Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.

Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.

Surgical margin status in relation to surgical approach in the management of early-stage cervical Cancer: A Canadian cervical Cancer collaborative (4C) study.

OBJECTIVE: Surgical margin status in women undergoing surgery for early-stage cervical cancer is an important prognostic factor. We sought to determine whether close (<3 mm) and positive surgical margins are associated with surgical approach and survival. METHODS: This is a national retrospective cohort study of cervical cancer patients treated with radical hysterectomy. Patients with stage IA1/LVSI-Ib2(FIGO 2018) with lesions up to 4 cm at 11 Canadian institutions from 2007 to 2019 were included. Surgical approach included robotic/laparoscopic (LRH), abdominal (ARH) or combined laparoscopic-assisted vaginal/vaginal (LVRH) radical hysterectomy. Recurrence free survival(RFS) and overall survival (OS) were estimated using Kaplan-Meier analysis. Chi-square and log-rank tests were used to compare groups. RESULTS: 956 patients met inclusion criteria. Surgical margins were as follows: negative (87.0%), positive (0.4%) or close <3 mm (6.8%), missing (5.8%). Most patients had squamous histology (46.9%); 34.6% had adenocarcinomas and 11.3% adenosquamous. Most were stage IB (75.1%) and 24.9% were IA. Mode of surgery included: LRH(51.8%), ARH (39.2%), LVRH (8.9%). Predictive factors for close/positive margins included stage, tumour diameter, vaginal involvement and parametrial extension. Surgical approach was not associated with margin status (p = 0.27). Close/positive margins were associated with a higher risk of death on univariate analysis (HR = non calculable for positive and HR = 1.83 for close margins, p = 0.017), but not significant for OS when adjusted for stage, histology, surgical approach and adjuvant treatment. There were 7 recurrences in patients with close margins (10.3%, p = 0.25). 71.5% with positive/close margins received adjuvant treatment. In addition, MIS was associated with a higher risk of death (OR = 2.39, p = 0.029). CONCLUSION: Surgical approach was not associated to close or positive margins. Close surgical margins were associated with a higher risk of death. MIS was associated with worse survival, suggesting that margin status may not be the driver of worse survival in these cases.

Comparison of outcomes between abdominal, minimally invasive and combined vaginal-laparoscopic hysterectomy in patients with stage IAI/IA2 cervical cancer: 4C (Canadian Cervical Cancer Collaborative) study.

OBJECTIVE: Although minimally invasive hysterectomy (MIS-H) has been associated with worse survival compared to abdominal hysterectomy (AH) for cervical cancer, only 8% of patients in the LACC trial had microinvasive disease (Stage IA1/IA2). We sought to determine differences in outcome among patients undergoing MIS-H, AH or combined vaginal-laparoscopic hysterectomy (CVLH) for microinvasive cervical cancer. METHODS: A retrospective cohort study of all patients undergoing hysterectomy (radical and non radical) for FIGO 2018, microinvasive cervical cancer across 10 Canadian centers between 2007 and 2019 was performed. Recurrence free survival (RFS) was estimated using Kaplan Meier Survival analysis. Chi-square and log-rank tests were used to compare outcomes. RESULTS: 423 patients with microinvasive cervical cancer were included; 259 (61.2%) Stage IA1 (22/8.5% with LVSI) and 164(38.8%) IA2. The median age was 44 years (range 24-81). The most frequent histology was squamous (59.4%). Surgical approach was: 50.1% MIS-H (robotic or laparoscopic), 35.0% AH and 14.9% CVLH. Overall, 70.9% underwent radical hysterectomy and 76.5% had pelvic lymph node assessment. There were 16 recurrences (MIS-H:4, AH:9, CVLH: 3). No significant difference in 5-year RFS was found (96.7% MIS-H, 93.7% AH, 90.0% CVLH, p = 0.34). In a sub-analysis of patients with IA1 LVSI+/IA2(n = 186), survival results were similar. Further, there was no significant difference in peri-operative complications (p = 0.19). Patients undergoing MIS-H had a shorter median length of stay(0 days vs 3 (AH) vs. 1.5 (CVLH), p < 0.001), but had more ER visits (16.0% vs 3.6% (AH), 3.5% (CVLH), p = 0.036). CONCLUSION: In this cohort, including only patients with microinvasive cervical cancer, no difference in recurrence was found by surgical approach. This may be due to the low rate of recurrence making differences hard to detect or due to a true lack of difference. Hence, this patient population may benefit from MIS without compromising oncologic outcomes.

Implications for management of ovarian cancer in a transgender man: Impact of androgens and androgen receptor status.

A 36-year-old transgender man (assigned female at birth) on exogenous testosterone therapy was found to have stage IIA ovarian endometrioid carcinoma, and underwent adjuvant chemotherapy. Diffuse androgen receptor expression in the tumor initiated a multidisciplinary discussion regarding the safety of continuing exogenous testosterone as gender-affirming hormone therapy.

Myometrial Pseudoaneurysm and Myelosuppression Following Conservative Management of Cesarean Scar Ectopic Pregnancy.

BACKGROUND: Treatment of cesarean scar pregnancy is based on clinical context. This report describes two rare complications of conservative management: non-steroidal anti-inflammatory drug-induced methotrexate myelosuppression and myometrial pseudoaneurysm. CASE: A 34-year-old woman was treated conservatively for a cesarean scar pregnancy with systemic methotrexate and intragestational potassium chloride, resulting in pancytopenia secondary to concurrent non-steroidal anti-inflammatory drug use. She presented again with a myometrial pseudoaneurysm, which was treated with bilateral uterine artery embolization and, ultimately, hysterectomy. The final pathology report confirmed a pseudoaneurysm, retained villi within the myometrium, and acute endometritis and myometritis. CONCLUSION: Myelosuppression resulting from use of non-steroidal anti-inflammatory drugs affecting renal excretion of methotrexate can occur at low dosages. Additionally, there is a risk of pseudoaneurysms with vascular damage and trophoblastic tissue. Drug interactions and procedure-related risks must be considered when managing cesarean scar pregnancy conservatively.

Vesicovaginal Fistula Following Loop Electrosurgical Excision Procedure: A Case Report.

BACKGROUND: The loop electrosurgical excision procedure (LEEP) is commonly used to treat cervical dysplasia and has few procedural risks. We report a rare complication: vesicovaginal fistula (VFF). CASE: A 47-year-old G3P1 woman with a previous LEEP underwent a second procedure 9 years later and was diagnosed as having microinvasive cervical cancer. Subsequently, at the time of her scheduled robotic-assisted laparoscopic total hysterectomy, examination under anaesthesia revealed a VFF, confirmed with cystoscopy. A joint VFF repair and total abdominal hysterectomy bilateral salpigo-oophorectomy subsequently ensued with an uncomplicated postoperative course. CONCLUSION: VFF is a rare but recognized complication of LEEP, particularly in women with risk factors, such as a prior LEEP. Examination under anesthesia prior to commencing surgery facilitated recognition and appropriate management of this case.

Perspectives of Immigrant Women on the Gender of Provider During Childbirth.

OBJECTIVE: This study sought to gain an understanding of the importance and effect of provider gender for immigrant women accessing obstetrical care. METHODS: A focused ethnography was conducted using purposive sampling of 38 immigrant women from one hospital in Edmonton, Alberta. Data collection consisted of semistructured interviews conducted antenatally (n = 38); an attempt was made to conduct interviews postpartum (n = 21), and intrapartum observations were made (n = 17). Interviews were audio-recorded and transcribed verbatim. Data were managed using qualitative data analysis software and analyzed through thematic analysis. RESULTS: Study participants came from varied educational and ethnic backgrounds (predominately North/East African, Middle Eastern, and South Asian), but most were Muslim (n = 30) and married (n = 36), with a mean age of 27.7. All of the women stated that they preferred a female provider, which they explained in terms of the high value they placed on modesty, often as part of the Muslim faith. The women deemed provider competency and having safe childbirth more important, however, and said that they would accept intrapartum care from a male provider. A small minority of the women reported experiencing psychological stress as a consequence of having received care from a male provider. CONCLUSION: As a whole, our study population accepted care from male providers, yet for some women this compromise came at a price, and a small minority of women perceived it as profoundly detrimental. There is a need to identify those women for whom gender of provider is a substantial barrier, so that optimal support can be provided.

Gender of Provider-Barrier to Immigrant Women's Obstetrical Care: A Narrative Review.

OBJECTIVE: To explore the preference for female obstetrician/gynaecologists among immigrant women, and providers' understandings of these preferences, to identify challenges and potential solutions. METHODS: Five databases (Medline, Embase, CINAHL, Global Health, and Scopus) were searched using combinations of search terms related to immigrant, refugee, or Muslim women and obstetrics or gynaecological provider gender preference. STUDY SELECTION: Peer reviewed, English-language articles were included if they discussed either patient or provider perspectives of women's preference for female obstetrics or gynaecological care provider among immigrant women in Western and non-western settings. After screening, 54 met inclusion criteria and were reviewed. DATA EXTRACTION: Studies were divided first into those specifically focusing on gender of provider, and those in which it was one variable addressed. Each category was then divided into those describing immigrant women, and those conducted in a non-Western settings. The research question, study population, methods, results, and reasons given for preferences in each article were then examined and recorded. CONCLUSION: Preference for female obstetricians/gynaecologists was demonstrated. Although many will accept a male provider, psychological stress, delays, or avoidance in seeking care may result. Providers' views were captured in only eight articles, with conflicting perspectives on responding to preferences and the health system impact.

The association between body mass index and molecular subtypes in endometrial carcinoma.

Objective: This study aims to investigate the relationship between body mass index (BMI) and molecular subtypes of endometrial carcinoma using an immunohistochemistry (IHC)-based classification approach. Methods: We analyzed a consecutive series of endometrial cancer cases undergoing surgical staging in southern Alberta (2019-2021). Molecular classification was determined through IHC-based molecular typing, incorporating p53 and mismatch repair (MMR), and further characterized with the addition of ER and PR. BMI associations with molecular classification were assessed using t-tests. Hormone receptor status was further examined in a separate cohort of MMRd endometrial cancer patients undergoing surgical staging at Foothills Medical Centre (Alberta, Canada). Results: Among 289 cases, comprising various histological subtypes, the pNSMP subtype exhibited the highest average BMI (33.93 kg/m2) compared to the p53 abnormal subtype (30.40 kg/m2, p = 0.02). The MMRd subtype had an average BMI of 33.22 kg/m2. While there were no significant BMI differences between FIGO grade 1 and grade 2/3 tumours in the pNSMP or MMRd, a trend toward higher BMI in grade 1 tumours versus grade 2/3 tumours in the MMRd was observed (p = 0.13). A separate cohort of 53 MMRd endometrial carcinomas revealed that FIGO grade 1 tumours were associated with higher BMI (p < 0.05) and more frequent ER/PR expression compared to grade 2/3 tumours (p < 0.05). Conclusions: This study suggests an association between obesity and NSMP endometrial carcinoma. The relationship between BMI and low-grade MMRd endometrial carcinomas with increased ER/PR expression warrants further exploration.

Safety of vaginal surgery for early-stage cervical cancer: A retrospective multicenter cohort study.

OBJECTIVE: Abdominal Radical hysterectomy (ARH) with pelvic lymph node assessment is considered the standard treatment for early-stage cervical cancer. Accepted routes have previously included laparoscopic or robotic approaches (LRH). Laparoscopy-assisted vaginal or vaginal radical hysterectomy (LVRH) are performed in some centers. The objective of this study is to compare surgical and oncological outcomes of LVRH, to laparoscopic and abdominal approaches. DESIGN PATIENTS SETTING: A retrospective multicenter analysis of consecutive cervical cancer cases who underwent a radical hysterectomy between 2007 and 2017 in eleven regional cancer centers across Canada. MEASUREMENTS: A comparison of patients stratified by surgical technique was undertaken. T-test, Wilcoxon rank-sum and chi-square were used to compare patient characteristics. Log-rank tests and Cox proportional hazards models were employed to compare recurrence and survival across surgical groups. MAIN RESULTS: A total of 1071 patients with cervical cancer stage IA1 with lymphovascular invasion to stage IIIC (FIGO 2018) <4 cm were identified. Postoperative complication rate was lowest for women undergoing LVRH (9.1 %, vs 18.3 % and 22.1 % for minimally invasive and open respectively). During follow up, 114 women recurred, and 70 women died. 5-year recurrence-free survival was 85.4 % for LRH, 89.4 % for ARH and 92.2 % for LVRH. LVRH was not found to be associated with a higher risk of recurrence or death than ARH on multivariable analysis (aHR for recurrence 0.62, CI 0.21-1.77; aHR for death 0.63, CI 0.14-2.77) CONCLUSION: In this retrospective study, vaginal or laparoscopy-assisted vaginal radical hysterectomy for cervical cancer was associated with favorable perioperative and oncological outcomes.

Enhanced Recovery after Surgery (ERAS) for Minimally Invasive Gynecologic Oncology Surgery: A Review.

Enhanced recovery after surgery (ERAS) has established benefits in open gynecologic oncology surgery. However, the benefits for gynecologic oncology patients undergoing minimally invasive surgery (MIS) are less well defined. We conducted a review of this topic after a comprehensive search of the peer-reviewed literature using MEDLINE and PubMed databases. Our search yielded 25 articles, 14 of which were original research articles, in 10 distinct patient cohorts describing ERAS in minimally invasive gynecologic oncology surgery. Major benefits of ERAS in MIS included: decreased length of stay and increased rates of same-day discharge, cost-savings, decreased opioid use, and increased patient satisfaction. ERAS in minimally invasive gynecologic oncology surgery is an area of great promise for both patients and the healthcare system.

Oncologic Outcomes of Surgically Treated Cervical Cancer with No Residual Disease on Hysterectomy Specimen: A 4C (Canadian Cervical Cancer Collaborative) Working Group Study.

Minimally invasive surgery for the treatment of macroscopic cervical cancer leads to worse oncologic outcomes than with open surgery. Preoperative conization may mitigate the risk of surgical approach. Our objective was to describe the oncologic outcomes in cases of cervical cancer initially treated with conization, and subsequently found to have no residual cervical cancer after hysterectomy performed via open and minimally invasive approaches. This was a retrospective cohort study of surgically treated cervical cancer at 11 Canadian institutions from 2007 to 2017. Cases initially treated with cervical conization and subsequent hysterectomy, with no residual disease on hysterectomy specimen were included. They were subdivided according to minimally invasive (laparoscopic/robotic (MIS) or laparoscopically assisted vaginal/vaginal hysterectomy (LVH)), or abdominal (AH). Recurrence free survival (RFS) and overall survival (OS) were estimated using Kaplan-Meier analysis. Chi-square and log-rank tests were used to compare between cohorts. Within the total cohort, 238/1696 (14%) had no residual disease on hysterectomy specimen (122 MIS, 103 AH, and 13 VLH). The majority of cases in the cohort were FIGO 2018 stage IB1 (43.7%) and underwent a radical hysterectomy (81.9%). There was no statistical difference between stage, histology, and radical vs simple hysterectomy between the abdominal and minimally invasive groups. There were no significant differences in RFS (5-year: MIS/LVH 97.7%, AH 95.8%, p = 0.23) or OS (5-year: MIS/VLH 98.9%, AH 97.4%, p = 0.10), although event-rates were low. There were only two recurrences. In this large study including only patients with no residual cervical cancer on hysterectomy specimen, no significant differences in survival were seen by surgical approach. This may be due to the small number of events or due to no actual difference between the groups. Further studies are warranted.

Selection of endometrial carcinomas for p53 immunohistochemistry based on nuclear features.

The World Health Organization endorses molecular subclassification of endometrial endometrioid carcinomas (EECs). Our objectives were to test the sensitivity of tumor morphology in capturing p53 abnormal (p53abn) cases and to model the impact of p53abn on changes to ESGO/ESTRO/ESP (European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology) risk stratification. A total of 292 consecutive endometrial carcinoma resections received at Foothills Medical Centre, Calgary, Canada (2019-2021) were retrieved and assigned to ESGO risk groups with and without p53 status. Three pathologists reviewed the representative H&E-stained slides, predicted the p53 status, and indicated whether p53 immunohistochemistry (IHC) would be ordered. Population-based survival for endometrial carcinomas diagnosed during 2008-2016 in Alberta was obtained from the Alberta Cancer Registry. The cohort consisted mostly of grade 1/2 endometrioid carcinomas (EEC1/2; N = 218, 74.6%). One hundred and fifty-two EEC1/2 (52.1% overall) were stage IA and 147 (50.3%) were low risk by ESGO. The overall prevalence of p53abn and subclonal p53 was 14.5 and 8.3%, respectively. The average sensitivity of predicting p53abn among observers was 83.6%. Observers requested p53 IHC for 39.4% with 98.5% sensitivity to detect p53abn (99.6% negative predictive value). Nuclear features including smudged chromatin, pleomorphism, atypical mitoses, and tumor giant cells accurately predicted p53abn. In 7/292 (2.4%), p53abn upgraded ESGO risk groups (2 to intermediate risk, 5 to high risk). EEC1/2/stage IA patients had an excellent disease-specific 5-year survival of 98.5%. Pathologists can select cases for p53 testing with high sensitivity and low risk of false negativity. Molecular characterization of endometrial carcinomas has great potential to refine ESGO risk classification for a small subset but offers little value for approximately half of endometrial carcinomas, namely, EEC1/2/stage IA cases.

Preoperative weight loss in women with obesity in gynaecologic oncology: A retrospective study.

To retrospectively review the efficacy of short term supervised medical weight loss for women with obesity, body mass index (BMI ≥40 kg/m2 ) in gynaecologic oncology, and the associated perioperative and pathologic outcomes. A retrospective study of a dedicated preoperative weight loss clinic for gynaecologic oncology patients from March to December 2019. Statistical analysis was performed with McNemar's test for correlated proportions, Pearson's correlation tests for continuous variables, and paired t-tests to compare means. Generalized estimating equations (GEE) were used to determine the factors associated with weight loss over time. A P-value of <.05 was used for statistical significance. Review of cases up-graded after surgery was performed by a gynaecologic pathologist. There were a total of 49 women included in the study. The most common referral reason was endometrioid carcinoma or hyperplasia of the endometrium (77.6%). Mean initial weight was 130.2 kg, and corresponding mean BMI 48.1 kg/m2 . Patients attended on average nine preoperative weight loss visits. A significant difference between initial weight and weight at surgery was demonstrated, from 129.6 to 118.0 kg (8.4% weight loss) (P < .0001). This difference persisted to their post-surgical visit, with an additional mean loss of 1.89 kg (9.4% weight loss) (P = .044). The majority (92.1%) of patients with endometrial pathology had surgical management, and of these 85.7% were minimally invasive. Preoperative weight loss is a feasible option in gynaecologic oncology patients. Greater understanding of clinical significance, follow-up, and ideal target population for this intervention is needed.

Protracted clinical course of an AFF1 fusion positive uterine smooth muscle tumor causing diagnostic confusion over a course of 15 years.

•Histologic diagnostic criteria alone for uterine smooth muscle tumors lacks robust prognostication.•Molecular/genetic techniques should be advocated to further investigate unusual case presentations.•Novel identification of a PTP4A2-AFF1 genetic fusion was identified.•The novel PTP4A2-AFF1 genetic fusion may have further diagnostic prognostic, and therapeutic implications.

Endometrial cancer and bariatric surgery: A scoping review.

BACKGROUND: Endometrial cancer is strongly associated with obesity, and weight reduction has been demonstrated to decrease risk and overall mortality. Bariatric surgery results in the most dramatic weight loss among morbidly obese individuals, and the impact of bariatric surgery on endometrial cancer requires further investigation. OBJECTIVE: To conduct a scoping review of the published literature of the effects of bariatric surgery on endometrial cancer, as risk reduction and potential adjunct to treatment. SETTING: University Hospital, Canada. METHODS: A comprehensive search of peer-reviewed literature was conducted by an expert searcher and librarian to retrieve relevant articles discussing aspects of endometrial cancer or endometrial hyperplasia and bariatric surgery. RESULTS: After screening, 23 articles met inclusion for review. They were categorized into evidence for risk reduction of bariatric surgery on endometrial cancer, the impact of bariatric surgery on endometrial pathology, immunohistochemistry, metabolic profiles, and bariatric surgery as a potential adjunct to treatment in endometrial cancer. CONCLUSION: There is ample evidence demonstrating a risk reduction in women with obesity (body mass index >30 kg/m2) undergoing bariatric surgery for subsequent development of endometrial cancer. However, there is a paucity of data investigating its role as an adjunct for therapy. There is sufficient evidence to argue for the inclusion of endometrial hyperplasia and endometrial cancer as obesity-related conditions and the access to bariatric surgery should be broadened for affected individuals to reflect this.

Accommodating Immigrant Women's Preferences for Female Health Care Providers.

OBJECTIVE: To investigate obstetricians' perspectives of the importance, effect, and challenges of providing intrapartum care to immigrant women who request a female obstetrician. METHODS: A focused ethnography was conducted at a large teaching hospital, which serves a high proportion of immigrant clientele (predominantly North or East African, Middle Eastern, and South Asian) in Edmonton, Alberta, Canada. Data collection comprised single, semistructured interviews with a purposive sample of 20 obstetric health care providers (10 resident and 10 staff obstetricians). Interviews were audio-recorded and transcribed verbatim. Data were managed with Quirkos and analyzed using thematic analysis. RESULTS: A total of 13 female and seven male physicians were interviewed. Physicians recognized the validity of immigrant women's preference and requests for female health care providers and expressed sympathy for them. However, they were also resistant and expressed several concerns about accommodating these requests, including fear of perpetuating and exacerbating gender inequalities in medicine, the extent to which patient decision-making was coercion-free, the ability of the health system to meet the demands, and implications for training and quality of care. CONCLUSION: Although physicians were sympathetic to immigrant women's requests for female obstetricians, they placed greater value on maintaining gender equity both within the medical profession and in wider society and resisted accommodating gender-of-health-care-provider requests. Our qualitative study suggests a need for greater research to inform policy that meets the professional and personal values of both physicians and patients.