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ObjectiveTo describe the evolution of perioperative opioid management in gynecologic oncology patients after open surgeries and determine current opioid over-prescription rates.MethodsPart one of this two-part study was a retrospective chart review of adult patients who underwent laparotomy by a gynecologic oncologist from July 1, 2012 to June 30, 2021, comparing changes in clinical characteristics, pain management and discharge opioid prescription sizes between fiscal year 2012 (FY2012) and 2020 (FY2020). In part two, we prospectively surveyed patients after laparotomy in 2021 to determine opioid use after hospital discharge.Results1187 patients were included in the chart review. Demographic and surgical characteristics remained stable from FY2012 to FY2020 with differences notable for increased rates of interval cytoreductive surgeries for advanced ovarian cancer and decreased rates of full lymph node dissection. Median inpatient opioid use decreased by 62 % from FY2012 to FY2020. Median discharge opioid prescription size was 675 oral morphine equivalents (OME) per patient in FY2012 and decreased by 77.7 % to 150 OME in FY2020. Of 95 surveyed patients in 2021, median self-reported opioid use after discharge was 22.5 OME. Patients had an excess of opioids equivalent to 1331 doses of 5-milligram oxycodone tablets per 100 patients.ConclusionInpatient opioid use in our gynecologic oncology open surgical patients and post-discharge opioid prescription size significantly decreased over the last decade. Despite this progress, our current prescribing patterns continue to significantly overestimate patients' actual opioid use after hospital discharge. Individualized point of care tools are needed to determine an appropriate opioid prescription size.

UNLABELLED: The PI3K pathway may be a potential mechanism to overcome cisplatin resistance. We conducted a phase Ib trial of alpelisib and cisplatin for patients with solid tumor malignancies with planned dose expansion in HPV-associated tumors. The primary objective was to determine the MTD and recommended phase II dose. Two different weekly doses of cisplatin (30 and 35 mg/m2) were evaluated with escalating doses of alpelisib, administered daily during a 21-day treatment cycle. Twenty-three patients were enrolled: 91% received >3 prior regimens with median of 4 (range 1-10), and 78% progressed on prior platinum. The MTD was alpelisib 250 mg daily with weekly cisplatin 30 mg/m2. There were 3 DLTs: all grade 4 hyperglycemia. Frequent treatment-related adverse events of any grade included fatigue (52%), diarrhea (39%), nausea (38%), hyperglycemia (30%), anemia (22%), and nephropathy (17%). Hyperglycemia was linked to baseline hemoglobin A1C, but not body mass index. Twelve patients discontinued treatment for toxicity (n = 9 during cycle 1) and 11 discontinued for progression. Of 14 evaluable patients who received at least one treatment cycle, 4 (29%) patients demonstrated partial response, and 7 had stable disease for a disease control rate of 79%. The median PFS measured 4.3 months (95% CI, 1.6-4.5). No difference in PFS was observed between PIK3CA-mutated and wild-type tumors. While the combination of alpelisib and cisplatin demonstrated preliminary evidence of activity despite platinum resistance, toxicities hindered prolonged treatment. Prospective studies are planned using carboplatin and alpelisib to improve toxicity and tolerability. SIGNIFICANCE: The PI3K inhibitor alpelisib has limited activity alone, but there is interest in combinations in platinum-resistant tumors. In this phase Ib study of alpelisib with cisplatin, the objective response rate measured 29% but adverse events limited dose intensity. These promising results provide rationale for studying combinations with better tolerated platinum agents.

ObjectiveSomatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors.MethodsPatients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety.ResultsSixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5-57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1-78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7-18.3 months); median OS was 16.8 months (95%CI 4.1-NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations.ConclusionsNeratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population.Trial registration numberNCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).

•Genomic tumor testing is an important tool in guiding treatment for gynecologic malignancies.•Targetable mutations may lead to new therapies in gynecologic cancer treatment.•Her2/neu mutations in serous ovarian carcinomas can be targeted with ERBB2 inhibitors.•Afatinib shows promising response rates in lung cancers carrying Her2/neu mutations.•Afatinib may be effective in serous ovarian tumors exhibiting Her2/neu or ERBB2 mutations.

•Genomic tumor testing is an important tool in guiding treatment for gynecologic malignancies.•Targetable mutations may lead to new therapies in gynecologic cancer treatment.•Her2/neu mutations in serous ovarian carcinomas can be targeted with ERBB2 inhibitors.•Afatinib shows promising response rates in lung cancers carrying Her2/neu mutations.•Afatinib may be effective in serous ovarian tumors exhibiting Her2/neu or ERBB2 mutations.

Recently, there has been a huge increase in the different ways to manufacture polymer-based sensors. Methods like additive manufacturing, microfluidic preparation, and brush painting are just a few examples of new approaches designed to improve sensor features like self-healing, higher sensitivity, reduced drift over time, and lower hysteresis. That being said, we believe there is still a lot of potential to boost the performance of current sensors by applying modeling, classification, and machine learning techniques. With this approach, final sensor users may benefit from inexpensive computational methods instead of dealing with the already mentioned manufacturing routes. In this study, a total of 96 specimens of two commercial brands of Force Sensing Resistors (FSRs) were characterized under the error metrics of drift and hysteresis; the characterization was performed at multiple input voltages in a tailored test bench. It was found that the output voltage at null force (Vo_null) of a given specimen is inversely correlated with its drift error, and, consequently, it is possible to predict the sensor's performance by performing inexpensive electrical measurements on the sensor before deploying it to the final application. Hysteresis error was also studied in regard to Vo_null readings; nonetheless, a relationship between Vo_null and hysteresis was not found. However, a classification rule base on k-means clustering method was implemented; the clustering allowed us to distinguish in advance between sensors with high and low hysteresis by relying solely on Vo_null readings; the method was successfully implemented on Peratech SP200 sensors, but it could be applied to Interlink FSR402 sensors. With the aim of providing a comprehensive insight of the experimental data, the theoretical foundations of FSRs are also presented and correlated with the introduced modeling/classification techniques. [ABSTRACT FROM AUTHOR]

PurposeTo study the prevalence and effect of smoking on cervical cancer recurrence and mortality in patients undergoing definitive treatment with radiation.Materials and methodsBetween July 2007 and September 2013, 96 locally advanced cervical cancer patients received definitive radiation or chemoradiation followed by brachytherapy. Smoking status was obtained from prospective intake questionnaires and quantified by pack-years. Pelvic control (PC), disease-free survival (DFS), and overall survival (OS) were analyzed by multivariable Cox proportional hazards models.ResultsSmoking history included 51 (53.1%) nonsmokers, 45 active smokers, and former smokers: 20 (20.8%) with 1 to 20 pack-years and 25 (26%) with 21+ pack-years. With a median follow-up of 2 years on univariate analysis, the impact of 1 to 20 pack-years on PC, DFS, and OS relative to nonsmokers was hazard ratio (HR) 4.29 (95% confidence interval [CI], 1.36-14.1; P=0.014), 4.99 (95% CI, 1.21-22.4; P=0.027), and 4.77 (95% CI, 1.34-17.8; P=0.017), respectively. For patients with 21+ pack-years, the impact on PC, DFS, and OS was HR=6.13 (95% CI, 2.29-18.6; P

PurposeWe examined the incidence and the effect of alcohol abuse on pelvic control (PC), disease-free survival (DFS), and overall survival (OS) in locally advanced cervical cancer patients undergoing definitive radiation therapy (RT).MethodsBetween 2007 and 2013, 95 patients treated with RT were reviewed, and the tumor characteristics, the RT dose, the treatment time, chemotherapy, and the number of cycles were recorded. The association between alcohol abuse and DFS, OS, and the duration of PC was analyzed using multivariable Cox proportional hazards models.ResultsOf the 95 patients with an average age of 54.8 years (range, 27 to 91 y), 30% were FIGO stage 1B1, 1B2, 2A, 52% stage 2B, 3A; and 18% stage 3B; 86% of the patients were treated with weekly cisplatin chemotherapy. Alcohol history showed that 10 (10.5%) patients met the CDC criteria for heavy alcohol use. With a mean follow-up time of 2 years, 85 patients (88.5%) achieved PC and 86 patients (90.5%) were free of distant metastasis. A total of 82 patients (86.3%) were alive at the last follow-up. When controlling for the total treatment time, excessive alcohol abuse was significantly associated with a decrease in DFS (P=0.005; hazard ratio [HR], 6.19; 95% confidence interval [CI]: 1.73, 22.18), OS (P=0.001; HR, 6.68; 95% CI: 2.10, 21.26), and PC (P=0.029; HR, 3.10; 95% CI: 1.13, 8.56) on univariable analysis. On multivariable analysis, excessive alcohol abuse was significantly associated with a decrease in DFS (P=0.005; HR, 10.57; 95% CI: 2.07, 53.93) and OS (P=0.001; HR, 10.80; 95% CI: 2.57, 45.40).ConclusionsIn this small hypothesis-generating series of patients with heavy alcohol use, the data support the association that heavy alcohol use increases the risk of cancer recurrence and mortality. Additional research is required to better define the patient- and treatment-related factors that may be targeted for intervention.

Peritoneal carcinomatosis is a major source of morbidity and mortality in patients with advanced abdominal neoplasms. Intraperitoneal chemotherapy (IPC) is an area of intense interest given its efficacy in ovarian cancer. However, IPC suffers from poor drug penetration into peritoneal tumors. As such, extensive cytoreductive surgery is required prior to IPC. Here, we explore the utility of iRGD, a tumor-penetrating peptide, for improved tumor-specific penetration of intraperitoneal compounds and enhanced IPC in mice. Intraperitoneally administered iRGD significantly enhanced penetration of an attached fluorescein into disseminated peritoneal tumor nodules. The penetration was tumor-specific, circulation-independent, and mediated by the neuropilin-binding RXXK tissue-penetration peptide motif of iRGD. Q-iRGD, which fluoresces upon cleavage, including the one that leads to RXXK activation, specifically labeled peritoneal metastases displaying different growth patterns in mice. Importantly, iRGD enhanced intratumoral entry of intraperitoneally co-injected dextran to approximately 300% and doxorubicin to 250%. Intraperitoneal iRGD/doxorubicin combination therapy inhibited the growth of bulky peritoneal tumors and reduced systemic drug toxicity. iRGD delivered attached fluorescein and co-applied nanoparticles deep into fresh human peritoneal metastasis explants. These results indicate that intraperitoneal iRGD co-administration serves as a simple and effective strategy to facilitate tumor detection and improve the therapeutic index of IPC for peritoneal carcinomatosis.

The extent of tight junction (TJ) formation is one of many factors that regulate motility, invasion, and metastasis. Claudins are required for the formation and maintenance of TJs. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are highly expressed in the majority of ovarian cancers. We report here that CLDN3 and CLDN4 each serve to constrain the growth of human 2008 cancer xenografts and limit metastatic potential. Knockdown of CLDN3 increased in vivo growth rate by 2.3-fold and knockdown of CLDN4 by 3.7-fold in the absence of significant change in in vitro growth rate. Both types of tumors exhibited increase in birth rate as measured by Ki67 staining and decrease in death rate as reflected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Knockdown of either claudin did not alter expression of other TJ protein but did reduce TJ formation as measured by transepithelial resistance and paracellular flux of dextran, enhance migration and invasion in in vitro assays, and increase lung colonization following intravenous injection. Knockdown of CLDN3 and CLDN4 increased total lung metastatic burden by 1.7-fold and 2.4-fold, respectively. Loss of either CLDN3 or CLDN4 resulted in down-regulation of E-cadherin mRNA and protein, increased inhibitory phosphorylation of glycogen synthase kinase-3β (GSK-3β), and activation of β-catenin pathway signaling as evidenced by increases in nuclear β-catenin, the dephosphorylated form of the protein, and transcriptional activity of β-catenin/T-cell factor (TCF). We conclude that both CLDN3 and CLDN4 mediate interactions with other cells in vivo that restrain growth and metastatic potential by sustaining expression of E-cadherin and limiting β-catenin signaling.

The purpose of this study was to determine whether the introduction of psychosocial services to gynecologic oncology outpatients by a social worker increases service use. During the initial six weeks (phase I), patients were referred for psychosocial services by clinic staff. During the second six weeks (phase II), a nurse introduced available services to each patient with a brochure. During the final 12 weeks (phase III), a social worker introduced services to each patient. The authors then compared psychosocial service referral rates. The sample included 196 patients, During phase III, the probability of a patient-initiated referral increased 3.4-fold (95 percent confidence interval [CI] [1.1, 10.4], p = .04) compared with baseline; the probability of any referral rose 2.7-fold (95 percent CI [1.1, 6.3], p = .03). The mean time to referral decreased from 79.4 days at baseline to 3.9 days during phase III (p < .001). The phase III intervention was accomplished only in 34 patients (39 percent) because of scheduling conflicts. Of these, eight requested referral, resulting in a 24 percent patient-initiated referral rate after meeting with a social worker. The introduction of psychosocial services by a social worker to gynecologic oncology outpatients increases referral rates and expedites evaluation. KEY WORDS: distress; gynecologic oncology; psychosocial services; quality of life; social work, A holistic approach to the evaluation and management of cancer patients has become well recognized in clinical oncology as an essential feature of patient-centered care (National Comprehensive Cancer Network, 2003). [...]