Research autopsy programmes in oncology: shared experience from 14 centres across the world.

While there is a great clinical need to understand the biology of metastatic cancer in order to treat it more effectively, research is hampered by limited sample availability. Research autopsy programmes can crucially advance the field through synchronous, extensive, and high-volume sample collection. However, it remains an underused strategy in translational research. Via an extensive questionnaire, we collected information on the study design, enrolment strategy, study conduct, sample and data management, and challenges and opportunities of research autopsy programmes in oncology worldwide. Fourteen programmes participated in this study. Eight programmes operated 24 h/7 days, resulting in a lower median postmortem interval (time between death and start of the autopsy, 4 h) compared with those operating during working hours (9 h). Most programmes (n = 10) succeeded in collecting all samples within a median of 12 h after death. A large number of tumour sites were sampled during each autopsy (median 15.5 per patient). The median number of samples collected per patient was 58, including different processing methods for tumour samples but also non-tumour tissues and liquid biopsies. Unique biological insights derived from these samples included metastatic progression, treatment resistance, disease heterogeneity, tumour dormancy, interactions with the tumour micro-environment, and tumour representation in liquid biopsies. Tumour patient-derived xenograft (PDX) or organoid (PDO) models were additionally established, allowing for drug discovery and treatment sensitivity assays. Apart from the opportunities and achievements, we also present the challenges related with postmortem sample collections and strategies to overcome them, based on the shared experience of these 14 programmes. Through this work, we hope to increase the transparency of postmortem tissue donation, to encourage and aid the creation of new programmes, and to foster collaborations on these unique sample collections. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Personalized Versus Precision Nanomedicine for Treatment of Ovarian Cancer.

The response to treatment is substantially varied between individual patients with ovarian cancer. However, chemotherapy treatment plans rarely pay sufficient attention to the mentioned factors. Instead, standardized treatment protocols are usually employed for most ovarian cancer patients. Variations in an individual's sensitivity to drugs significantly limit the effectiveness of treatment in some patients and lead to severe toxicities in others. In the present investigation, a nanotechnology-based approach for personalized treatment of ovarian carcinoma (the most lethal type of gynecological cancer) constructed on the individual genetic profile of the patient's tumor is developed and validated. The expression of predefined genes and proteins is analyzed for each patient sample. Finally, a mixture of the complex nanocarrier-based targeted delivery system containing drug(s)/siRNA(s)/targeted peptide is selected from the pre-synthesized bank and tested in vivo on murine cancer model using cancer cells isolated from tumors of each patient. Based on the results of the present study, an innovative approach and protocol for personalized treatment of ovarian cancer are suggested and evaluated. The results of the present study clearly show the advantages and perspectives of the proposed individual treatment approach.

Safety and Efficacy of Oxaliplatin Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) in Colorectal and Appendiceal Cancer with Peritoneal Metastases: Results of a Multicenter Phase I Trial in the USA.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.

Impact of Sodium Thiosulfate on Prevention of Nephrotoxicities in HIPEC: An Ancillary Evaluation of Cisplatin-Induced Toxicities in Ovarian Cancer.

PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin confers a survival benefit in epithelial ovarian cancer (EOC) but is associated with renal toxicity. Sodium thiosulfate (ST) is used for nephroprotection for HIPEC with cisplatin, but standard HIPEC practices vary. METHODS: A prospective, nonrandomized, clinical trial evaluated safety outcomes of HIPEC with cisplatin 75 mg/m2 during cytoreductive surgery (CRS) in patients with EOC (n = 34) and endometrial cancer (n = 6). Twenty-one patients received no ST (nST), and 19 received ST. Adverse events (AEs) were reported according to CTCAE v.5.0. Serum creatinine (Cr) was collected preoperatively and postoperatively (Days 5-8). Progression-free survival (PFS) was followed. Normal peritoneum was biopsied before and after HIPEC for whole transcriptomic sequencing to identify RNAseq signatures correlating with AEs. RESULTS: Forty patients had HIPEC at the time of interval or secondary CRS. Renal toxicities in the nST group were 33% any grade AE and 9% grade 3 AEs. The ST group demonstrated no renal AEs. Median postoperative Cr in the nST group was 1.1 mg/dL and 0.5 mg/dL in the ST group (p = 0.0001). Median change in Cr from preoperative to postoperative levels were + 53% (nST) compared with - 9.6% (ST) (p = 0.003). PFS did not differ between the ST and nST groups in primary or recurrent EOC patients. Renal AEs were associated with downregulation of metabolic pathways and upregulation of immune pathways. CONCLUSIONS: ST significantly reduces acute renal toxicity associated with HIPEC with cisplatin in ovarian cancer patients. As nephrotoxicity is high in HIPEC with cisplatin, nephroprotective agents should be considered.

Feasibility of combining pelvic reconstruction with gynecologic oncology-related surgery.

INTRODUCTION AND HYPOTHESIS: At our institution, every patient seen by the gynecologic oncology service is screened for pelvic floor dysfunction. This study was aimed at determining if a combined surgical approach by gynecologic oncology and urogynecology services at our institution was feasible and safe for this patient population. METHODS: We performed a retrospective review of patients undergoing combined surgery by gynecologic oncology and urogynecology services at our institution from 2013 to 2021. Perioperative variables, postoperative adverse events, and long-term outcomes were assessed, and descriptive statistics were performed. RESULTS: From 20 December 2013 to 29 January 2021, a total of 102 patients underwent concurrent surgical repair of pelvic organ prolapse and/or stress urinary incontinence. Seventy-three patients (71.6%) had normal/benign pathologic conditions, and 29 (28.4%) had premalignant/malignant pathologic conditions. Ten patients (9.8%) had a postoperative complication, including reoperation for exposed midurethral sling (4.9%), urinary retention requiring midurethral sling release (2.9%), reoperation for hemoperitoneum (1.0%), and anemia requiring blood transfusion (1.0%). Nine complications occurred in patients with benign/normal pathologic conditions (12.3%), and one complication occurred in patients with pre-malignant/malignant pathologic conditions (3.4%). CONCLUSIONS: In our single-institution experience, concurrent gynecologic oncology and pelvic floor reconstructive surgery were safe and feasible in combination with no reported major morbidity events.

PIPAC for the Treatment of Gynecologic and Gastrointestinal Peritoneal Metastases: Technical and Logistic Considerations of a Phase 1 Trial.

BACKGROUND: Peritoneal metastases (PM) from ovarian, gastric, appendiceal, or colorectal origin can be treated via cytoreductive surgery with or without the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) for selected patients. Unfortunately, not all patients are candidates for aggressive surgical debulking. For these patients, pressurized intraperitoneal aerosolized chemotherapy (PIPAC) has emerged as an alternative method for intraperitoneal (IP) chemotherapy administration. This report presents the design and implementation of the first phase 1 trial to evaluate the safety and efficacy of PIPAC in the United States. METHODS: This is an ongoing prospective phase 1 clinical trial of PIPAC for patients who have histologically confirmed ovarian, uterine, gastric, appendiceal, or colorectal cancer with PM and have progressed to at least one evidence-based chemotherapeutic regimen. The trial has two clinical arms. The patients in arm 1 have gynecologic and gastric malignancies treated with IP cisplatin and doxorubicin, and the arm 2 patients have colorectal and appendiceal malignancies treated with intravenous fluorouracil and leucovorin followed by IP oxaliplatin. All the patients are monitored for dose-limiting toxicities and adverse events. RESULTS: Practical and technical considerations for the phase 1 PIPAC trial are presented. These considerations include patient selection, operating room setup, and technical details for successful aerosolized chemotherapy delivery. The phase 1 study results will be reported separately at completion of the trial. CONCLUSIONS: The PIPAC treatment is a feasible, minimally invasive approach that permits IP delivery of chemotherapy. Once completed, the ongoing phase 1 trial will help to provide safety and initial efficacy data.

Phase I trial of daily subcutaneous SPL-108 injections in combination with paclitaxel in patients with platinum resistant CD44+ advanced ovarian epithelial cancer.

OBJECTIVE: Preclinical evidence and early clinical trials have demonstrated the activity of SPL-108, a targeted agent that inhibits CD44 mediated induction of multidrug resistance specifically to paclitaxel and platinum agents. We conducted a phase I, open label, dose escalation study of the safety and tolerability of the combination of SPL-108 with weekly paclitaxel in patients with platinum resistant CD44+ ovarian, primary peritoneal, or fallopian tube cancer. METHODS: Patients with platinum resistant histologically proven epithelial ovarian, primary peritoneal, or fallopian tube cancers and measurable disease according to RECIST (Response Evaluation Criteria in Solid Tumours) version 1.1 were selected. Tumors were tested for CD44 expression for eligibility, defined as strong (+++) or moderate (++) staining in ≥20% of the tumor tissue or diffuse + staining. Patients were treated with daily and then twice daily SPL-108 subcutaneous injections and weekly intravenous paclitaxel on days 1, 8, and 15 of a 28 day cycle. Endpoints included safety, determination of maximum tolerated dose, and efficacy. Tumors underwent comprehensive genomic profiling, and cell lines and western blotting were used to study markers of response. RESULTS: We screened 16 patients, and 14 were enrolled based on CD44+ expression. A total of 86% of patients had high grade serous tumors and all had received multiple prior therapies. There were no grade 4-5 toxicities. One patient had grade 3 peripheral sensory neuropathy attributed to paclitaxel and one patient developed presumed colonic perforation attributed to the study drug. No dose reductions or treatment discontinuations were required. All patients tolerated the maximum planned dose; no maximum tolerated dose was reached. Overall response rate was 36%; 5 (36%) patients had partial response and 5 (36%) patients had stable disease. CONCLUSIONS: The combination of SPL-108 with weekly paclitaxel was safe and well tolerated. Encouraging antitumor activity was observed, with 72% of patients deriving a clinical benefit. TRIAL REGISTRATION: NCT03078400.

Evaluating unplanned readmission and prolonged length of stay following minimally invasive surgery for endometrial cancer.

OBJECTIVE: To evaluate risk factors for 30-day unplanned readmission and increased length of stay (LOS) following minimally invasive surgery (MIS) for endometrial cancer. METHODS: This was a retrospective, case-control study using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). Multivariable logistic regression was used to assess perioperative variables associated with readmission and increased LOS after MIS for endometrial cancer. RESULTS: The study population included 10,840 patients who met the criteria of having undergone MIS with a resultant endometrial malignancy confirmed on postoperative pathology. Common reasons for readmission included organ/space surgical site infection (65 cases), sepsis/septic shock (19 cases), and venous thromboembolism (20 cases). Notable risk factors for readmission included (Odds Ratio, Confidence Interval, p-value): dialysis dependence (6.77, 2.51-17.80, <0.01), increased length of stay (3.00, 2.10-4.10, <0.01), and preoperative weight loss (2.80, 1.06-7.17, 0.03); notable risk factors for increased LOS: ascites (8.51, 2.00-36.33, <0.01), operation duration >5 h (6.93, 5.29-9.25, <0.01), and preoperative blood transfusion (5.37, 2.05-14.04, <0.01). CONCLUSIONS: Identification of risk factors for adverse postoperative outcomes is necessary to inform and improve standards of care in MIS for endometrial cancer. Using nationally reported data from the ACS NSQIP, this study identifies independent risk factors for unplanned readmission and prolonged LOS, and in doing so, highlights potential avenues for quality improvement.

Phase I trial of selenium plus chemotherapy in gynecologic cancers.

PURPOSE: Preclinical studies performed in our laboratory have shown that high-dose selenium inhibits the development of carboplatin drug resistance in an ovarian cancer mouse xenograft model. Based on these data, as well as the potential serious toxicities of supranutritional doses of selenium, a phase I trial of a combination of selenium/carboplatin/paclitaxel was designed to determine the maximum tolerated dose, safety, and effects of selenium on carboplatin pharmacokinetics in the treatment of chemo-naive women with gynecologic cancers. Correlative studies were performed to identify gene targets of selenium. METHODS: Chemo-naïve patients with gynecologic malignancy received selenious acid IV on day 1 followed by carboplatin IV and paclitaxel IV on day 3. A standard 3 + 3 dose-escalating design was used for addition of selenium to standard dose chemotherapy. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. RESULTS: Forty-five patients were enrolled and 291 treatment cycles were administered. Selenium was administered as selenious acid to 9 cohorts of patients with selenium doses ranging from 50 µg to 5000 µg. Grade 3/4 toxicities included neutropenia (66.7%), febrile neutropenia (2.2%), pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The maximum tolerated dose of selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. Correlative studies showed post-treatment downregulation of RAD51AP1, a protein involved in DNA repair, in both cancer cell lines and patient tumors. CONCLUSION: Overall, the addition of selenium to carboplatin/paclitaxel chemotherapy is safe and well tolerated, and does not alter carboplatin pharmacokinetics. A 5000 µg dose of elemental selenium as selenious acid is suggested as the dose to be evaluated in a phase II trial.

Impact of body mass index on ovarian cancer survival varies by stage.

BACKGROUND: Research on the effect of body mass index (BMI) on ovarian cancer survival is inconsistent, but previous studies did not consider the possible impact of ascites, bowel obstruction, or cachexia, which commonly occur in late-stage disease. METHODS: We evaluated the association of BMI, before and around the time of diagnosis, with overall and disease-specific survival in a cohort study of primary invasive epithelial ovarian cancers diagnosed from 2000 to 2013 in Kaiser Permanente Northern California (KPNC) (n=1184). Deaths were identified through December 2014, with a median follow-up of 37 months. Proportional hazards regression was used to estimate overall and ovarian cancer-specific mortality, accounting for prognostic variables including age at diagnosis, race, stage, grade, histology, comorbidities, treatment, post-treatment CA125 levels, ascites, and bowel obstruction. RESULTS: There was no evidence of an association between BMI and overall or ovarian cancer-specific survival. However, we found strong effect modification by stage (Pinteraction<0.01). Compared with normal prediagnosis BMI (18.5-24.9 kg m-2), for women who were obese before diagnosis (BMI⩾35 kg m-2) ovarian cancer-specific survival was lower among those diagnosed at stages I/II (hazard ratio (HR): 3.40; 95% confidence interval (CI): 1.16-9.99), but increased among those diagnosed with stage IV disease (HR: 0.58; 95% CI: 0.35-0.96). Associations were attenuated after excluding those diagnosed with cachexia (n=82) and further adjustment for ascites and bowel obstruction, with no evidence of effect modification by these factors. CONCLUSIONS: Associations of obesity with ovarian cancer survival may differ by stage, with decreased survival among those with localised disease and increased survival among those with late-stage disease. Stage-specific effects of obesity on survival suggest a tailored approach to improve prognosis may be appropriate.

Clinical Actionability of Comprehensive Genomic Profiling for Management of Rare or Refractory Cancers.

BACKGROUND: The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. METHODS: A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. RESULTS: Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0-10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. CONCLUSION: Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability. IMPLICATIONS FOR PRACTICE: Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents.

Use of comprehensive genomic profiling to direct point-of-care management of patients with gynecologic cancers.

OBJECTIVE: To determine the feasibility and clinical utility of using comprehensive genomic profiling (CGP) in the course of clinical care to identify clinically relevant tumor genomic alterations for patients with either rare or refractory gynecologic cancers to facilitate point-of-care management. Use of an expert, multidisciplinary, institutional molecular tumor board (MTB) assessment is discussed regarding input on putative targeted options for individualized therapy. METHODS: A prospective clinical trial is ongoing. We report on the initial 69 patients with gynecologic cancers that were either rare or refractory to standard therapy. CGP was performed by Foundation Medicine, Inc. Genomic alterations were reviewed by members of an MTB. Consensus recommendations on genomically targeted, FDA-approved, on- and off-label therapies and clinical trials were sent to the treating physician, and decisions and outcomes were assessed. RESULTS: Study outcomes were available for 64 patients. The mean number of genes altered per tumor was 4.97 (median=4; range, 1-26), and the average turnaround time from testing laboratory report to generation of formal recommendations was approximately three weeks. Evaluation of genomic and clinical data by the MTB led to generation of targeted treatment options in all 64 patients, and the percentage of patients for whom one or more of these recommendations were implemented by the treating physician was 39%. Sixty-four percent of the patients receiving targeted therapy based on a CGP result experienced radiologic response or showed evidence of clinical benefit or stable disease. CONCLUSION: These data suggest that an institutional MTB is a feasible venue for reviewing tumor genomic profiling results and generating clinical recommendations. These data also support the need for further studies and guidelines on clinical decision making with greater availability of broad genomically based diagnostics.

Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment.

Epithelial ovarian cancer is a highly heterogeneous disease characterized by multiple histological subtypes. Molecular diversity has been shown to occur within specific histological subtypes of epithelial ovarian cancer, between different tumors of an individual patient, as well as within individual tumors. Recent advances in the molecular characterization of epithelial ovarian cancer tumors have provided the basis for a simplified classification scheme in which these cancers are classified as either type I or type II tumors, and these two categories have implications regarding disease pathogenesis and prognosis. Molecular analyses, primarily based on next-generation sequencing, otherwise known as high-throughput sequencing, are allowing for further refinement of ovarian cancer classification, facilitating the elucidation of the site(s) of precursor lesions of high-grade serous ovarian cancer, and providing insight into the processes of clonal selection and evolution that may be associated with development of chemoresistance. Potential therapeutic targets have been identified from recent molecular profiling studies of these tumors, and the effectiveness and safety of a number of specific targeted therapies have been evaluated or are currently being studied for the treatment of women with this disease.

Tumor-targeted responsive nanoparticle-based systems for magnetic resonance imaging and therapy.

PURPOSE: Design and synthesis of a tumor responsive nanoparticle-based system for imaging and treatment of various cancers. METHODS: Manganese oxide nanoparticles (Mn3O4 NPs) were synthesized and modified with LHRH targeting peptide or anti-melanoma antibodies (cancer targeting moieties) and a MMP2 cleavable peptide (a possible chemotactic factor). Nanostructured lipid carriers (NLCs) were used to entrap the BRAF inhibitor, vemurafenib, and enhance cytotoxicity of the drug. Size distribution, stability, drug entrapment, cytotoxicity and genotoxicity of synthesized nanoparticles were studied in vitro. Enhancement of MRI signal by nanoparticles and their body distribution were examined in vivo on mouse models of melanoma, ovarian and lung cancers. RESULTS: Uniform, stable cancer-targeted nanoparticles (PEGylated water-soluble Mn3O4 NPs and NLCs) were synthesized. No signs of cyto-,genotoxicity and DNA damage were detected for nanoparticles that do not contain an anticancer drug. Entrapment of vemurafenib into nanoparticles significantly enhanced drug toxicity in cancer cells with targeted V600E mutation. The developed nanoparticles containing LHRH and MMP2 peptides showed preferential accumulation in primary and metastatic tumors increasing the MRI signal in mice with melanoma, lung and ovarian cancers. CONCLUSIONS: The proposed nanoparticle-based systems provide the foundation for building an integrated MRI diagnostic and therapeutic approach for various types of cancer.

Phase 2 trial of paclitaxel, 13-cis retinoic acid, and interferon alfa-2b in the treatment of advanced stage or recurrent cervical cancer.

OBJECTIVE: Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that down-regulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase 2 trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer. MATERIALS AND METHODS: Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid, 1 mg/kg, and subcutaneous interferon alfa-2b, 6 mU/m, days 1 to 4, and intravenous paclitaxel, 175 mg/m, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate. RESULTS: Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (6 complete responses and 4 partial responses). Furthermore, 7 patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n =16 [48%]), febrile neutropenia (n = 1 [3%]), and anemia (n = 1 [3%]). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% confidence interval, 2.0-7.4 months), and overall survival was 11.2 months (95% confidence interval, 7.5-26.2 months). Of 6 patients with complete responses, 5 patients survived more than 2 years. CONCLUSIONS: Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer.

Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer.

BACKGROUND: Ovarian cancer is the most lethal gynecological malignancy, with limited treatment options after failure of standard therapies. Despite the potential of poly(ADP-ribose) polymerase inhibitors in treating DNA damage response (DDR)-deficient ovarian cancer, the development of resistance and immunosuppression limit their efficacy, necessitating alternative therapeutic strategies. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) represent a novel class of inhibitors that are currently being assessed in preclinical and clinical studies for cancer treatment. METHODS: By using a PARG small-molecule inhibitor, COH34, and a cell-penetrating antibody targeting the PARG's catalytic domain, we investigated the effects of PARG inhibition on signal transducer and activator of transcription 3 (STAT3) in OVCAR8, PEO1, and Brca1-null ID8 ovarian cancer cell lines, as well as in immune cells. We examined PARG inhibition-induced effects on STAT3 phosphorylation, nuclear localization, target gene expression, and antitumor immune responses in vitro, in patient-derived tumor organoids, and in an immunocompetent Brca1-null ID8 ovarian mouse tumor model that mirrors DDR-deficient human high-grade serous ovarian cancer. We also tested the effects of overexpressing a constitutively activated STAT3 mutant on COH34-induced tumor cell growth inhibition. RESULTS: Our findings show that PARG inhibition downregulates STAT3 activity through dephosphorylation in ovarian cancer cells. Importantly, overexpression of a constitutively activated STAT3 mutant in tumor cells attenuates PARG inhibitor-induced growth inhibition. Additionally, PARG inhibition reduces STAT3 phosphorylation in immune cells, leading to the activation of antitumor immune responses, shown in immune cells cocultured with ovarian cancer patient tumor-derived organoids and in immune-competent mice-bearing mouse ovarian tumors. CONCLUSIONS: We have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer.

Identification of function for CD44 intracytoplasmic domain (CD44-ICD): modulation of matrix metalloproteinase 9 (MMP-9) transcription via novel promoter response element.

CD44 is a multifunctional cell receptor that conveys a cancer phenotype, regulates macrophage inflammatory gene expression and vascular gene activation in proatherogenic environments, and is also a marker of many cancer stem cells. CD44 undergoes sequential proteolytic cleavages that produce an intracytoplasmic domain called CD44-ICD. However, the role of CD44-ICD in cell function is unknown. We take a major step toward the elucidation of the CD44-ICD function by using a CD44-ICD-specific antibody, a modification of a ChIP assay to detect small molecules, and extensive computational analysis. We show that CD44-ICD translocates into the nucleus, where it then binds to a novel DNA consensus sequence in the promoter region of the MMP-9 gene to regulate its expression. We also show that the expression of many other genes that contain this novel response element in their promoters is up- or down-regulated by CD44-ICD. Furthermore, hypoxia-inducible factor-1α (Hif1α)-responsive genes also have the CD44-ICD consensus sequence and respond to CD44-ICD induction under normoxic conditions and therefore independent of Hif1α expression. Additionally, CD44-ICD early responsive genes encode for critical enzymes in the glycolytic pathway, revealing how CD44 could be a gatekeeper of the Warburg effect (aerobic glycolysis) in cancer cells and possibly cancer stem cells. The link of CD44 to metabolism is novel and opens a new area of research not previously considered, particularly in the study of obesity and cancer. In summary, our results finally give a function to the CD44-ICD and will accelerate the study of the regulation of many CD44-dependent genes.

Sugary food and beverage consumption and epithelial ovarian cancer risk: a population-based case-control study.

BACKGROUND: Ovarian cancer is the deadliest gynecologic cancer in the US. The consumption of refined sugars has increased dramatically over the past few decades, accounting for almost 15% of total energy intake. Yet, there is limited evidence on how sugar consumption affects ovarian cancer risk. METHODS: We evaluated ovarian cancer risk in relation to sugary foods and beverages, and total and added sugar intakes in a population-based case-control study. Cases were women with newly diagnosed epithelial ovarian cancer, older than 21 years, able to speak English or Spanish, and residents of six counties in New Jersey. Controls met same criteria as cases, but were ineligible if they had both ovaries removed. A total of 205 cases and 390 controls completed a phone interview, food frequency questionnaire, and self-recorded waist and hip measurements. Based on dietary data, we computed the number of servings of dessert foods, non-dessert foods, sugary drinks and total sugary foods and drinks for each participant. Total and added sugar intakes (grams/day) were also calculated. Multiple logistic regression models were used to estimate odds ratios and 95% confidence intervals for food and drink groups and total and added sugar intakes, while adjusting for major risk factors. RESULTS: We did not find evidence of an association between consumption of sugary foods and beverages and risk, although there was a suggestion of increased risk associated with sugary drink intake (servings per 1,000 kcal; OR=1.63, 95% CI: 0.94-2.83). CONCLUSIONS: Overall, we found little indication that sugar intake played a major role on ovarian cancer development.