Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies.

BACKGROUND: Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4-1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4-1BB agonist), PF-04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies. METHODS: The primary end point in this six-arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune-related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression-free survival, and overall survival. RESULTS: Forty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A-C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1-7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression-free survival was 2.1 months (95% CI, 1.8-3.5 months), and overall survival was 9.4 months (95% CI, 5.6-11.9 months). No dose-limiting toxicities or grade 3-5 immune-related adverse events were observed. CONCLUSIONS: The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted.

Randomized phase 2 trial of tremelimumab and durvalumab in combination versus sequentially in recurrent platinum-resistant ovarian cancer.

BACKGROUND: Single-agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%-40% of patients achieve stable disease. The primary objective was to estimate progression-free survival (PFS) after sequential versus combination cytotoxic T-lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum-resistant high-grade serous ovarian cancer (HGSOC). METHODS: Patients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end point was immune-related PFS (irPFS). RESULTS: Sixty-one subjects were randomized to sequential (n = 38) or combination therapy (n = 23). Thirteen patients (34.2%) in the sequential arm received durvalumab. There was no difference in PFS in the sequential arm (1.84 months; 95% CI, 1.77-2.17 months) compared with the combination arm (1.87 months; 95% CI, 1.77-2.43 months) (p = .402). In the sequential arm, no responses were observed, although 12 patients (31.6%) demonstrated stable disease. In the combination arm, two patients (8.7%) had partial response, whereas one patient (4.4%) had stable disease. Adverse events were consistent with those previously reported for ICIs. Patient-reported outcomes were similar in both arms. CONCLUSIONS: There was no difference in irPFS for combination tremelimumab plus durvalumab compared to tremelimumab alone (administered as part of a sequential treatment strategy) in a heavily pretreated population of patients with platinum-resistant HGSOC. Response rates were comparable to prior reports, although the combination regimen did not add significant benefit, as has been previously described.

Efficacy, safety, and feasibility of Apixaban for postoperative venous thromboembolism prophylaxis following open gynecologic cancer surgery at a comprehensive cancer center.

OBJECTIVES: To evaluate safety, efficacy, and feasibility of apixaban for postoperative venous thromboembolism (VTE) prophylaxis following open gynecologic cancer surgery at a comprehensive cancer center. METHODS: This retrospective, cohort study included patients with gynecologic cancer who underwent open surgery between 3/2021 and 3/2023 and received 28-day postoperative VTE prophylaxis. Patients on therapeutic anticoagulation preoperatively were excluded. Predictors of 90- and 30-day VTE and 30-day bleeding events were determined using multivariable logistic regression, adjusting for known confounders. RESULTS: 452 patients were included in the cohort: 348 received apixaban and 104 received enoxaparin. Those who received enoxaparin were more likely to be American Society of Anesthesiologists class III/IV (compared to I/II) (p = 0.033), current or former smokers (p = 0.012) and have a higher BMI (p < 0.001), Charlson Comorbidity Index (p = 0.005), and age (p = 0.046). 30-day VTE rate was significantly lower in the apixaban group (0.6%) compared to the enoxaparin group (6.2%) (adjusted OR 0.13, 95% CI 0.03-0.56; p = 0.006). 90-day VTE rate was 2.7% and 6.2% in the apixaban and enoxaparin groups, respectively (adjusted OR 0.85, 95% CI 0.38-1.92; p = 0.704). Major bleeding complications (2.4% vs. 2.0%) and minor bleeding complications (0.9% vs. 3.0%) were similar in the apixaban and enoxaparin groups, respectively, on multivariate analyses. The median patient out of pocket cost was $10 (IQR 0.0-40.0) for apixaban and $20 (IQR 3.7-67.7) for enoxaparin (p = 0.001). CONCLUSIONS: Our findings along with previously published data suggest that apixaban should be considered the standard of care for VTE prophylaxis in patients undergoing open surgery for gynecologic malignancies.

Metronidazole and cefazolin vs cefazolin alone for surgical site infection prophylaxis in gynecologic surgery at a comprehensive cancer center.

BACKGROUND: Surgical site infection is one of the most common complications of gynecologic cancer surgery. Current guidelines recommend the administration of cefazolin preoperatively to reduce surgical site infection rates for patients undergoing clean-contaminated surgeries such as hysterectomy. OBJECTIVE: To evaluate the impact of a quality improvement project adding metronidazole to cefazolin for antibiotic prophylaxis on surgical site infection rate for women undergoing gynecologic surgery at a comprehensive cancer center. STUDY DESIGN: This retrospective, single-center cohort study included patients who underwent surgery in the gynecologic oncology department from May 2017 to June 2023. Patients with penicillin allergies and those undergoing concomitant bowel resections and/or joint cases were excluded. The preintervention group patients had surgery from May 2017 to April 2022, and the postintervention group patients had surgery from April 2022 to June 2023. The primary outcome was a 30-day surgical site infection rate. Sensitivity analyses were performed to compare surgical site infection rates on the basis of actual antibiotics received and for those who had a hysterectomy. Factors independently associated with surgical site infection were identified using a multivariable logistic regression model adjusting for confounding variables. RESULTS: Of 3343 patients, 2572 (76.9%) and 771 (23.1%) were in the pre-post intervention groups, respectively. Most patients (74.7%) had a hysterectomy performed. Thirty-four percent of cases were for nononcologic (benign) indications. Preintervention patients were more likely to receive appropriate preoperative antibiotics (95.6% vs 90.7%; P<.001). The overall surgical site infection rate before the intervention was 4.7% compared with 2.6% after (P=.010). The surgical site infection rate for all patients who underwent hysterectomy was 4.9% (preintervention) vs 2.8% (postintervention) (P=.036); a similar trend was seen for benign cases (4.4% vs 2.4%; P=.159). On multivariable analysis, the odds ratio for surgical site infection was 0.49 (95% confidence interval, 0.38-0.63) for the postintervention compared with the preintervention group (P<.001). In a sensitivity analysis (n=3087), the surgical site infection rate was 4.5% for those who received cefazolin alone compared with 2.3% for those who received cefazolin plus metronidazole, with significantly decreased odds of surgical site infection for the cefazolin plus metronidazole group (adjusted odds ratio, 0.40 [95% confidence interval, 0.30-0.53]; P<.001). Among only those who had a hysterectomy performed, the odds of surgical site infection were significantly reduced for those in the postintervention group (adjusted odds ratio, 0.63 [95% confidence interval, 0.47-0.86]; P=.003). CONCLUSION: The addition of metronidazole to cefazolin before gynecologic surgery decreased the surgical site infection rate by half, even after accounting for other known predictors of surgical site infection and differences in practice patterns over time. Providers should consider this combination regimen in women undergoing gynecologic surgery, especially for cases involving hysterectomy.

COVID-19 outcomes of patients with gynecologic cancer in New York City: An updated analysis from the initial surge of the pandemic.

BACKGROUND: Despite significant increase in COVID-19 publications, characterization of COVID-19 infection in patients with gynecologic cancer remains limited. Here we present an update of COVID-19 outcomes among people with gynecologic cancer in New York City (NYC) during the initial surge of severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]). METHODS: Data were abstracted from gynecologic oncology patients with COVID-19 infection among 8 NYC area hospital systems between March and June 2020. Multivariable logistic regression was utilized to estimate associations between factors and COVID-19 related hospitalization and mortality. RESULTS: Of 193 patients with gynecologic cancer and COVID-19, the median age at diagnosis was 65.0 years (interquartile range (IQR), 53.0-73.0 years). One hundred six of the 193 patients (54.9%) required hospitalization; among the hospitalized patients, 13 (12.3%) required invasive mechanical ventilation, 39 (36.8%) required ICU admission. Half of the cohort (49.2%) had not received anti-cancer treatment prior to COVID-19 diagnosis. No patients requiring mechanical ventilation survived. Thirty-four of 193 (17.6%) patients died of COVID-19 complications. In multivariable analysis, hospitalization was associated with an age ≥ 65 years (odds ratio [OR] 2.12, 95% confidence interval [CI] 1.11, 4.07), Black race (OR 2.53, CI 1.24, 5.32), performance status ≥2 (OR 3.67, CI 1.25, 13.55) and ≥ 3 comorbidities (OR 2.00, CI 1.05, 3.84). Only former or current history of smoking (OR 2.75, CI 1.21, 6.22) was associated with death due to COVID-19 in multivariable analysis. Administration of cytotoxic chemotherapy within 90 days of COVID-19 diagnosis was not predictive of COVID-19 hospitalization (OR 0.83, CI 0.41, 1.68) or mortality (OR 1.56, CI 0.67, 3.53). CONCLUSIONS: The case fatality rate among patients with gynecologic malignancy with COVID-19 infection was 17.6%. Cancer-directed therapy was not associated with an increased risk of mortality related to COVID-19 infection.

Racial disparities in patients with coronavirus disease 2019 infection and gynecologic malignancy.

BACKGROUND: Mounting evidence suggests disproportionate coronavirus disease 2019 (COVID-19) hospitalizations and deaths because of racial disparities. The association of race in a cohort of gynecologic oncology patients with severe acute respiratory syndrome-coronavirus 2 infection is unknown. METHODS: Data were abstracted from gynecologic oncology patients with COVID-19 infection among 8 New York City area hospital systems. A multivariable mixed-effects logistic regression model accounting for county clustering was used to analyze COVID-19-related hospitalization and mortality. RESULTS: Of 193 patients who had gynecologic cancer and COVID-19, 67 (34.7%) were Black, and 126 (65.3%) were non-Black. Black patients were more likely to require hospitalization compared with non-Black patients (71.6% [48 of 67] vs 46.0% [58 of 126]; P = .001). Of 34 (17.6%) patients who died from COVID-19, 14 (41.2%) were Black. Among those who were hospitalized, compared with non-Black patients, Black patients were more likely to: have ≥3 comorbidities (81.1% [30 of 37] vs 59.2% [29 of 49]; P = .05), to reside in Brooklyn (81.0% [17 of 21] vs 44.4% [12 of 27]; P = .02), to live with family (69.4% [25 of 36] vs 41.6% [37 of 89]; P = .009), and to have public insurance (79.6% [39 of 49] vs 53.4% [39 of 73]; P = .006). In multivariable analysis, among patients aged <65 years, Black patients were more likely to require hospitalization compared with non-Black patients (odds ratio, 4.87; 95% CI, 1.82-12.99; P = .002). CONCLUSIONS: Although Black patients represented only one-third of patients with gynecologic cancer, they accounted for disproportionate rates of hospitalization (>45%) and death (>40%) because of COVID-19 infection; younger Black patients had a nearly 5-fold greater risk of hospitalization. Efforts to understand and improve these disparities in COVID-19 outcomes among Black patients are critical.

Perioperative Morbidity and Mortality of Patients With COVID-19 Who Undergo Urgent and Emergent Surgical Procedures.

OBJECTIVE: To evaluate the perioperative morbidity and mortality of patients with COVID-19 who undergo urgent and emergent surgery. SUMMARY BACKGROUND DATA: Although COVID-19 infection is usually associated with mild disease, it can lead to severe respiratory complications. Little is known about the perioperative outcomes of patients with COVID-19. METHODS: We examined patients who underwent urgent and emergent surgery at 2 hospitals in New York City from March 17 to April 15, 2020. Elective surgical procedures were cancelled throughout and routine, laboratory based COVID-19 screening was instituted on April 1. Mortality, complications, and admission to the intensive care unit were compared between patients with COVID-19 detected perioperatively and controls. RESULTS: Among 468 subjects, 36 (7.7%) had confirmed COVID-19. Among those with COVID-19, 55.6% were detected preoperatively and 44.4% postoperatively. Before the routine preoperative COVID-19 laboratory screening, 7.7% of cases were diagnosed preoperatively compared to 65.2% after institution of screening (P = 0.0008). The perioperative mortality rate was 16.7% in those with COVID-19 compared to 1.4% in COVID-19 negative subjects [aRR = 9.29; 95% confidence interval (CI), 5.68-15.21]. Serious complications were identified in 58.3% of COVID-19 subjects versus 6.0% of controls (aRR = 7.02; 95%CI, 4.96-9.92). Cardiac arrest, sepsis/shock, respiratory failure, pneumonia, acute respiratory distress syndrome, and acute kidney injury were more common in those with COVID-19. The intensive care unit admission rate was 36.1% in those with COVID-19 compared to 16.4% of controls (aRR = 1.34; 95%CI, 0.86-2.09). CONCLUSIONS: COVID-19 is associated with an increased risk for serious perioperative morbidity and mortality. A substantial number of patients with COVID-19 are not identified until after surgery.

The Role of Minimally Invasive Surgery in the Care of Women with Ovarian Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: To synthesize evidence from studies investigating survival outcomes for patients with ovarian cancer undergoing minimally invasive surgery (traditional or robotic laparoscopy) compared with those for patients with ovarian cancer undergoing laparotomy. DATA SOURCES: We searched Ovid MEDLINE and Embase (from inception to December 2019). METHODS OF STUDY SELECTION: Observational cohort studies and randomized controlled trials that compared risk of recurrence or death between women undergoing minimally invasive and open procedures for staging (10), interval cytoreduction (4), secondary cytoreduction (2), and evaluation of resectability (1) were included. TABULATION, INTEGRATION, AND RESULTS: Data on the number of participants, number of deaths and recurrences, and results of analyses of overall or progression-free survival were abstracted for all studies. A random-effects meta-analysis was used to pool the results of studies comparing minimally invasive staging and open staging. The surgical approach (minimally invasive versus open) was not significantly associated with hazard of death or recurrence (pooled hazard ratio 0.92; 95% confidence interval, 0.61-1.38) or all-cause mortality (pooled hazard ratio 0.96; 95% confidence interval, 0.49-1.89). One randomized trial demonstrated that diagnostic laparoscopy could triage patients to neoadjuvant chemotherapy and avoid suboptimal primary surgery, without affecting recurrence-free or overall survival. Most studies included in this review were observational and at high risk for bias, and few studies accounted for potential confounding. CONCLUSION: Although existing studies do not demonstrate deleterious survival effects associated with minimally invasive surgery for ovarian cancer, these data must be viewed with caution given the significant methodologic shortcomings in the existing literature.

COVID-19 outcomes of patients with gynecologic cancer in New York City.

BACKGROUND: New York City (NYC) is the epicenter of severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) in the United States. Clinical characteristics and outcomes of vulnerable populations, such as those with gynecologic cancer who develop COVID-19 infections, is limited. METHODS: Patients from 6 NYC-area hospital systems with known gynecologic cancer and a COVID-19 diagnosis were identified. Demographic and clinical outcome data were abstracted through a review of electronic medical records. RESULTS: Records for 121 patients with gynecologic cancer and COVID-19 were abstracted; the median age at the COVID-19 diagnosis was 64.0 years (interquartile range, 51.0-73.0 years). Sixty-six of the 121 patients (54.5%) required hospitalization; among the hospitalized patients, 45 (68.2%) required respiratory intervention, 20 (30.3%) were admitted to the intensive care unit, and 9 (13.6%) underwent invasive mechanical ventilation. Seventeen patients (14.0%) died of COVID-19 complications. No patient requiring mechanical ventilation survived. On multivariable analysis, hospitalization was associated with an age ≥64 years (risk ratio [RR], 1.73; 95% confidence interval [CI], 1.18-2.51), African American race (RR, 1.56; 95% CI, 1.13-2.15), and 3 or more comorbidities (RR, 1.43; 95% CI, 1.03-1.98). Only recent immunotherapy use (RR, 3.49; 95% CI, 1.08-11.27) was associated with death due to COVID-19 on multivariable analysis; chemotherapy treatment and recent major surgery were not predictive of COVID-19 severity or mortality. CONCLUSIONS: The case fatality rate among gynecologic oncology patients with a COVID-19 infection is 14.0%. Recent immunotherapy use is associated with an increased risk of mortality related to COVID-19 infection. LAY SUMMARY: The case fatality rate among gynecologic oncology patients with a coronavirus disease 2019 (COVID-19) infection is 14.0%; there is no association between cytotoxic chemotherapy and cancer-directed surgery and COVID-19 severity or death. As such, patients can be counseled regarding the safety of continued anticancer treatments during the pandemic. This is important because the ability to continue cancer therapies for cancer control and cure is critical.

Coronavirus Spectrum Infections (COVID-19, MERS, SARS) in Cancer Patients: A Systematic Review of the Literature.

BACKGROUND: Coronavirus 2019 (COVID-19) has spread rapidly around the world to become a global pandemic. There is limited data on the impact of COVID-19 among patients with cancer. METHODS: A systematic review was performed to determine outcomes of adult patients with cancer affected by coronavirus infections, specifically SARS, MERS, and COVID-19. Studies were independently screened by two reviewers and assessed for quality and bias. Outcomes measured included study characteristics, cancer type, phase of care at the time of diagnosis, and clinical presentation. Morbidity and mortality outcomes were analyzed to assess the severity of infection as compared to the general population. RESULTS: A total of 19 studies with 110 patients were included. Of these, 66.4% had COVID-19 infections, 32.7% MERS and only one patient with SARS. The majority of COVID-19 studies were based on studies in China. There was a 56.6% rate of a severe event, including ICU admission or requiring mechanical ventilation, with an overall 44.5% fatality rate. CONCLUSIONS: Patients with cancer with coronavirus infections may be more susceptible to higher morbidity and mortality.

Travel distance, hospital volume and their association with ovarian cancer short- and long-term outcomes.

OBJECTIVE: To examine patterns of patient travel among women with ovarian cancer and to explore the association between travel distance and short and long-term outcomes. METHODS: Women with stage II-IV epithelial ovarian cancer diagnosed from 2004 to 2016 who underwent primary surgery were identified in the National Cancer Database. Mixed-effect log-linear models and proportional hazards models were developed to evaluate the association between travel distance and short and long-term outcomes after propensity score weighting. A further analysis was performed to compare patients who traveled a short distance to a low volume center (Local) to patients who traveled farther to a high volume hospital (Travel). RESULTS: We identified 56,834 patients treated in 1201 hospitals. Hispanic women were 58% and black women 64% less likely than white women to travel to a center in the greatest distance quartile for care. Similarly, Medicaid recipients (vs. commercially insured) were less likely to travel to a quartile four hospital (compared to Q1 of distance traveled). Of all patients, 90-day mortality was significantly lower in patients who traveled farther (Q4 vs. Q1; P < 0.0001). Compared to women in the Local group, patients in the Travel group had a decreased 30-day readmission rate. There was no difference in 30-day, 90-day, or 5-year mortality when comparing the Local to the Travel group. CONCLUSIONS: Travel distance for ovarian cancer surgery has increased over time. While there may be some short-term benefits in traveling to a regional center for care, there was little difference in long term outcomes based on travel distance.

Inflammatory markers in gynecologic oncology patients hospitalized with COVID-19 infection.

OBJECTIVE: Elevated inflammatory markers are predictive of COVID-19 infection severity and mortality. It is unclear if these markers are associated with severe infection in patients with cancer due to underlying tumor related inflammation. We sought to further understand the inflammatory response related to COVID-19 infection in patients with gynecologic cancer. METHODS: Patients with a history of gynecologic cancer hospitalized for COVID-19 infection with available laboratory data were identified. Admission laboratory values and clinical outcomes were abstracted from electronic medical records. Severe infection was defined as infection requiring ICU admission, mechanical ventilation, or resulting in death. RESULTS: 86 patients with gynecologic cancer were hospitalized with COVID-19 infection with a median age of 68.5 years (interquartile range (IQR), 59.0-74.8). Of the 86 patients, 29 (33.7%) patients required ICU admission and 25 (29.1%) patients died of COVID-19 complications. Fifty (58.1%) patients had active cancer and 36 (41.9%) were in remission. Patients with severe infection had significantly higher ferritin (median 1163.0 vs 624.0 ng/mL, p < 0.01), procalcitonin (median 0.8 vs 0.2 ng/mL, p < 0.01), and C-reactive protein (median 142.0 vs 62.3 mg/L, p = 0.02) levels compared to those with moderate infection. White blood cell count, lactate, and creatinine were also associated with severe infection. D-dimer levels were not significantly associated with severe infection (p = 0.20). CONCLUSIONS: The inflammatory markers ferritin, procalcitonin, and CRP were associated with COVID-19 severity in gynecologic cancer patients and may be used as prognostic markers at the time of admission.

Effect of regionalization of endometrial cancer care on site of care and patient travel.

BACKGROUND: Complex oncologic surgeries, including those for endometrial cancer, increasingly have been concentrated to greater-volume centers, owing to previous research that has demonstrated associations between greater surgical volume and improved outcomes. There is a potential for concentration of care to have unwanted consequences, including cost burden, delayed treatment, patient dissatisfaction, and possibly worse clinical outcomes, especially for more vulnerable populations. OBJECTIVE: To describe changes in site of care for patients with endometrial cancer in New York State and to determine whether the distance women traveled for hysterectomy has changed over time. STUDY DESIGN: We used the New York Statewide Planning and Research Cooperative System to identify women with endometrial cancer who underwent hysterectomy from 2000 to 2014. Demographic and clinical data as well as hospital data were collected. Trends in travel distance (straight-line distance) were analyzed within all hospital referral regions and differences in travel distance over times and across sociodemographic characteristics analyzed. RESULTS: We identified 41,179 subjects. The number of hospitals and surgeons performing hysterectomy decreased across all hospital referral regions over time. The decline in the number of hospitals caring for women with endometrial cancer ranged from -16.7% in Syracuse (12 to 10 hospitals) to -76.5% in Rochester (17 to 4 hospitals). Similarly, the percentage of surgeons within a given hospital referral region operating on women declined from -45.2% in Buffalo (84-46 surgeons) to -77.8% in Albany (72 to 16 surgeons). The median distance to the index hospital for patients increased in all Hospital Referral Regions. For residents in Binghamton, median travel distance increased by 46.9 miles (95% confidence interval, 33.8-60.0) whereas distance increased in Elmira by 19.7 miles (95% confidence interval, 7.3-32.1) and by 12.4 miles (95% confidence interval, 6.4-18.4) in Albany. For residents of Binghamton and Albany, there was a greater than 100% increase in distance traveled over the 15-year time period, with increases of 551.8% (46.9 miles; 95% confidence interval, 33.8-60.0 miles) and 102.5% (12.4 miles; 95% confidence interval, 6.4-18.4 miles), respectively. Travel distance increased for all races and regardless of insurance status but was greatest for white patients and those with private insurance (P<.0001 for both). CONCLUSION: The number of surgeons and hospitals caring for women with endometrial cancer in New York State has decreased, whereas the distance that patients travel to receive care has increased over time.

Diabetes Mellitus and Metformin Are Not Associated With Breast Cancer Pathologic Complete Response.

BACKGROUND: Metformin use has been linked to pathologic complete response (pCR) following neoadjuvant chemotherapy for several malignancies. We aimed to investigate the association of diabetes mellitus (DM) and metformin use with pCR in breast cancer. MATERIALS AND METHODS: All breast cancer patients who received neoadjuvant chemotherapy during June 2013-October 2016 at two academic medical centers were identified. A retrospective cohort study evaluated patients who did and did not achieve pCR. Multivariable logistic regression identified independent predictors of pCR, specifically looking at metformin use and DM. RESULTS: The study group included 351 breast cancer patients, with 90 (25.6%) achieving pCR after neoadjuvant chemotherapy. The rate of DM did not differ between those with and without pCR, nor did the rate of metformin use. Multivariable logistic regression identified HER2-positive tumors and smaller preoperative tumor size as predictors of pCR. The estrogen receptor (ER) positivity was associated with an absence of pCR. Importantly, neither DM nor metformin use was predictive of pCR. CONCLUSIONS: This study by the two institutions supports previous data of tumor-related factors known to be associated with pCR; however, the current analysis found neither DM nor metformin to be independently associated with pCR. Thus, additional prospective study is warranted prior to validating metformin as an antitumor agent.

The impact of bariatric surgery on qualitative and quantitative breast density.

BACKGROUND: Obesity and breast density are associated with breast cancer in postmenopausal women. Bariatric surgery effectively treats morbid obesity, with sustainable weight loss and reductions in cancer incidence. We evaluated changes in qualitative and quantitative density; hypothesizing breast density would increase following bariatric surgery. METHODS: Women undergoing bariatric surgery from 1990 to 2015 were identified, excluding patients without a mammogram performed both before and after surgery. Changes in body mass index (BMI), time between mammograms and surgery, and American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) scores were assessed. VolparaDensity™ automated software calculated volumetric breast density (VBD), fibroglandular volume (FGV), and total breast volume for the 82 women with digital data available. Differences between pre- and postsurgery values were assessed. RESULTS: One hundred eighty women were included. Median age at surgery was 50.0 years, with 8.8 months between presurgery mammogram and surgery and 62.3 months between surgery and postsurgery mammogram. Median BMI significantly decreased over the study period (46.0 vs 35.4 kg/m2 ; P < 0.001). No change in BI-RADS scores was seen between the pre- and postsurgery mammograms. Eighty-two women had VolparaDensity™ data available. While VBD increased in these patients, FGV and total breast volume both decreased following bariatric surgery. CONCLUSIONS: Increased VBD, decreased FGV, and decreased total breast volume were seen following bariatric surgery-induced weight loss. There was no difference in qualitative breast density, highlighting the discrepancy between BI-RADS and VolparaDensity™ measurements. Further investigation will be required to determine how differential changes in components of breast density may affect breast cancer risk.

Retrospective case-control non-inferiority analysis of intravenous lidocaine in a colorectal surgery enhanced recovery program.

BACKGROUND: Enhanced recovery after surgery (ERAS) programs typically utilizes multi-modal analgesia to reduce perioperative opioid consumption. Systemic lidocaine is used in several of these ERAS algorithms and has been shown to reduce opioid use after colorectal surgery. However it is unclear how much the other components of an ERAS protocol contribute to the final outcome. Using a noninferiority analysis we sought to assess the role of perioperative lidocaine in an ERAS program for colorectal surgery, using pain and opioid consumption as outcomes. METHODS: We conducted a retrospective review of patients who had received intravenous lidocaine perioperatively during colorectal surgery. We matched them with patients who were managed using a multi-component ERAS protocol, which included perioperative lidocaine. We tested a joint hypothesis of noninferiority of lidocaine infusion to ERAS protocol in postoperative pain scores and opioid consumption. We assigned a noninferiority margin of 1 point (on an 11-point numerical rating scale) difference in pain and a ratio [mean (lidocaine) / mean (ERAS)] of 1.2 in opioid consumption, respectively. RESULTS: Fifty-two patients in the lidocaine group were matched with patients in the ERAS group. With regards to opioid consumption, in the overall [1.68 (1.43-1.98)] [odds ratio (95% confidence interval)] analysis and on postoperative day (POD) 1 [2.38 (1.74-3.31)] lidocaine alone was inferior to multi-modal analgesia. On POD 2 and beyond, although the mean odds ratio for opioid consumption was 1.43 [1.43 (1.17-1.73)], the lower limit extended beyond the pre-defined cut-off of 1.2, rendering the outcome inconclusive. For pain scores lidocaine is non-inferior to ERAS [-0.17 (-1.08-0.74)] on POD 2 and beyond. Pain scores on POD 1 and in the overall cohort were inconclusive based on the noninferiority analysis. CONCLUSIONS: The addition of a multi-component ERAS protocol to intravenous lidocaine incrementally reduces opioid consumption, most evident on POD 1. For pain scores the data is inconclusive on POD 1, however on POD 2 and beyond lidocaine alone is non-inferior to an ERAS program with lidocaine. Opioid-related complications, including return of bowel function, were not different between the groups despite reduced opioid use in the ERAS group.

SEER Sonorheometry Versus Rotational Thromboelastometry in Large Volume Blood Loss Spine Surgery.

BACKGROUND: Sonic estimation of elasticity via resonance (SEER) sonorheometry is a novel technology that uses acoustic deformation of the developing clot to measure its viscoelastic properties and extract functional measures of coagulation. Multilevel spine surgery is associated with significant perioperative blood loss, and coagulopathy occurs frequently. The aim of this study was to correlate SEER sonorheometry results with those of equivalent rotation thromboelastometry (ROTEM) and laboratory parameters obtained during deformity correction spine surgery. METHODS: Four independent SEER sonorheometry hemostatic indices (clot time, clot stiffness, fibrinogen, and platelet contribution) were measured. SEER sonorheometry clot time, using kaolin as an activator, was correlated with ROTEM intrinsic temogram clotting time and the activated partial thromboplastin time. For clot stiffness, thromboplastin was the primary activator, and this was correlated against ROTEM external temogram amplitude at 10 minutes (A10). The assay for the fibrinogen contribution was similar to clot stiffness, but abciximab was added to inhibit platelet function. The fibrinogen contribution assay was correlated with the ROTEM fibrinogen temogram A10. Finally, the SEER sonorheometry platelet contribution was calculated by subtracting the fibrinogen contribution from the clot stiffness. This variable was correlated with both absolute platelet counts, and ROTEM determined clot elasticity attributable to platelets. RESULTS: Fifty-one patients were enrolled in this prospective observational study. SEER sonorheometry clot stiffness, fibrinogen, and platelet contribution had a very strong correlation with ROTEM external temogram A10 (rs = .92; 99% confidence interval, .85-.96), fibrinogen temogram A10 (rs = .90; 99% confidence interval, .83-.93), and ROTEM-determined clot elasticity attributable to platelets (rs = .89; 99% confidence interval, .80-.95). SEER sonorheometry clot time exhibited moderate correlation with ROTEM intrinsic temogram clotting time (rs = .62; 99% confidence interval, .44-.77) and very weak correlation with activated partial thromboplastin time (rs = .33; 99% confidence interval, .10-.51). CONCLUSIONS: SEER sonorheometry demonstrates very strong correlation with ROTEM for determining clot stiffness and assessing fibrinogen and platelet contribution to clot strength in major spine surgery. An advantage of SEER sonorheometry is direct measurement of clot elasticity with no need to transform amplitude oscillation to elasticity.

Phase 1b study of batiraxcept in combination with durvalumab in patients with platinum-resistant ovarian cancer.

Combining an immune checkpoint inhibitor with batiraxcept (AVB-S6-500), an AXL inhibitor that acts via selective binding to growth arrest-specific protein 6 (GAS6), may improve anti-tumor immunity in platinum-resistant ovarian cancer (PROC). This phase 1b trial of durvalumab in combination with escalating doses of batiraxcept enrolled patients with recurrent PROC (NCT04019288). The primary objective was to determine the toxicity profile of the combination. Eleven patients were enrolled on the trial. No dose-limiting toxicities were observed, and no objective responses were noted. Median progression free survival (PFS) was 1.81 months (95% confidence interval (CI) 1.71-2.40), and median overall survival (OS) was 4.53 months (95% CI 2.10-24.74). Batiraxcept effectively reduced serum GAS6 levels at 1-h post-treatment, resulting in trough levels below the limit of detection in all cases but one. In conclusion, the combination of batiraxcept and durvalumab was safe and tolerable but did not demonstrate anti-tumor activity in a heterogenous population of patients with recurrent PROC.

Phase 1b study of intraperitoneal ipilimumab and nivolumab in patients with recurrent gynecologic malignancies with peritoneal carcinomatosis.

BACKGROUND: Intravenous immune checkpoint blockade (ICB) has shown poor response rates in recurrent gynecologic malignancies. Intraperitoneal (i.p.) ICB may result in enhanced T cell activation and anti-tumor immunity. METHODS: In this phase 1b study, registered at Clinical. TRIALS: gov (NCT03508570), initial cohorts received i.p. nivolumab monotherapy, and subsequent cohorts received combination i.p. nivolumab every 2 weeks and i.p. ipilimumab every 6 weeks, guided by a Bayesian design. The primary objective was determination of the recommended phase 2 dose (RP2D) of the combination. Secondary outcomes included toxicity, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). FINDINGS: The trial enrolled 23 patients: 18 with ovarian cancer, 2 with uterine cancer, and 3 with cervical cancer. Study evaluable patients (n = 16) received a median of 2 prior lines of therapy (range: 1-8). Partial response was observed in 2 patients (12.5%; 1 ovarian, 1 uterine), and complete response was observed in 1 patient (6.3%) with cervical cancer, for an ORR of 18.8% (95% confidence interval: 4.0%-45.6%). The median duration of response was 14.8 months (range: 4.1-20.8), with one complete response ongoing. Median PFS and OS were 2.7 months and not reached, respectively. Grade 3 or higher immune-related adverse events occurred in 2 (8.7%) patients. CONCLUSIONS: i.p. administration of dual ICB is safe and demonstrated durable responses in a subset of patients with advanced gynecologic malignancy. The RP2D is 3 mg/kg i.p. nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks. FUNDING: This work was funded by Bristol Myers Squibb (CA209-9C7), an MD Anderson Cancer Center Support Grant (CA016672), the Ovarian Cancer Moon Shots Program, the Emerson Collective Fund, and a T32 training grant (CA101642).