Radical hysterectomy case volume and cervical cancer treatment in the era of COVID-19: A multi-site analysis of National Cancer Institute-designated Comprehensive Cancer Centers.

OBJECTIVE: To compare radical hysterectomy case volume, cancer stage, and biopsy-to-treatment time of invasive cervical cancer diagnosed before and after onset of the COVID-19 pandemic. METHODS: In a multi-institution retrospective cohort study conducted at 6 large, geographically diverse National Cancer Institute-designated cancer centers, patients treated for newly diagnosed invasive cervical cancer were classified into 2 temporal cohorts based on date of first gynecologic oncology encounter: (1) Pre-Pandemic: 3/1/2018-2/28/2020; (2) Pandemic & Recovery: 4/1/2020-12/31/2021. The primary outcome was total monthly radical hysterectomy case volume. Secondary outcomes were stage at diagnosis and diagnosis-to-treatment time. Statistical analyses used chi-squared and two sample t-tests. RESULTS: Between 3/1/2018-12/31/2021, 561 patients were diagnosed with cervical cancer. The Pre-Pandemic and Pandemic & Recovery cohorts had similar age, race, ethnicity, smoking status, and Body Mass Index (BMI). During Pandemic & Recovery, the mean monthly radical hysterectomy case volume decreased from 7[SD 2.8] to 5[SD 2.0] (p = 0.001), the proportion of patients diagnosed with Stage I disease dropped from 278/561 (49.5%) to 155/381 (40.7%), and diagnosis of stage II-IV disease increased from 281/561 (50.1%) to 224/381 (58.8%). Primary surgical management was less frequent (38.3% Pandemic & Recovery versus 46.7% Pre-Pandemic, p = 0.013) and fewer surgically-treated patients received surgery within 6 weeks of diagnosis (27.4% versus 38.9%; p = 0.025). CONCLUSIONS: Lower radical hysterectomy case volume, a shift to higher cervical cancer stage, and delay in surgical therapy were observed across the United States following the COVID-19 outbreak. Decreased surgical volume may result from lower detection of early-stage disease or other factors.

OvaPrint-A Cell-free DNA Methylation Liquid Biopsy for the Risk Assessment of High-grade Serous Ovarian Cancer.

PURPOSE: High-grade serous ovarian carcinoma (HGSOC) is the most lethal epithelial ovarian cancer (EOC) and is often diagnosed at late stage. In women with a known pelvic mass, surgery followed by pathologic assessment is the most reliable way to diagnose EOC and there are still no effective screening tools in asymptomatic women. In the current study, we developed a cell-free DNA (cfDNA) methylation liquid biopsy for the risk assessment of early-stage HGSOC. EXPERIMENTAL DESIGN: We performed reduced representation bisulfite sequencing to identify differentially methylated regions (DMR) between HGSOC and normal ovarian and fallopian tube tissue. Next, we performed hybridization probe capture for 1,677 DMRs and constructed a classifier (OvaPrint) on an independent set of cfDNA samples to discriminate HGSOC from benign masses. We also analyzed a series of non-HGSOC EOC, including low-grade and borderline samples to assess the generalizability of OvaPrint. A total of 372 samples (tissue n = 59, plasma n = 313) were analyzed in this study. RESULTS: OvaPrint achieved a positive predictive value of 95% and a negative predictive value of 88% for discriminating HGSOC from benign masses, surpassing other commercial tests. OvaPrint was less sensitive for non-HGSOC EOC, albeit it may have potential utility for identifying low-grade and borderline tumors with higher malignant potential. CONCLUSIONS: OvaPrint is a highly sensitive and specific test that can be used for the risk assessment of HGSOC in symptomatic women. Prospective studies are warranted to validate OvaPrint for HGSOC and further develop it for non-HGSOC EOC histotypes in both symptomatic and asymptomatic women with adnexal masses.

Metastatic extent-specific prognosis of women with stage IVB cervical cancer: multiple versus single distant organ involvement.

PURPOSE: Despite the heterogeneity of anatomical sites that metastases may affect, within the current cancer staging schematic, stage IVB encompasses all distant metastasis. This study examined survival outcomes based on the extent of distant organ metastasis in stage IVB cervical cancer. METHODS: This retrospective cohort study utilized the National Cancer Institute's Surveillance, Epidemiology, and End Result Program from 2010 to 2018. The study population included 1772 women with stage IVB cervical cancer who had tumor metastasis to one or more of the following four organs: bone, brain, liver, or lung. Overall survival was assessed based on the metastatic extent in multivariable analysis. RESULTS: The most common metastatic site was lung (68.3%) followed by bone (35.2%), liver (30.0%), and brain (1.2%). Multiple organ metastases were seen in 26.5% of study population, with lung / liver metastases being the most frequent combination pattern (9.6%) followed by lung / bone (9.4%), and lung / bone / liver (6.4%). A total of 1442 (81.4%) deaths occurred during the follow-up. The cohort-level median overall survival was 7 months, ranging from 3 months in all four organ metastases to 11 months in bone metastasis alone when stratified (absolute difference 8 months, P < 0.001). Multiple organ metastases were independently associated with nearly 50% increased all-cause mortality risk compared to single organ metastasis (adjusted-hazard ratio 1.51, 95% CI 1.34-1.70). CONCLUSION: Survival outcomes in those with stage IVB cervical cancer with distant organ involvement can vary based on the extent of metastasis. Incorporation of single versus multiple distant organ metastasis into the cancer staging schema may be valuable (IVB1 versus IVB2).

Association between sentinel lymph node biopsy and micrometastasis in endometrial cancer.

OBJECTIVE: Sentinel lymph node (SLN) biopsy is increasingly utilized at surgical staging for early endometrial cancer. This study examined the association between SLN biopsy and micrometastasis in endometrial cancer. METHODS: This is a retrospective cohort study examining the National Cancer Institute's Surveillance, Epidemiology, and End Result Program. The study population was 6,414 women with T1-2 endometrial cancer who underwent primary hysterectomy and surgical nodal evaluation. Exclusion criteria included cases with isolated tumor cells. Exposure assignment was surgical nodal evaluation (SLN biopsy or lymphadenectomy). Main outcome measure was micrometastasis, assessed by inverse probability of treatment weighting propensity score in a stage-specific fashion. RESULTS: In T1a disease (n = 4,608), SLN biopsy was performed in 1,164 (25.3%) cases. SLN biopsy was associated with a 90% increased likeliness of identifying micrometastasis compared to lymphadenectomy (1.3% versus 0.7%, odds ratio 1.90, 95% confidence interval 1.02-3.55, P = 0.040). In T1b disease (n = 1,369), 270 (19.7%) cases had SLN biopsy. The incidence of micrometastasis was significantly higher in the SLN biopsy group compared to the lymphadenectomy group (8.4% versus 5.0%, odds ratio 1.74, 95% confidence interval 1.06-2.86, P = 0.028). In T2 disease (SLN biopsy in 57 [13.0%] of 437 cases), the incidence of micrometastasis was similar between the two groups (7.9% versus 7.0%, odds ratio 0.88, 95% confidence interval 0.30-2.60, P = 0.818). CONCLUSION: This study suggests that SLN biopsy protocol may identify more micrometastasis in the regional lymph nodes of T1 endometrial cancer. Whether national-level increase in the utilization of SLN biopsy for early endometrial cancer results in a stage-shifting to advanced disease on a population-basis warrants further investigation.

Side-to-end reanastomosis after low-anterior resection (STELAR): Outcomes, feasibility, and description of procedure performed by a gynecologic oncology service.

BACKGROUND AND OBJECTIVES: Low anterior rectosigmoid resection for a gynecologic disease is usually performed in concert with other procedures and can result in significant morbidity should anastomotic complication occur. This study examined surgical outcomes of side-to-end reanastomosis after low anterior resection (STELAR) performed by gynecologic oncology service. METHODS: This is a case series examining consecutive patients who underwent STELAR for gynecologic indications by a single gynecologic oncology group from 2009 to 2018. Prospectively collected institutional surgical database was searched for STELAR, and standard descriptive statistics were used to describe intraoperative and postoperative complications specific to reanastomosis. RESULTS: A total of 69 women underwent STELAR, with median age and body mass index of 54 years and 24 kg/m2 , respectively. 63.8% of patients had ovarian cancer and 84.4% had stage III-IV disease. The median estimated blood loss was 875 ml. Four (5.8%) women underwent protective loop colostomy at the time of STELAR. Postoperatively, there was 1 (1.4%) case of abscess formation within 30 days and 1 (1.4%) case of anastomotic leak 5 weeks after STELAR that required reoperation and diversion. No cases of fistula were clinically identified. CONCLUSION: Side-to-end reanastomosis may be a safe and feasible procedure to accomplish low rectosigmoid anastomosis in women with gynecologic disease.

Uptake in sentinel lymph node biopsy for endometrial cancer with T3 classification.

OBJECTIVE: The current clinical practice guidelines for endometrial cancer specify sentinel lymph node (SLN) biopsy to be performed in apparent uterine-confined disease. However, a recent population-based analysis found that the utilization of SLN biopsy is increasing in extra-uterine disease such as T2 classification. The objective of this study was to examine trends and outcomes related to SLN biopsy for endometrial cancer with T3 classification, another extra-uterine disease. METHODS: A population-based retrospective cohort study was conducted to examine 7004 women with T3 endometrial cancer who underwent primary surgery between 2010 and 2018, identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Trends and characteristics related to SLN biopsy were assessed by multinomial regression analysis, and inverse probability of treatment weighting propensity score was used to assess overall survival related to SLN biopsy. RESULTS: Nodal evaluation type included lymphadenectomy (n = 5276, 75.3%), SLN biopsy (n = 287, 4.1%), and none (n = 1441, 20.6%). The utilization of SLN biopsy increased from 0.4% to 12.9% between 2010 and 2018 (P < 0.001) that this association remained independent in multivariable analysis (adjusted-odds ratio compared to 2010-2012, 2.63 [95% confidence interval 1.57-4.42] for 2013-2015 and 10.1 [95% confidence interval 6.30-16.2] for 2016-2018). When compared to the lymphadenectomy group, the SLN biopsy group was less likely to have T3b disease (adjusted-odds ratio 0.69, 95% confidence interval 0.51-0.94) but had similar postoperative chemotherapy and radiotherapy (both, P > 0.05). In a weighted model, the 3-year overall survival rate was 66.3% for the SLN biopsy group and 64.7% for the lymphadenectomy group (hazard ratio 0.85, 95% confidence interval 0.69-1.05). Similar association was observed in subcohorts for young, old, endometrioid, non-endometrioid, T3a, T3b, and N0 cases. CONCLUSION: Utilization of SLN biopsy in T3 endometrial cancer is increasing in the United States.

Characterizing isolated tumor cells in regional lymph nodes of early endometrial cancer.

OBJECTIVE: To examine the characteristics of isolated tumor cells (ITCs) in regional lymph nodes of early-stage endometrial cancer. METHODS: This is a retrospective cohort study examining the National Cancer Institute's Surveillance, Epidemiology, and End Result Program. The study population was 6472 women with non-metastatic, node-negative T1 endometrial cancer who underwent primary hysterectomy and surgical nodal evaluation. Multivariable binary logistic regression model was used to identify the independent characteristics for ITCs. Postoperative therapy according to ITCs status was also assessed with propensity score weighting. RESULTS: ITCs were seen in 111 (1.7%) cases. In a multivariable analysis, ITCs were largely associated with tumor factors including deep myometrial invasion (T1b versus T1a, 4.0% versus 1.0%, adjusted-odds ratio [aOR] 3.42, P < 0.001) and larger tumor size (>4 versus ≤4 cm, 3.0% versus 1.6%, aOR 1.55, P = 0.037). Moreover, women undergoing sentinel lymph node (SLN) biopsy had a higher likelihood of identifying ITCs compared to those undergoing lymphadenectomy (LND): 2.7% for SLN alone, 3.7% for SLN/LND, and 1.2% for LND alone (aOR ranged 2.60-2.99, P < 0.001). Women who had ITCs identified were more likely to receive postoperative therapy (81.8% versus 31.7%, P < 0.001), including external beam radiotherapy (EBT) alone (25.1% versus 3.2%) and chemotherapy/EBT (16.3% versus 1.9%). Similar associations were observed in the low-risk group (stage IA, grade 1-2 endometrioid, 78.4% versus 9.2%, P < 0.001), including EBT alone (35.3% versus 0.6%). CONCLUSION: This study suggests that a SLN protocol can identify more ITCs in the regional lymph nodes of early endometrial cancer. Deep myometrial invasion and large tumor size were associated with increased risk of ITCs. Postoperative therapy is offered more frequently in the setting of ITCs with variable treatment patterns, warranting further outcome studies and practice guidelines.

Population-level trends and outcomes of sentinel lymph node biopsy in vulvar cancer surgery in the United States.

OBJECTIVE: To examine population-level trends, characteristics, and outcomes related to nodal assessment for vulvar cancer surgery in the United States. METHODS: This is a retrospective cohort study querying the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. The study population was 5604 women with T1b or T2-smaller(≤4 cm) squamous cell carcinoma of the vulva who underwent primary vulvectomy from 2003 to 2018. The exposure allocation was based on nodal evaluation type: lymphadenectomy (LND; n = 3319, 59.2%), sentinel lymph node (SLN) biopsy (n = 751, 13.4%), or no surgical nodal evaluation (n = 1534, 27.4%). The main outcomes were (i) trends and characteristics related to SLN biopsy assessed by multinomial regression model, and (ii) vulvar cancer-specific survival assessed by competing risk analysis and inverse probability of treatment weighting propensity score. Sensitivity analysis included evaluation of external cohort with T1a disease (n = 1291). RESULTS: The utilization of SLN biopsy increased from 5.7% to 23.3% in 2006-2018, while the proportion of LND decreased from 64.1% to 48.8% in 2010-2018, and these associations remained independent in multivariable analysis (adjusted-P < 0.05). In the propensity score weighted model, 5-year cumulative rate for vulvar cancer-specific mortality was 15.2% (interquartile range 12.1-18.9) for the SLN biopsy group and 16.9% (interquartile range 15.6-18.3) for the LND group (subdistribution-hazard ratio 0.90, 95% confidence interval 0.76-1.06, P = 0.217). The increasing SLN biopsy use was also observed in T1a disease from 1.3% to 7.3% during the study period (P < 0.001). CONCLUSION: The landscape of surgical nodal evaluation is shifting from lymphadenectomy to SLN biopsy in vulvar cancer surgery in the United States. SLN biopsy-incorporated treatment approach was not associated with worse survival compared to LND.

Sentinel lymph node biopsy for stage II endometrial cancer: Recent utilization and outcome in the United States.

OBJECTIVE: To examine trends and outcomes related to sentinel lymph node (SLN) biopsy for stage II endometrial cancer. METHODS: This is a retrospective observational cohort study querying the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. The study population was 6,314 women with T2 endometrial cancer who underwent hysterectomy from 2010-2018. Exposure allocation was based on nodal evaluation type: lymphadenectomy (LND; n=4,915, 77.8%), SLN biopsy (n=340, 5.4%), or no surgical nodal evaluation (n=1,059, 16.8%). The main outcomes were (i) trends and characteristics related to nodal evaluation assessed by multinomial regression, and (ii) overall survival (OS) assessed by an inverse probability of treatment weighting propensity score analysis. A sensitivity analysis was performed to examine concurrent LND in women who underwent SLN biopsy. RESULTS: The utilization of SLN biopsy increased from 1.6% to 16.1%, while the number of LND decreased from 81.5% to 65.7% between 2010-2018 (P<0.05). In multivariable analysis, the utilization of SLN biopsy increased 45% annually (adjusted-odds ratio 1.45, 95% confidence interval [CI] 1.37-1.54, P<0.001). The frequency of SLN biopsy alone exceeded the frequency of SLN biopsy with concurrent LND in 2017 (6.8% versus 3.4%), followed by continued increase in SLN biopsy alone (11.2% versus 4.9%) in 2018. In the weighted model, the 3-year OS rate was 79.9% for the SLN biopsy group and 78.6% for the LND group (hazard ratio 0.98, 95%Cl 0.80-1.20, P=0.831). Similarly, the SLN biopsy alone without concurrent LND had comparable OS compared to the LND group (hazard ratio 0.90, 95%CI 0.59-1.36, P=0.615). CONCLUSION: Utilization of SLN biopsy in stage II endometrial cancer increased significantly over time, and SLN biopsy-incorporated nodal assessment was not associated with worsened short-term survival outcome.

Rhabdomyolysis following single administration of pembrolizumab: Is severe immune-reaction a marker for durable treatment response?

•Immune checkpoint inhibitors are approved for all mismatch repair deficient tumors.•Although rare, autoimmune myositis complicating pembrolizumab therapy may be fatal.•In this case, pembrolizumab caused rhabdomyolysis but also a durable response.•Severe autoimmune reaction may be associated with durable treatment response.

Populational trends and outcomes of postoperative radiotherapy for high-risk early-stage cervical cancer with lymph node metastasis: concurrent chemo-radiotherapy versus radiotherapy alone.

BACKGROUND: Pelvic lymph node metastasis carries the highest impact on decreased survival among surgical-pathological risk factors for early-stage cervical cancer. Although concurrent administration of chemotherapy during postoperative radiotherapy is the current standard treatment for surgically treated high-risk early-stage cervical cancer, its effectiveness specific to node-positive disease has not been completely studied. OBJECTIVE: To examine the association between the use of concurrent chemotherapy and survival in women with early-stage cervical cancer and nodal metastasis receiving adjuvant radiotherapy. MATERIALS AND METHODS: This is a population-based cohort study using the Surveillance, Epidemiology, and End Results Program from 1988 to 2016. Women with stage T1-2 cervical cancer with pelvic lymph node metastasis who underwent hysterectomy and received postoperative radiotherapy were examined. Trends, characteristics, and overall survival were compared between women who received postoperative radiotherapy alone (n = 729) or in combination with concurrent chemo-radiotherapy (n = 1809). Propensity score-based inverse probability of treatment weighting was used to account for the effect of measured covariates on treatment selection. RESULTS: Among 2538 women, there was a marked increase in the use of concurrent chemotherapy from 1997 to 2000 (20.7% to 78.5%, P = .052), followed by a more gradual rise through 2016 (88.3%, P < .001). In a multivariable model, women with non-squamous cell carcinomas and those diagnosed more recently were more likely to receive concurrent chemo-radiotherapy, whereas older women were less likely to receive concurrent chemo-radiotherapy (all, P < .05). At the population level, the 5-year overall survival rates remained unchanged (annual percent change for 1997-2012: -0.1; 95% confidence interval, -1.2 to 1.0; P = .776). In a propensity score weighted cohort, women who received concurrent chemo-radiotherapy had a 5-year overall survival rate similar to women treated with radiotherapy alone (73.1% vs 73.6%; hazard ratio, 1.004; 95% confidence interval, 0.887-1.136; P = .955). Significant differences were also not seen in older women, nonsquamous types, stage T2 disease, and multiple node metastases (all, P > .05). CONCLUSION: Despite the marked increase in the use of concurrent chemo-radiotherapy for women with early-stage cervical cancer and nodal metastases, there was no association between use of concurrent chemotherapy during postoperative radiotherapy and improved survival.

Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension.

BACKGROUND & AIMS: Hepatic stellate cells (HSCs) are vital to hepatocellular function and the liver response to injury. They share a phenotypic homology with astrocytes that are central in the pathogenesis of hepatic encephalopathy, a condition in which hyperammonemia plays a pathogenic role. This study tested the hypothesis that ammonia modulates human HSC activation in vitro and in vivo, and evaluated whether ammonia lowering, by using l-ornithine phenylacetate (OP), modifies HSC activation in vivo and reduces portal pressure in a bile duct ligation (BDL) model. METHODS: Primary human HSCs were isolated and cultured. Proliferation (BrdU), metabolic activity (MTS), morphology (transmission electron, light and immunofluorescence microscopy), HSC activation markers, ability to contract, changes in oxidative status (ROS) and endoplasmic reticulum (ER) were evaluated to identify effects of ammonia challenge (50 µM, 100 µM, 300 µM) over 24-72 h. Changes in plasma ammonia levels, markers of HSC activation, portal pressure and hepatic eNOS activity were quantified in hyperammonemic BDL animals, and after OP treatment. RESULTS: Pathophysiological ammonia concentrations caused significant and reversible changes in cell proliferation, metabolic activity and activation markers of hHSC in vitro. Ammonia also induced significant alterations in cellular morphology, characterised by cytoplasmic vacuolisation, ER enlargement, ROS production, hHSC contraction and changes in pro-inflammatory gene expression together with HSC-related activation markers such as α-SMA, myosin IIa, IIb, and PDGF-Rß. Treatment with OP significantly reduced plasma ammonia (BDL 199.1 µmol/L±43.65 vs. BDL+OP 149.27 µmol/L±51.1, p<0.05) and portal pressure (BDL 14±0.6 vs. BDL+OP 11±0.3 mmHg, p<0.01), which was associated with increased eNOS activity and abrogation of HSC activation markers. CONCLUSIONS: The results show for the first time that ammonia produces deleterious morphological and functional effects on HSCs in vitro. Targeting ammonia with the ammonia lowering drug OP reduces portal pressure and deactivates hHSC in vivo, highlighting the opportunity for evaluating ammonia lowering as a potential therapy in cirrhotic patients with portal hypertension.

Pharmacotherapy for hyperammonemia.

INTRODUCTION: Hepatic encephalopathy (HE) is a serious neuropsychiatric complication that is seen in patients with liver failure. The pathogenesis of HE is not entirely understood, but several hypotheses have emerged and persisted during the years. Despite the many prevalent hypotheses, most of the existing evidence point to ammonia as the main culprit behind primary and secondary symptoms making it the center of potential therapeutic options for the treatment of HE. Most treatments of hyperammonemia target the organs and metabolic processes involved in ammonia detoxification. AREAS COVERED: This article provides a review of the current targets of therapy as well as the drugs used for hyperammonemia treatment. EXPERT OPINION: Lactulose and rifaximin have a proven role as measures to use for secondary prophylaxis and are the mainstay of current therapy. The use of molecular adsorbent recirculating system in patients with severe HE has been proven to be efficacious, but through mechanisms that appear to be independent of ammonia. The main challenge that faces the further development of treatments for HE is finding appropriate end points, and the next step would be to provide evidence of the effectiveness of established treatments and define the role of emerging new treatments.

Treatment of hyperammonemia in liver failure.

PURPOSE OF REVIEW: Hyperammonemia is thought to be central in the pathophysiology of hepatic encephalopathy in patients suffering from liver failure. The purpose of this article is to explore existing treatment options that help lower ammonia levels in patients and alleviate symptoms of hepatic encephalopathy. RECENT FINDINGS: There are two ways to approach modulating ammonia levels and its effect on the brain. The first targets ammonia levels itself and the second targets inflammation, which makes the brain susceptible to the deleterious effect of ammonia. Recent studies provide new evidence for the use of lactulose, probiotics and rifaximin, as well as closure of large portosystemic shunts in the treatment of hepatic encephalopathy. SUMMARY: Over the past 20 years or so, many new approaches to treat hepatic encephalopathy have been developed based upon better understanding of interorgan ammonia metabolism. Reduction in ammonia can be achieved by targeting its production, absorption or elimination. This review will primarily focus on these strategies that reduce ammonia levels in liver failure patients.