stark reminder of the importance of detecting skin cancer early, when it’s most treatable. Anyone who notices any new, changing or suspicious spots on their skin, or any spots that are changing, itching or bleeding, should see a board-certified dermatologist for diagnosis.

The public can take steps to reduce their melanoma risk by protecting themselves from exposure to harmful ultraviolet radiation from the sun and indoor tanning beds, a risk factor for all types of skin cancer. The AAD recommends that everyone protect their skin from the sun by seeking shade, wearing protective clothing and using a broad-spectrum, water-resistant sunscreen with an SPF of 30 or higher.