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Cancer has an obesity-related risk factor, and it depends on sex and cancer type

Source: Cell Press
Date: 6/12/2023
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Obesity has been previously linked to an increased risk of cancer, but most studies have not differentiated the risks between male and female patients. A new study published June 12 in the journal Cancer Cell takes a closer look at this connection. The investigators report that both overall fat accumulation and fat distribution in different parts of the body confer different cancer risks depending on sex. Additionally, the risks vary across cancer types, like colorectal, esophageal, and liver cancer.

“Doctors and scientists are aware that obesity increases cancer risk, but this connection is less well known to members of the public,” says first author Mathias Rask-Andersen, a researcher at Uppsala University in Sweden. “These observations are important for risk assessment and to gain a deeper understanding of adiposity-related disease risks.”

“An important aspect of obesity-associated disease risk is the distribution of fat in different compartments of the body,” says senior author Åsa Johansson, also of Uppsala University. “Fat stored in the abdomen is considered more pathogenic compared to subcutaneous fat. In addition, the amount of fat stored in different compartments, as well as the rates of most cancers, is known to differ between females and males. These facts motivated a careful sex-stratified analysis of adiposity-related cancer risk.”

The investigators used data from the UK Biobank, a cross-sectional cohort of 500,000 U.K. residents aged between 37 and 73 who were recruited between 2006 and 2010 and then followed for a mean time of 13.4 years. Among the data collected from participants in the database were details about the distribution of fat in their bodies and whether they developed cancer.

The researchers used Cox proportional hazards modeling to identify the associations between the levels and distribution of fat in the participants’ bodies at the time of the initial assessment and their later rates of cancer. The team found that all cancer types except brain, cervical, and testicular cancers are associated with at least one obesity-related trait.

In female patients, the strongest links between overall fat accumulation and cancer were in gallbladder cancer, endometrial cancer, and esophageal adenocarcinoma. In males, the strongest links between overall fat accumulation and cancer were in breast cancer, hepatocellular carcinoma, and renal cell carcinoma. In terms of fat accumulation and distribution, there were differential effects between sexes on colorectal, esophageal, and liver cancer. For instance, a larger proportion of fat stored in the abdomen was associated with esophageal squamous cell carcinoma in females, but not in males. Additionally, body fat accumulation was associated with a high risk for hepatocellular carcinoma in males, an effect that was not present in females.

“We were surprised to see that there appeared to be a difference in the effect of obesity on cancer risk, not only between males and females, but also between post- and pre-menopausal females,” Johansson says. “Most remarkable, obesity is only a risk factor for breast cancer after menopause, probably due to the change in estrogen production in association with menopause.”

The investigators note limitations to this study, especially that it was limited largely to British White participants, which make up almost 95% of the UK Biobank. They explain that their findings may differ from or may not be applicable to other ethnicities. They also say that because participants were older, the results are likely not directly transferable to younger populations.

They plan to do additional studies to help develop a complete understanding of the molecular mechanisms underlying these findings. Future work will also focus on genetic and environmental risk factors for cancer, which are not static but differ across a person’s lifespan. This includes taking a closer look at the variation in the effects of obesity before and after menopause.

“Given the rapidly increasing rates of obesity globally, obesity is now the fastest-growing risk factor for overall cancer risk,” Rask-Andersen says. “Measures to prevent and reduce the occurrence of obesity and being overweight are therefore highly motivated. However, it is important to consider that reducing weight does not eliminate the risk of cancer. There are still many individual risk factors that play a much larger impact on specific types of cancer, such as smoking for lung cancer and exposure to sun for skin cancer.”

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Combining time-restricted eating and HIIT improves health measures in women with obesity

Source: Cell Press
Date: 10/4/2022
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Both time-restricted eating (TRE) and high-intensity interval training (HIIT) have been shown to improve cardiometabolic health in people who are overweight and at risk of serious disease. Now a randomized, controlled trial has tested whether combining these two approaches is more effective than either of them on their own. The results, publishing in the journal Cell Metabolism on October 4, show that the combination improved the average long-term glycemic control compared to a no-intervention control group and induced 2-fold greater reductions in fat mass and visceral fat area compared with each intervention in isolation.

“Isolated TRE and HIIT have received increasing attention for being effective and feasible strategies for at-risk populations,” says senior author Trine Moholdt, head of the Exercise, Cardiometabolic Health, and Reproduction Research Group at Norwegian University of Science and Technology (NTNU). “We wanted to compare the effects of the combination of TRE and HIIT with their isolated effects and to determine whether TRE and HIIT would act synergistically in improving health in individuals with risk for cardiometabolic disease. This finding highlights the importance of changing both dietary and physical activity habits for individuals who wish to rapidly improve their health and lower their disease risk.”

The trial had four arms: HIT alone, TRE alone, the TRE-HIIT combination, and a control group. A total of 131 women were enrolled, with 32 or 33 in each arm. All of them had overweight or obesity and had risk factors for cardiometabolic diseases like type 2 diabetes and cardiovascular disease. TRE was defined as consuming all daily calories within a 10-hour time window. HIIT was defined as exercise done at 90% of maximum heart rate for 35 minutes, three times per week. The exercise sessions were supervised by the investigators, and the participants were asked to log their first and last calories every day.

The interventions lasted for 7 weeks. Several measures were taken both before and after the study, including the participants’ blood pressure, body mass index, fat and cholesterol levels in the blood, and several measures of blood glucose and insulin levels.

The researchers found that the participants who combined TRE and HIIT were able to improve their average long-term glycemic control measured as HbA1c. They were also able to effectively reduce fat mass and visceral fat and increase their cardiorespiratory fitness measured as peak oxygen uptake. However, there were no statistically significant differences in blood lipids, appetite hormones, or vital signs after any of the interventions compared with the control group.

Another important finding from the study was that adherence to the study was high. “High adherence rates are important,” says first author Kamilla La Haganes, a PhD student at NTNU. “Adherence rates to general lifestyle recommendations are low, and our diet-exercise strategies may serve as an alternative.” After the study was completed, 18 participants from the control group also chose to try one of the study interventions.

“We recommend this kind of program for people who wish to have a relatively simple way of changing diet and exercise habits and improving their health,” Moholdt says. “TRE is a less tedious and time-efficient method to lose weight compared with daily calorie counting, and HIIT is tolerable and safe for previously sedentary individuals and can be completed within 30-40 minutes.”

A limitation of the study was that the intervention period was only 7 weeks; longer-term investigations are needed to determine effects and feasibility for longer periods of time. The study also took place during COVID-19 lockdowns, which affected the participants’ lifestyles and could have influenced the results.

The researchers are currently inviting the participants back for follow-up testing 2 years after they completed the study to find out if they have continued with the interventions. They also plan to determine whether the combination of TRE and HIT will induce the same health benefits and have equally good adherence rates in a completely home-based setting. That study will include both men and women. “Together, these two new studies will tell us more about the long-term feasibility and also the possibility for implementation in a real-world setting,” Haganes says. “Additionally, we can investigate if there are any sex differences in response to these interventions.”

This research is supported by the Liaison Committee for Education, Research and Innovation in Central Norway, the EFSD/Novo Nordisk Foundation Future Leaders Awards Programme, the Norwegian University of Science and Technology (NTNU), and by a Novo Nordisk Foundation Challenge Grant.

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STEM CELLS RESTORE OVARIAN FUNCTION AND FERTILITY TO MICE TREATED WITH CHEMOTHERAPY

Source: Brigham and Women's Hospital
Date: 8/15/2023
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Researchers at Brigham and Women’s Hospital have demonstrated that mice with ovarian failure caused by chemotherapy can restore their fertility using induced pluripotent stem cells (iPSCs). Not only were the mice able to make functional eggs from the iPSCs, but those eggs developed into pups that could reproduce.

Although more research is needed before this approach can be evaluated in humans, this marks a big step toward reaching that goal. The study was published in July 2023 in Lancet Biomedicine.

“This research shows a novel, cell-based approach to treating infertility,” says senior author Raymond Manohar Anchan, MD, PhD, director of the Stem Cell Biology and Regenerative Medicine Research Laboratory at the Brigham. “It builds on earlier work from our lab that demonstrated that iPSCs can be used to generate ovarian and oocyte cell types.”

Using Stem Cells to Restore Ovarian Function

In the study, mice were treated with chemotherapy known to be toxic to the gonads.

The iPSCs used in the research were derived from somatic ovarian granulosa cells. The cells were cultured in a three-dimensional environment that mimics the structure of the ovary, using human ovarian follicular fluid that otherwise would have been discarded by an in vitro fertilization clinic. The stem cells were engineered to carry a label with green fluorescent protein so their lineage could be traced after placing them in the mice.

“Because we labeled the stem cells, this gives us a high level of confidence that the developed eggs came from the stem cells that we introduced,” Dr. Anchan says. “These eggs clearly carry the label. Furthermore, we used short tandem repeat lineage training to confirm the stem-cell lineage of the resultant pups and litters.”

Nine of the mice that received iPSC transplants were crossbred with wild-type mice and were able to bear pups. Those pups were also bred to confirm their viability and fertility.

‘Epigenetic Memory’ Helps Stem Cells Form Ovarian Tissues

Dr. Anchan says another important finding from this work is that, in addition to being able to differentiate into egg cells, the stem cells can also make the reproductive hormones estrogen and progesterone. Additionally, the stem cells not only restored fertility to the ovary where they were placed but also boosted activity in the other ovary.

“We know this is the case because we get eggs in both ovaries, not just the one we injected,” Dr. Anchan says. “The stem cells are secreting something that helps the other ovary to recover some of its function. We confirmed this because not all the eggs contain the protein label.”

The researchers use the term “epigenetic memory” to describe the ability of cells taken from an organ to differentiate into the various cell types from that organ. Once placed into the ovaries of the mice, some of the cells were able to make follicles—the cavity where the eggs develop. “It’s intriguing because a single type of stem cell has the ability to do many different things,” Dr. Anchan adds.

Translating Ovarian Research to Human Cells

Ongoing experiments in Dr. Anchan’s lab are taking the next step toward translating these findings into approaches that would benefit human patients with ovarian failure. A common cause of this issue in women still of reproductive age is the chemotherapy regimen used to treat breast cancer. These drugs are known to deplete the follicles in the ovaries.

Dr. Anchan and his colleagues are already conducting research in cell cultures of human ovarian cells. They have shown that the iPSCs derived from discarded amniocytes can produce estradiol and progesterone when the same protocol is used. “Of course, we will need to come up with different ways to test the normal genetics of any eggs that may form before we begin to think about human trials,” he notes.

One thing that is still unknown is whether this approach would be effective only in patients who have lost ovarian function due to chemotherapy treatments or whether it would also work in those whose ovaries stop working prematurely due to a genetic condition. This is something the team plans to study, both in human cells and in animal models.

The authors also note that if this approach proves effective, it could provide the opportunity to develop a type of “autologous” hormone replacement therapy using patients’ own ovarian cells.

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Feeding C-section newborns their mother’s poop may help build healthy microbiota: study

Source: Cell Press
Date: 10/1/2020
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Infants delivered by cesarean section have an increased risk of developing asthma and allergies as babies and toddlers, probably because they don’t get exposed to the microbiota in the mother’s vagina and perineum during birth, negatively impacting how their immune systems develop. While a few studies have looked at whether swabbing a newborn’s skin with vaginal fluid immediately after birth reduces this risk, a paper published October 1 in the journal Cell offers a more drastic way to expose newborns to their mother’s microbiota: by diluting a small amount of their mother’s feces in breast milk and feeding it to them just after birth. The researchers report that the proof-of-concept procedure appears to be safe and at three months resulted in the newborns having a microbial makeup that looks more similar to babies born vaginally than to those born by C-section.

“From a clinical point of view, this transfer of microbial material is happening during a vaginal delivery,” says co-senior author Sture Andersson, of the Pediatric Research Center at the University of Helsinki and Helsinki University Hospital in Finland. “This is a gift the mother gives to her baby.”

At birth, the immune system is undeveloped, but once a baby begins living in the outside world, their immune system matures in response to microbial exposure. Although every person’s microbiota is individualized, the overall patterns of which bacteria types colonize the gut are different in babies born vaginally and those born by C-section. These variations appear to make a difference in how the immune system learns to respond to outside stimuli, including potential allergens.

The mothers who took part in the study were recruited with leaflets placed in doctors’ waiting rooms. About 30 women contacted the researchers to learn more, and 17 agreed to participate. Ten of them were found to have contraindications, such as a recent course of antibiotics or a potentially dangerous microbe, and ultimately seven mothers who were scheduled to have C-sections were enrolled.

The babies were given the fecal microbiota transplants (FMTs) shortly after birth. The mothers’ fecal samples were collected three weeks beforehand. The babies stayed in the hospital for two days after the transplant to make sure there were no complications. The babies’ own fecal microbiota was tested at birth (the meconium) and again at two days, one week, two weeks, three weeks, and three months. The babies also had blood work done two days after birth.

The investigators found that by three months of age, the microbiotas of the babies who received the FMTs were similar to those of babies born vaginally. They were different from those of babies born by C-section, as well as from their mothers’ microbiotas. As a baseline for these comparisons, the researchers used data collected previously at the same hospital, as well as global datasets.

“This was not designed as a safety study, but we found it to be effective and supporting the concept of vertical transfer from mother to baby,” says co-senior author Willem de Vos, of the Human Microbiome Research Program at the University of Helsinki and the Laboratory of Microbiology at Wageningen University in the Netherlands. “However, it’s very important to tell people that this is not something they should try on their own. The samples have to be tested for safety and suitability.”

Andersson notes that despite how unpalatable this research may seem to most people, the mothers who agreed to participate in the study were very motivated. One woman who was having twins was told the FMT could be giving to one baby, with the other one used as a sort of control. She declined, stating that she didn’t want one of her babies to have an unfair advantage by receiving the transplant.

In future work, the researchers plan to study the development of the immune systems in C-section babies who receive FMTs and compare it to those who don’t. Unlike the current study, which was observational, the future studies will have a control group and will be blinded to the mothers.

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Blood Test Offers Better Prediction of Preeclampsia Risk

Source: Brigham and Women's Hospital
Date: 5/9/2022
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Improvement in rates of maternal morbidity and mortality has been limited by the inability to assess fetal and maternal tissues before symptoms develop. Thomas McElrath, MD, PhD, an obstetrician in the Division of Maternal-Fetal Medicine at Brigham and Women’s Hospital, Michal A. Elovitz, MD, of the University of Pennsylvania, and colleagues have shown in a publication in Nature that the patterns of cell-free RNA (cfRNA) from maternal plasma progress in a predictable gestational-age dependent fashion. As such, these molecular signatures can be used to survey the gestational age of the pregnancy as well as the overall wellbeing of mother, placenta and baby. The team demonstrated this concept by predicting the risk of preeclampsia, a hypertensive condition unique to pregnancy, on average 14 weeks prior to the development of symptoms.

Methods

The researchers measured cfRNA in 2,539 plasma samples drawn from 1,840 pregnant women of multiple ethnicities, nationalities, geographic locations and socioeconomic circumstances, while covering a range of gestational ages. This was the largest and most diverse dataset of maternal transcriptomes ever analyzed.

Measuring Gestational Age

The researchers first restricted their study to plasma samples from healthy pregnancies, building a machine learning model of normal cfRNA patterns in uncomplicated pregnancies. By design, these models also served to predict gestational age. A cfRNA signature was as accurate as second-trimester ultrasound and superior to third-trimester ultrasound while also providing insights into the biology of pregnancy progression.

Thus, the model could offer alternative dating for women who start prenatal care later in pregnancy. Its predictions were driven almost entirely by information from the cfRNA transcripts, as body mass index, maternal age and race accounted for less than 1% of the variance.

A Window into Maternal–Fetal Development

cfRNA profiles also made it possible to assess the molecular status of the placenta, fetal organs, cervix and uterus. Hundreds of independently identified gene sets in maternal blood mirrored the maternal and fetal physiological changes expected during pregnancy.

A study of three independent cohorts verified that multiple gene sets were uniquely associated with specific tissues of origin. These included the uterus and cervix as well as the placenta. Most intriguingly, however, the team also detected the unique signature of fetal tissues including fetal heart, GI tract and kidneys. Thus, the use of cfRNA signatures could reveal and characterize molecular changes in the maternal–fetal dyad during gestation.

Early Prediction of Preeclampsia

As an example of predicting adverse outcomes, the team evaluated the ability of cfRNA signatures in maternal blood during the second trimester to identify women at risk of preeclampsia. A case–control study included 72 women with preeclampsia and 452 without, selected from two independent cohorts.

Correlation tests identified signatures that separated the cases and controls and identified seven genes consistently associated with preeclampsia. A screening test based on those genes achieved a sensitivity of 75%, with an area under the receiver operating curve of 0.82.

The inclusion of maternal body mass index, age and race had no effect on the new test’s performance.

Women who tested positive delivered significantly earlier during gestation than women who tested negative. In addition, a positive test correctly identified 73% of women who had a medically indicated preterm birth—more than three months ahead of clinical symptoms or delivery.

Hypertension vs. Normotension

In pregnant women who have preexisting hypertension, it can be quite challenging to distinguish superimposed preeclampsia from exacerbation of hypertension. The difference is important because one requires delivery for a cure and the other usually doesn’t.

One of the cohorts used to estimate preeclampsia risk included 50 women with hypertension (chronic hypertension, n=31; gestational, n=19) and 263 normotensive women. Genes identified by comparing the two groups showed no overlap with genes significant for preeclampsia. Also, none of the genes were differentially expressed. Thus, the molecular signal for preeclampsia was specific to hypertension driven by a placental disorder.

Clinical Importance

Considering the large, diverse study population, it’s noteworthy that race had almost no effect on gestational age estimates or preeclampsia risk evaluation. Including race in clinical risk assessment has been shown in several fields to be problematic, have little or no utility, and in fact represent a source of latent bias against members of underrepresented minority communities. In contrast, the cfRNA signature directly exposes the development of preeclampsia.

A better understanding of the maternal–fetal–placental transcriptome should lead to precision therapeutic interventions that can target molecular subtypes of preeclampsia and preterm birth.

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Improving Microbial Balance in Female Genital Tract May Boost Health

Source: Brigham and Women's Hospital
Date: 3/7/2022
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Advances in gene sequencing and computational biology have revolutionized the study of the microbiome over the past decade. But compared with other bodily systems like the gastrointestinal tract and skin, much less attention has been paid to the microbiome of the female genital tract. This is despite its important role in modulating reproductive health.

Raina Fichorova, MD, PhD, is the director of the Laboratory of Genital Tract Biology, the Walter Channing Distinguished Chair in Obstetrics and Gynecology, the inaugural BWH OBGYN vice chair for Research at Brigham and Women’s Hospital, and professor of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School. She is also a leader in studying host-microbe interactions in the female reproductive tract, including their role in inflammation, resilience to infection and reproduction. Some of her efforts have focused on the development of a novel biotherapeutic treatment, which she has patented and is now working to bring into clinical trials.

“There is an overwhelming body of evidence showing that the resident vaginal microbes are a fundamental part of the fabric of innate immunity in the female genital tract,” Dr. Fichorova says. “They have consequences not only for women’s health, but also for the health and development of their offspring.”

Addressing an Unmet Need in Women’s Health

Central to the work in Dr. Fichorova’s laboratory is the characterization of the microbes that play a role in bacterial vaginal dysbiosis, which is associated with increased inflammation in the genital mucosa, increased susceptibility to sexual transmitted infections and adverse pregnancy outcomes.

Despite available antibiotic treatment, an estimated 21.2 million women of reproductive age in the United States have this condition, including 23% of white women, 51% of Black women and 32% of Latina women. In African countries, where Dr. Fichorova has conducted much of her research, the prevalence among reproductive age women is between 35% and 50%.

“There is an unmet need for better ways to treat this condition, which affects up to half of women of reproductive age in the most vulnerable populations around the globe,” she says. “There are major gaps in the study of this condition and how to address it therapeutically.”

Dr. Fichorova and her team have developed metrics to distinguish good from bad maternal bacteria and to identify microbes that can affect the offspring either directly or through epigenetic changes, due to the presence or absence of inflammation in the uterus and placenta. The investigators discovered that maternal bacteria ascending to the placenta are associated with newborn inflammation and that maternal bacteria are also linked to epigenetic regulation of inflammatory genes in the placental tissue.

“We’ve found that certain types of lactobacilli in the uterus and placenta reduce inflammation at all molecular checkpoints,” Dr. Fichorova says.

Developing a Live Biotherapeutic Treatment

One effort to come from this work is the development of live biotherapeutics, which “have the potential to reduce inflammation and prevent the ascendance of harmful bacteria to the placenta,” according to Dr. Fichorova.

In 2021, Dr. Fichorova and her colleagues at the Brigham were granted a patent for a mixture of strains of lactobacilli that has the potential to correct the microbial balance in the female reproductive tract.

“We have identified and cloned bacterial strains of the human vaginal microbiome obtained from healthy moms who delivered healthy babies at term here at the Brigham,” she says. “These strains synergistically colonize the human vaginal cells, are homeostatic and noninflammatory and have genomes that are fully characterized.”

In addition to the biotherapeutic blend, the patent includes an algorithm to synthesize a unique cocktail of these strains in optimal proportions.

With funding from the National Institutes of Health as well as internal funding from within the Brigham through its “Shark Tank” program, Dr. Fichorova and her colleagues have made progress toward developing vaginal delivery systems for their biotherapeutic. They are also collaborating with the pharmaceutical industry.

“The successful translation of our research concept and implementation of a live biotherapeutic device would contribute to improved reproductive and sexual health and also reduce preterm birth, infant mortality and disability rates associated with a disturbed vaginal microbiome,” she says. “Our research has the potential to benefit at least 500 babies born preterm at the Brigham each year.”

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NIH-FUNDED EFFORTS CENTER ON HOW MICRORNAS REGULATE WOMEN’S HEALTH

Source: Brigham and Women's Hospital
Date: 6/24/2021
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Clinical studies for new drugs and vaccines, including the recent trials that led to the approval of COVID-19 vaccines, generally exclude women who are pregnant or lactating. For that reason, little is known about how hormonal changes affect drug pharmacokinetics and pharmacodynamics.

The National Institutes of Health (NIH) is supporting new efforts to address the shortage of research in this area. A team from Brigham and Women’s Hospital recently received two grants, which together total over $4.2 million, to look at various aspects of this connection. One grant is focused on drug metabolism and transport in pregnant and lactating women. The other is looking at predictors of HIV risk in women of reproductive age, a related area of research that also traditionally has been underfunded. Both are studying the role of noncoding microRNAs and how they lead to epigenetic changes in the body.

“There is a huge gap in knowledge, and the NIH has recognized the importance of shedding light on these topics,” said Raina Fichorova, MD, PhD, director of the Laboratory of Genital Tract Biology at the Brigham and Harvard University, who is leading the projects related to these grants. “Our group has a lot to contribute, because we already have a huge cohort of specimens that have been collected as part of our earlier work.”

The team has hundreds of samples from women’s health clinics in Zimbabwe and Uganda as well as clinics in the United States. Fichorova’s group has received approval for secondary use of the biospecimens, which include serum, vaginal and cervical samples collected in different stages of pregnancy and lactation as well as at different parts of the menstrual cycle.

Focusing on Mechanisms That Underlie Biological Change

Some of Dr. Fichorova’s previous research looked at the effect of reproductive hormones on women’s susceptibility to infection. One of the two new projects is taking a deeper look at the mechanisms that underlie the changes in infection susceptibility, including how the mucosal environment in the reproductive tract contributes to systemic factors. This includes the role of the microbiota in addition to differences in hormone levels.

“Our hypothesis is that noncoding microRNAs that are being released from the mucosal environment affect susceptibility to infection at the systemic level,” Dr. Fichorova said. “The mucus membrane releases vesicles containing these microRNAs, which are like little bullets of information. They travel through the blood circulation and are taken up by distant sites in the body.”

The study will investigate how these microRNAs act on the immune response, both directly and indirectly. First results were presented at the international Conference on Retroviruses and Opportunistic Infections, and manuscripts and data sharing have been prepared for submission in this funding period.

Characterizing Metabolic Changes

Many of the existing biospecimens that the lab has collected for its study of infection susceptibility, including vaginal swabs and serum samples, will also be used in the research related to drug metabolism. By characterizing the content of the microRNA in extracellular vesicles and how that content fluctuates in relation to pregnancy and breastfeeding, the researchers will be able to identify changes that are influenced by hormone levels as well as the makeup of the microbiota in the vaginal tract.

“MicroRNAs are one way to epigenetically control which proteins are actually manufactured by our bodies, and proteins are what ultimately determines phenotype,” Dr. Fichorova said. “Through these microRNA-containing vesicles, the hormonal environment and the microbial environment interact with each other, and they have an effect on the rest of our bodies, including how they use drugs.”

The study of microRNAs, she added, can also help to illuminate whether drugs are safe for the babies of pregnant women by revealing information about receptors and transporters that are specific to the placenta.

“We have multiple samples from each woman, which will allow us to translate findings and make many kinds of connections,” she concluded. “It’s really a goldmine of data that we hope many other researchers will find useful as well.”

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DOUBLE DISCRIMINATION: A CALL TO END PAY AND GENDER DISPARITIES IN GYNECOLOGIC SURGERY

Source: Brigham and Women's Hospital
Date: 5/11/2021
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The disparity in pay between gynecologic surgery and other surgical specialties has been well-established. In a recent commentary, faculty from Brigham and Women’s Hospital and Northwestern University describe the history of this issue and other influences that drive what they call “double discrimination” — lower pay in an area of surgery that has the largest proportion of female surgeons and one that serves primarily female patients.

The authors call for changes that would create equity in reimbursement rates for gynecologic surgery, raising them to the level of other similar surgical specialties. The commentary was published in April 2021 in Obstetrics & Gynecology (download paper here).

“From an anatomical standpoint, we shouldn’t reimburse at lower rates for women’s surgery than for men’s surgery,” said senior author Louise Perkins King, MD, JD, a surgeon in the Brigham’s Division of Minimally Invasive Gynecologic Surgery and a member of the Center for Bioethics at Harvard Medical School. Some of the reasons why this is the case are noted in the commentary.

The Basis for Differences in Reimbursement

The differences in fees are due in large part to the rates at which Medicare and Medicaid reimburse surgeons. In the article, the authors cited two papers — one from 1997 and one from 2017 — that described the differences in the relative value unit assigned to gynecologic procedures compared to urologic procedures. Urologic procedures were used as the comparison because they are most closely related to gynecologic surgeries. Additionally, because a higher proportion of urologic surgeries are performed on men, it allowed the researchers to look at the differences in relation to patients’ biological sex.

They also discussed the 2007 Supreme Court case in which a woman named Lilly Ledbetter sued her former employer, Goodyear Tire and Rubber Company, over gender-based pay discrimination. The late Justice Ruth Bader Ginsburg dissented to the ruling against Ms. Ledbetter’s case, noting the many harms of gender-based pay discrimination. Justice Ginsburg’s legacy compelled the authors to point out this discrimination in medicine and the potential harm for patients.

“The fact that gynecologic surgery doesn’t pay as much as other specialties means that most obstetrician-gynecologists primarily practice obstetrics, which also pays lower than many other subspecialties, but pays a little bit better [than gynecologic surgery],” Dr. King said. “For that reason, many gynecologic surgeons, especially those in private practice, operate infrequently. This, in turn, can lead to higher complication rates, as referenced in literature included in the commentary, because the surgeons don’t have as much experience.”

Creating Equity in Billing and Reimbursement

The paper calls for new legislation that would create equity in billing and reimbursement from Medicare and Medicaid, which Dr. King said would have the trickle-down effect of also increasing reimbursement levels from private insurance companies. She explained that this would allow more gynecologists to focus exclusively on surgery, raising their level of expertise and ultimately leading to better patient outcomes.

Dr. King added that, in an unusual move, the journal published all of the reviewer comments and allowed the authors to respond directly to them.

“I appreciate the journal’s efforts to make the discussions around this topic open and transparent,” Dr. King concluded. “I encourage anyone who is interested to review the many points that we have put forward about why this issue is so important.”

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T Cell Therapies Offer a New Way to Treat Gynecologic Cancers

Source: Memorial Sloan Kettering - On Cancer
Date: 09/30/2020
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The American Cancer Society estimates that more than 113,000 people in the United States are diagnosed with a gynecologic cancer every year. Memorial Sloan Kettering is a leader in treating people with these cancers, which include tumors of the cervix, ovaries, and uterus.

Among the new treatments being developed for gynecologic cancers are a type of immunotherapy called T cell therapies. These are treatments in which a patient’s own immune cells are modified to recognize and attack cancer cells. MSK doctors and scientists were the first to develop these treatments for leukemia and lymphoma. Now, many researchers are focused on further advancing this approach to make it effective against solid tumors.

“For certain blood cancers, cellular therapy can be remarkably potent, perhaps even curative,” says physician-scientist Christopher Klebanoff, whose lab is focused on developing new cell therapy approaches. One challenge of immunotherapy is directing the immune cells only to tumors so they don’t cause injury to healthy tissues.

Treating Cancer with CARs and TRUCKs

The most well-known cell therapy is chimeric antigen receptor (CAR) T therapy, which has shown success in treating certain blood cancers. CAR T modifies a patient’s immune cells (T cells) so they can recognize a protein (called an antigen) on the outer surface of cancerous cells. These supercharged T cells then seek out and destroy the cancer. For many cancers, especially cancers originating from a solid organ, the antigen isn’t quite as easy for the T cell to find, making cell therapies more challenging to develop.

This has led to a related tactic called T cell receptor (TCR) therapy, in which T cells are engineered to detect antigens on the inside of the cancer cell. “The ability to do this is one of the greatest tricks in biology,” Dr. Klebanoff says. “That is, how can you allow an immune cell to look inside other cells to detect if the proteins inside are normal or abnormal?”

As it turns out, the way this “looking” works is actually indirect: As part of normal cellular operations, proteins eventually get broken down and recycled to make new proteins. One step in this recycling process displays protein fragments on the surface of cells — allowing them to be seen by engineered T cells. TCR therapies are designed to take advantage of this natural process that the immune system uses to survey tissues in the body.

Some of the newest cell therapies known as TRUCKs — T cells redirected for antigen‐unrestricted cytokine‐initiated killing — work by combining the antitumor abilities of CAR T or TCR therapy with a molecule called a cytokine. The cytokine recruits another wave of immune cells to the tumor.

A Personalized Approach to Cancer Care

Medical oncologist Roisin O’Cearbhaill is the research director for the Gynecologic Medical Oncology Service and a leader in studying new cell therapies and immunotherapy approaches for treating gynecologic cancers, including a treatment for cervical cancer and other tumors caused by the human papillomavirus (HPV). “We’re building up our clinical trial program at MSK so that we will be able to offer more cellular therapies for patients with gynecologic cancers,” she says.

“With cell therapies, we use our knowledge about specific molecular and genomic properties of the patient’s cancer,” Dr. O’Cearbhaill explains. “And we may also use certain markers on their blood cells in order to get the best possible match for a targeted therapy for that individual patient.”

“For each of our patients, we take a very personalized approach to match the best possible medicines, including experimental medicines offered in clinical trials, with the patient’s disease,” Dr. Klebanoff says. “I’m a big believer in the concept of partnership and shared purpose, and this is how we work in collaboration with our patients. We have a shared purpose to try to improve things both for them and for others with similar diseases in the future.”

Clinical Trials Offering Cell Therapies for Gynecologic Cancers

MSK currently has a number of clinical trials that are examining this approach.

  • Dr. O’Cearbhaill is co-leading a phase I study with Dr. Klebanoff that is assessing the safety and effectiveness of using a TCR therapy called KITE-439 to treat cancers caused by a strain of HPV called HPV 16. The majority of cervical cancers as well as many cancers of the mouth, throat, vagina, vulva, penis, and anus are associated with HPV 16. In this study, a patients’ immune cells are modified to recognize and attack tumor cells that contain HPV 16.
  • The doctors are also co-leading a phase I trial for a cell therapy called KITE-718, which targets cancers containing MAGE-A3/A6, a protein found in some ovarian and cervical cancers as well as other kinds of cancer.
  • To study another treatment for ovarian cancer and cancers of the fallopian tubes and the peritoneal cavity (the lower abdomen), Dr. O’Cearbhaill is leading a phase I trial for a CAR T therapy that targets a protein called MUC16, which is made by many of these tumors. MUC16, also called CA125, is best known as a biomarker used to monitor treatment for ovarian cancer.
  • Dr. O’Cearbhaill is also leading a phase I/II trial for a TRUCK drug called TC-210, which is being tested in combination with chemotherapy. This cell therapy targets tumors that make a protein called mesothelin, which is found in several cancers, including some ovarian tumors.
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Reality Check: Study Examines Metastasis after Breast Cancer Surgery

Source: Memorial Sloan Kettering - On Cancer
Date: 04/13/2018
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Earlier this week, scientists from the Massachusetts Institute of Technology published a study looking at some of the ways in which breast cancer spreads, or metastasizes, in mice. They reported data showing that surgery may trigger an immune response that makes it easier for cancer to spread throughout the body. Additionally, the study pointed to anti-inflammatory drugs like aspirin and ibuprofen as a possible way to decrease cancer’s ability to spread.

The news media reported on the research, which is still in early stages. These headlines may be scary or confusing for people facing a recent diagnosis, as well as for those who have already had surgery.

We spoke with Larry Norton, Memorial Sloan Kettering’s Senior Vice President and Medical Director of the Evelyn H. Lauder Breast Center, about what people should know about the study and why it shouldn’t affect decisions about treatment.

Can you tell us how this study was conducted?

This was a study done in the lab using a mouse model. The mice had been injected with cancer cells and then underwent simulated surgeries. Those mice later developed tumors. However, when the mice were given an anti-inflammatory drug at the time of the surgical procedure, the tumors were smaller.

I want to emphasize that this is an excellent lab experiment, and it fits in with much of the lab research we’re doing here at MSK. But it’s far from ready to influence clinical care.

What is the take-home message from the findings?

There is nothing in this study that should lead to any changes in the way we treat breast cancer. I don’t want anyone to read the media coverage of this study and think that they shouldn’t have surgery. That would be a disaster.

From studies conducted in London way back in the 1800s, we know that before doctors started doing surgery for breast cancer, everyone with breast cancer died. Some died soon after diagnosis, within months or a few years, and some lived for many years. But everyone eventually developed metastases and died from them. Surgery is still the mainstay of treatment for breast cancer and is the most important way to prevent metastases.

We have come a long way in the diagnosis and treatment of breast cancer since those early days, and today most people do very well. It’s true that some people still develop metastases, even if their cancer is caught early. Therefore, it’s clear that some tumors seed metastases very early in their development, long before they are ever detected and surgically removed. So it is not the surgery that causes the metastases.

What about taking anti-inflammatory drugs like aspirin or ibuprofen to reduce any potential risk?

I think a lot of people will hear about the study and grab onto this notion of taking these drugs at the time of surgery. But just because these drugs are available over the counter, it doesn’t mean they’re completely without risk. We know they can increase bleeding, and that may turn out to be more harmful than the response to inflammation.

It’s important to note that today many people with breast cancer get drug therapy before or immediately after their surgery. This includes chemotherapy and steroids. The steroids we give are much more potent than aspirin as far as their anti-inflammatory abilities. So there’s no reason to automatically assume that a small additional boost from aspirin or ibuprofen would make a difference. It’s an interesting question and it merits further research, but it’s something that needs to be studied with controlled clinical trials in patients.

What is MSK’s role in studying cancer metastasis?

MSK is conducting a great deal of research on the question of metastases. For example, Sloan Kettering Institute Director Joan Massagué is a world leader in studying how cancer metastasizes. Many of his studies also have looked the role of the immune system in suppressing cancer cells that have broken off from a tumor. He’s conducted research on how these cells later wake up and start to cause trouble. The biology is complex, and there are still a lot of things we don’t know. But everyone agrees this is a very important area of research, and one we will continue to study.

Is there anything else you’d like to say about the research?

This study was an interesting piece of well-conducted science. It’s certainly adding to our knowledge and giving us some ideas for new things to look at in the lab and in the clinic. But while it would be terrific if stopping metastasis were as easy as taking an over-the-counter anti-inflammatory drug, everyone studying metastasis knows that it’s not.

However, this work and much of the other work on this topic is pointing us in a good direction, with the ultimate aim of stopping cancer cells from spreading from the very beginning, or even before the beginning — as in cancer prevention. I do believe that the future is bright in this regard, although there is much work still to do to make it a reality.