Search

Objectives: In previous clinical studies using a murine-derived CAR construct targeted to mesothelin (SS1 CAR), we observed limited persistence and efficacy. To improve the outcome, we created a fully human anti-mesothelin scFV fused to the intracellular signaling domains 4-1BB (CD137) and TCR zeta (M5 CAR). Pre-clinical evaluation of the M5 CAR revealed enhanced in vivo antitumor activity compared to the SS1 CAR. Methods: Fourteen patients with mesothelin-expressing tumors (ovarian, lung, malignant mesothelioma) were treated with the M5 CAR. Three patients received a single IV dose of 3 x 107 CART-meso cells/m2 (Cohort 1), three patients received a single IV dose of 3 x 107 CART-meso cells/m2 following lymphodepletion (Cohort 2), and two patients received a single IV dose of 3 x 108 CART-meso cells/m2 (Cohort 3). Due to toxicity, the last six patients received lymphodepletion and an initial IV dose of 3 x 107 CART-meso cells/m2 followed by up to two additional IV doses spaced 21-42 days apart (Cohort 4). Results: The infusions were well tolerated. M5 CART cells were detectable in blood one hour after infusion and expanded to a peak at Day 7-10. Higher levels were detected in patients treated with the higher dose CART cells and with lymphodepletion. M5 CART cells persisted up to 28-42 days in all subjects and at three and six months in two patients. M5 CART cells were trafficked to tumors in nine of the 14 patients. At 28-35 days after treatment, eight patients showed stable disease (8/14, 57%) per RECIST criteria. One patient had SD for three months; another had SD for nine months. Four subjects experienced cytokine release syndrome (CRS) (three grade 3 and one grade 4), and related AEs included hypoxia, hypotension, hyponatremia, fatigue, and febrile neutropenia. In Cohort 3, both subjects had acute respiratory SAEs. One patient experienced grade 3 SAEs (CRS, hypotension, hypoxia) but fully recovered. The other patient, with extensive pulmonary tumor burden and residual PD-1 blockade, suffered fatal respiratory failure. Due to these SAEs, the MTD was defined at 3 x 107 CART-meso cells/m2 and six subsequent patients had no pulmonary SAEs. Conclusions: This dose-escalation trial demonstrates the feasibility of treating multiple tumor types with M5 CART cells. The M5 CART cells engrafted and expanded in the blood of all subjects but persisted at relatively low blood levels and for short time periods. CART trafficking into tumors was identified in 9/14 patients. Short-term stable disease was noted in the majority of patients, but no clinical responses were seen. Pulmonary toxicity was seen when given at the 3 x 10 8 CART cells/m2 dose. These preliminary results may help guide future M5 CART clinical trials, such as loco-regional delivery or modifications to the CART cells to improve safety and enhance trafficking and persistence. [ABSTRACT FROM AUTHOR]

Approximately 10–25% of patients with locally advanced cervical cancer harbor metastases to the para-aortic lymph nodes. Staging of patients with locally advanced cervical cancer can be performed with imaging techniques, such as PET-CT; however, false negative rates can be as high as 20%, especially for patients with pelvic lymph node metastases. Surgical staging can identify patients with microscopic lymph nodes metastases and aid in accurate treatment planning with the administration of extended-field radiation therapy. Data from retrospective studies investigating the impact of para-aortic lymphadenectomy on the oncological outcomes of patients with locally advanced cervical cancer are mixed, while data from randomized controlled trials do not demonstrate a progression-free survival benefit. In the present review, we explore controversies in the staging of patients with locally advanced cervical cancer and summarize the available literature. [ABSTRACT FROM AUTHOR]

Anti- N-methyl- d-aspartate (NMDA) receptor encephalitis is a recently described potentially lethal but treatable disorder that often occurs as a paraneoplastic manifestation of ovarian teratomas. We report three women with this disorder who presented with subacute onset of delirium, seizures and autonomic instability. Anti-NMDA receptor antibodies were detectable in the serum or cerebrospinal fluid of each patient. Ovarian masses were detected in two patients, and subsequently excised. In the third patient, an empirical bilateral salpingo-oophorectomy was performed and revealed a microscopic neoplasm. All patients experienced slow reversal of the neurological symptoms following surgery and immunotherapy. Our experience suggests that prompt syndrome recognition followed by tumor removal and immunotherapy usually results in neurological recovery. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Bevacizumab is a generally well-tolerated drug, but bevacizumab-associated gastrointestinal perforations (BAP) occur in 0 to 15% of patients with ovarian carcinoma. Our goal was to evaluate the clinical predictors of BAP in order to identify factors, which may preclude patients from receiving treatment. Methods: We conducted a review of patients with recurrent epithelial ovarian carcinoma treated with bevacizumab between 2006 and 2009. Demographic and treatment data were collected for statistical analysis. Results: Eighty-two patients were identified; perforation occurred in 8 (9.76%). Among patients with perforation, a significantly higher incidence of prior bowel surgeries (p =0.0008) and prior bowel obstruction or ileus (p <0.0001) were found compared to non-perforated patients. The median age at onset of bevacizumab in the perforated group was 3years younger (60 vs. 63years, p =0.61). The incidence of thromboembolic events, GI comorbidities, number of prior chemotherapies, and body mass index were similar between the groups. None of the patients in the perforated group developed grade 3 or 4 hypertension, compared to a 32.4% incidence among the non-perforated patients (p =0.09). Upon multivariate analysis, when controlled for age greater or less than 60, prior bowel surgery, obstruction/ileus, and grade 3 or 4 hypertension, only the presence of obstruction/ileus was noted to be a significant predictor of perforation (p =0.04). Conclusions: Predicting BAP remains a challenge. Bowel obstruction or ileus appears to be associated with increased risk of BAP. [Copyright &y& Elsevier]

Abstract: Objective: Pegylated liposomal doxorubicin (PLD) was introduced to reduce the adverse effect of doxorubicin in treating recurrent ovarian cancer. We sought to characterize the efficacy and adverse-effect profile of PLD in different doses and to evaluate predictive factors of palmar-plantar erythrodysesthesia (PPE). Methods: Patients with recurrent ovarian, primary peritoneal, and fallopian tube carcinoma treated with single-agent PLD between 1996 and 2006 at The University of Texas M. D. Anderson Cancer Center were retrospectively identified, and charts were reviewed for patient demographics, PLD data, adverse effects, use of cooling mechanisms, and survival. Results: Three hundred-thirty patients were included and PPE of any grade occurred in 30.9%. Patients received a median of 3 (mean 4.32) cycles of PLD treatment. The different PLD doses (<30, 35, 40, and >50 mg/m2) were not associated with differences in overall survival (OS), progression-free survival (PFS), or time to progression (TTP). The incidences of mucositis, neutropenia, peripheral neuropathy, and vomiting were significantly higher at doses >50 mg/m2 than at doses <40 mg/m2. More patients who used cooling mechanisms (39%) had PPE than those who did not (26%). There was an association between mucositis, neutropenia, and peripheral neuropathy and PPE. More cycles of PLD (>6) also increased the incidence of PPE. In our study, only 7% of women discontinued PLD for toxicity while 74% discontinued for progression. Conclusion: There was no association between different doses of PLD and OS, PFS, or TTP. A higher dose and more cycles increased the incidence of several toxicities, including PPE. The use of cooling mechanisms, higher number of PLD cycles, and occurrence of mucositis, neutropenia, and peripheral neuropathy are possible predictors of PPE. [Copyright &y& Elsevier]

The article discusses a case study on balloon tamponade of hemorrhage after uterine curettage for gestational trophoblastic disease. The bleeding of the patient was controlled successfully using intrauterine tamponade performed through a balloon catheter. The study indicates that intrauterine balloon catheterization seems to be a promising alternative to control uterine hemorrhage while preserving fertility.

Objective. One potential limitation of gene therapy for epithelial tumors is the lack of tissue or tumor specificity of treatment. Tumor-selective expression of gene therapies may avoid deleterious side effects and improve the efficacy of the treatment. The aim of this study was to evaluate the tissue and tumor specificity of four different potential gene therapy promoters, to determine their usefulness in tissue-specific gene therapy of epithelial ovarian carcinomas.Methods. Three potential epithelial cell-selective (hESE1, SLP1, OSP1) and one potential tumor-selective (hTERT) promoter were placed upstream of a luciferase construct to determine relative activity in a wide variety of normal and malignant cell lines. Transient transfection and luciferase assays were carried out in 12 epithelial ovarian (3 SV40 T antigen-transfected normal and 9 malignant) and 8 control cell lines.Results. Luciferase assays revealed that the hTERT promoter presented the highest tumor selectivity. hESE1 and SLP1 promoters showed strong epithelial cell selectivity (hESE1, 16/17; SLP1, 15/17), with the OSP1 (11/17) promoter exhibiting lower epithelial selectivity. Of the potential promoters for gene therapy, hTERT promoter exhibited the strongest transcriptional activity in most of the tumor cell lines. None of the promoters exhibited strict ovarian epithelium selectivity.Conclusion. The hTERT promoter may be an optimal promoter for a univector gene therapy approach based on its high tumor selectivity. Utilization of multiple epithelial cell-specific promoters may result in a more tissue-selective gene therapy approach. Using a combination of promoters may prevent potential problems due to expression in nonepithelial stem cells that may constitutively express hTERT. [Copyright &y& Elsevier]

The article presents a case report of placenta percreta, which is a form of abnormal placentation, at weeks' gestation in a 32-year-old woman who underwent previous caesarean section. The patient was admitted to the medical institution due to continual bleeding following an elective abortion. It is noted that the patient's histology report showed placenta increta and percreta with placental implantation site into and through the previous hysterotomy incision with uterine rupture.

The success of chimeric antigen receptor T-cell (CAR-T) therapies in the treatment of hematologic malignancies has led to the investigation of their potential in the treatment of solid tumors, including ovarian cancer. While the immunosuppressive microenvironment of ovarian cancer has been a barrier in their implementation, several early phase clinical trials are currently evaluating CAR-T cell therapies targeting mesothelin, folate receptor a, HER2, MUC16, and B7H3. Ongoing challenges include cytokine-associated and "on-target, off-tumor" toxicities, while most common adverse events include cytokine release syndrome, hemophagocytic lymphohistiocytosis/macrophage activation-like syndrome (HLH/MAS), and neurotoxicity. In the present review, we summarize the current status of CAR-T therapy in ovarian cancer and discuss future directions. [ABSTRACT FROM AUTHOR]

Bevacizumab has demonstrated significant benefit in recurrent ovarian, fallopian tube and peritoneal cancer (OC), but its optimal position within the sequence of systemic therapies remains controversial. Since rebound progression after bevacizumab has been observed in other cancers, and because bevacizumab is incorporated in several regimens used in the recurrent setting, the duration of treatment may impact survival. We sought to identify whether earlier bevacizumab exposure is associated with prolonged bevacizumab therapy and survival by conducting a multi-institution retrospective study of recurrent OC patients treated with bevacizumab from 2004-2014. Multivariate logistic regression identified factors associated with receiving more than six bevacizumab cycles. Overall survival by duration and ordinal sequence of bevacizumab therapy were evaluated using logrank testing and Cox regression. In total, 318 patients were identified. 89.1% had stage III or IV disease; 36% had primary platinum resistance; 40.5% received two or fewer prior chemotherapy regimens. Multivariate logistic regression demonstrated that primary platinum sensitivity (Odds Ratio (OR) 2.34, p = 0.001) or initiating bevacizumab at the first or second recurrence (OR 2.73, p < 0.001) were independently associated with receiving more than six cycles of bevacizumab. Receiving more cycles of bevacizumab was associated with improved overall survival whether measured from time of diagnosis (logrank p < 0.001), bevacizumab initiation (logrank p < 0.001), or bevacizumab discontinuation (logrank p = 0.017). Waiting one additional recurrence to initiate bevacizumab resulted in a 27% increased hazard of death (Hazard Ratio (HR) 1.27, p < 0.001) by multivariate analysis. In conclusion, patients with primary platinum sensitive disease who received fewer prior lines of chemotherapy were able to receive more cycles of bevacizumab, which was associated with improved overall survival. Survival worsened when bevacizumab was initiated later in the ordinal sequence of therapies. [ABSTRACT FROM AUTHOR]

Abstract: New serological biomarkers for early detection and clinical management of ovarian cancer are urgently needed, and many candidates have been reported. A major challenge frequently encountered when validating candidates in patients is establishing quantitative assays that distinguish between highly homologous proteins. The current study tested whether multiple members of two recently discovered ovarian cancer biomarker protein families, chloride intracellular channel (CLIC) proteins and tropomyosins (TPM), were detectable in ovarian cancer patient sera. A multiplexed, label-free multiple reaction monitoring (MRM) assay was established to target peptides specific to all detected CLIC and TPM family members, and their serum levels were quantitated for ovarian cancer patients and non-cancer controls. In addition to CLIC1 and TPM1, which were the proteins initially discovered in a xenograft mouse model, CLIC4, TPM2, TPM3, and TPM4 were present in ovarian cancer patient sera at significantly elevated levels compared with controls. Some of the additional biomarkers identified in this homolog-centric verification and validation approach may be superior to the previously identified biomarkers at discriminating between ovarian cancer and non-cancer patients. This demonstrates the importance of considering all potential protein homologs and using quantitative assays for cancer biomarker validation with well-defined isoform specificity. Biological significance: This manuscript addresses the importance of distinguishing between protein homologs and isoforms when identifying and validating cancer biomarkers in plasma or serum. Specifically, it describes the use of targeted in-depth LC–MS/MS analysis to determine the members of two protein families, chloride intracellular channel (CLIC) and tropomyosin (TPM) proteins that are detectable in sera of ovarian cancer patients. It then establishes a multiplexed isoform- and homology-specific MRM assay to quantify all observed gene products in these two protein families as well as many of the closely related tropomyosin isoforms. Using this assay, levels of all detected CLICs and TPMs were quantified in ovarian cancer patient and control subject sera. These results demonstrate that in addition to the previously known CLIC1, multiple tropomyosins and CLIC4 are promising new ovarian cancer biomarkers. Based on these initial validation studies, these new ovarian cancer biomarkers appear to be superior to most previously known ovarian cancer biomarkers. [Copyright &y& Elsevier]

Platinum-resistant, high-grade serous ovarian cancer (HGSOC) has limited treatment options. Preclinical data suggest that poly(ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) are synergistic. CAPRI (NCT03462342) is an investigator-initiated study of olaparib plus ceralasertib in recurrent HGSOC. Herein, we present results from the platinum-resistant cohort. A Simon 2-stage design was utilized. Platinum-resistant HGSOC patients received ceralasertib 160 mg orally daily, days 1–7 and olaparib 300 mg orally twice daily, days 1–28 of a 28-day cycle until toxicity or progression. Primary endpoints were toxicity and efficacy including objective response rate (ORR) by RECIST. Secondary endpoint was progression-free survival (PFS). The null hypothesis (≤5% ORR) would be rejected if there were ≥ 1 responses in 12 patients. Fourteen PARPi-naïve patients were evaluable for toxicity; 12 were evaluable for response. Three had BRCA1 mutations (1 germline, 2 somatic). Adverse events possibly related to treatment were primarily grade (G) 1/2. G3 toxicities included nausea (14.3%), fatigue (7.1%), anorexia (7.1%), and anemia (7.1%). No objective responses occurred. Best response was stable disease in 9 patients and progressive disease in three. Five patients had a ≥ 20% to <30% reduction in disease burden, including 3 with BRCA1 mutations. Three of 11 patients (27%; 2 with BRCA1 mutations) evaluable by Gynecologic Cancer Intergroup criteria had >50% CA-125 decline, including 2 with CA-125 normalization. Median PFS was 4.2 months overall (90% CI:3.5–8.2) and 8.2 months (3.6 months–not determined) for patients with BRCA1 mutations. Olaparib plus ceralasertib is well-tolerated. No objective responses occurred, though a signal of activity was seen particularly in disease associated with BRCA1. Further evaluation of this combination should include alternate dosing strategies in genomically-selected populations. • Combination olaparib and ceralasertib is tolerable at the current RP2D. • No RECIST radiological responses occurred and PFS was 4.2 months. • PFS was 8.2 months in 3 subjects with BRCA1 mutations. • CA-125 responses by GCIG criteria were seen in 3 of 11 evaluable subjects. • A signal of activity was seen in DNA repair deficient platinum resistant HGSOC. [ABSTRACT FROM AUTHOR]

Purpose: Ovarian cancer, like most solid tumors, is in dire need of effective therapies. The significance of this trial lies in its promise to spearhead the development of combination immunotherapy and to introduce novel approaches to therapeutic immunomodulation, which could enable otherwise ineffective vaccines to achieve clinical efficacy. Rationale: Tumor-infiltrating T cells have been associated with improved outcome in ovarian cancer, suggesting that activation of antitumor immunity will improve survival. However, molecularly defined vaccines have been generally disappointing. Cancer vaccines elicit a modest frequency of low-to-moderate avidity tumor-specific T-cells, but powerful tumor barriers dampen the engraftment, expansion and function of these effector T-cells in the tumor, thus preventing them from reaching their full therapeutic potential. Our work has identified two important barriers in the tumor microenvironment: the blood-tumor barrier, which prevents homing of effector T cells, and T regulatory cells, which inactivate effector T cells. We hypothesize that cancer vaccine therapy will benefit from combinations that attenuate these two barrier mechanisms. Design: We propose a three-cohort sequential study to investigate a combinatorial approach of a new dendritic cell (DC) vaccine pulsed with autologous whole tumor oxidized lysate, in combination with antiangiogenesis therapy (bevacizumab) and metronomic cyclophosphamide, which impacts Treg cells. Innovation: This study uses a novel autologous tumor vaccine developed with 4-day DCs pulsed with oxidized lysate to elicit antitumor response. Furthermore, the combination of bevacizumab with a whole tumor antigen vaccine has not been tested in the clinic. Finally the combination of bevacizumab and metronomic cyclophosphamide in immunotherapy is novel. [ABSTRACT FROM AUTHOR]

Abstract: In human epithelial cancers, the microRNA (miRNA) mir-30d is amplified with high frequency and serves as a critical oncomir by regulating metastasis, apoptosis, proliferation, and differentiation. Autophagy, a degradation pathway for long-lived protein and organelles, regulates the survival and death of many cell types. Increasing evidence suggests that autophagy plays an important function in epithelial tumor initiation and progression. Using a combined bioinformatics approach, gene set enrichment analysis, and miRNA target prediction, we found that mir-30d might regulate multiple genes in the autophagy pathway including BECN1, BNIP3L, ATG12, ATG5, and ATG2. Our further functional experiments demonstrated that the expression of these core proteins in the autophagy pathway was directly suppressed by mir-30d in cancer cells. Finally, we showed that mir-30d regulated the autophagy process by inhibiting autophagosome formation and LC3B-I conversion to LC3B-II. Taken together, our results provide evidence that the oncomir mir-30d impairs the autophagy process by targeting multiple genes in the autophagy pathway. This result will contribute to understanding the molecular mechanism of mir-30d in tumorigenesis and developing novel cancer therapy strategy. [Copyright &y& Elsevier]

All cells release low molecular weight organic compounds that possess finite vapor pressures at body and/or ambient temperatures. These volatile organic compounds (VOCs) may possess an odor and can be found emanating from all body fluids. As cells turn malignant, analysis of changes in these VOCs can provide insight into cancer onset and diagnosis. Previous studies have demonstrated that dogs can be trained to distinguish ovarian cancer tissues of various stages and grades from normal ovarian tissue and other gynecological malignancies with sensitivity and specificity over 95%. When trained on biopsied tissue, dogs were able to detect the VOC disturbances in peripheral blood samples with the same accuracy. Building on these earlier studies, we examined the VOCs emanating from plasma samples from primary ovarian cancer patients, patients with benign reproductive tract growths, and healthy controls. We used a three-pronged sensor approach to analyze the VOCs from plasma: canines trained on tissue and plasma samples, analysis using solid phase microextraction gas chromatography–mass spectrometry, and novel single stranded DNA-coated carbon nanotube sensor field effect transistors. Each of the three experimental approaches used in this study provided preliminary evidence that plasma from ovarian cancer patients emits a volatile odor signature that can be distinguished from the VOCs of patients with benign ovarian tumors and controls. Our results provide optimism that a diagnostic approach based on the analysis of the VOC odor signature of ovarian cancer is achievable. [ABSTRACT FROM AUTHOR]

Men of predominantly African Ancestry (AA) have higher prostate cancer (CaP) incidence and worse survival than men of predominantly European Ancestry (EA). While socioeconomic factors drive this disparity, genomic factors may also contribute to differences in the incidence and mortality rates. To compare the prevalence of prostate tumor genomic alterations and transcriptomic profiles by patient genetic ancestry, we evaluated genomic profiles from The Cancer Genome Atlas (TCGA) CaP cohort (n = 498). Patient global and local genetic ancestry were estimated by computational algorithms using genotyping data; 414 (83.1%) were EA, 61 (12.2%) were AA, 11 (2.2%) were East Asian Ancestry (EAA), 10 (2.0%) were Native American (NA), and 2 (0.4%) were other ancestry. Genetic ancestry was highly concordant with self-identified race/ethnicity. Subsequent analyses were limited to 61 AA and 414 EA cases. Significant differences were observed by ancestry in the frequency of SPOP mutations (20.3% AA vs. 10.0% EA; p = 5.6×10−03), TMPRSS2-ERG fusions (29.3% AA vs. 39.6% EA; p = 4.4×10−02), and PTEN deletions/losses (11.5% AA vs. 30.2% EA; p = 3.5×10−03). Differentially expressed genes (DEGs) between AAs and EAs showed significant enrichment for prostate eQTL target genes (p = 8.09×10−48). Enrichment of highly expressed DEGs for immune-related pathways was observed in AAs, and for PTEN/PI3K signaling in EAs. Nearly one-third of DEGs (31.3%) were long non-coding RNAs (DE-lncRNAs). The proportion of DE-lncRNAs with higher expression in AAs greatly exceeded that with lower expression in AAs (p = 1.2×10−125). Both ChIP-seq and RNA-seq data suggested a stronger regulatory role for AR signaling pathways in DE-lncRNAs vs. non-DE-lncRNAs. CaP-related oncogenic lncRNAs, such as PVT1, PCAT1 and PCAT10/CTBP1-AS, were found to be more highly expressed in AAs. We report substantial heterogeneity in the prostate tumor genome and transcriptome between EA and AA. These differences may be biological contributors to racial disparities in CaP incidence and outcomes. Author summary: Disparities in cancer defined by self-identified race or ethnicity have been a long-standing and persistent challenge. It is well documented that certain racial and ethnic populations in the US experience higher incidence of specific cancer types, higher incidence of aggressive cancers, and higher mortality. The Cancer Genome Atlas (TCGA) data resource contains multi-omic profiles and clinical annotations of large-scale samples, and therefore serves as an excellent resource for the evaluation of the relationship between genetic ancestry and genomic alterations in cancers. In this study, we performed a cancer type specific analysis of the influence of genetic ancestry on genomic alterations in prostate cancers–a malignancy for which there are some of the largest cancer disparities by race and ethnicity in the US. We found that there is substantial heterogeneity in the genomic alterations and transcriptomic dysregulation occurring in men of African (AA) and European (EA) ancestry in the TCGA prostate cancer cohort. SPOP mutations, TMPRSS2-ERG fusions, PTEN deletions/losses, immune signaling, and expression of non-coding RNAs were identified as potential contributors to prostate cancer racial disparities. Our comprehensive characterization of genetic ancestry and genomic/transcriptomic alterations would provide new insight into the biology of prostate cancer racial disparities in the AA population. [ABSTRACT FROM AUTHOR]

Background: Mutation of TP53 is the most frequent genetic alteration in high-grade serous ovarian cancer (HGSOC). The impact of hotspot mutations of TP53 and protein levels on patient outcomes in HGSOC has not been fully elucidated.Methods: The study population (n = 791) comprised of HGSOC samples with TP53 mutation from TCGA and other publicly available data. Univariate and multivariate cox proportional hazards regression analyses were used to select variables that were correlated with patient survival.Results: We assessed the effects of TP53 mutations based on type and individual hotspot mutations on patient outcomes in HGSOC. Only hotspot mutations were associated with outcomes. Three hotspot mutations: G266, Y163C, and R282, in aggregate were associated with a worsened overall and recurrence-free survival compared with other hotspot mutations (p < 0.0001 and p = 0.001), other non-hotspot missense mutations (p < 0.0001 and p = 0.008), truncated mutations (p < 0.0001 and p = 0.001), and all other mutations (p < 0.0001 and p = 0.001). Specific hotspot mutations were associated with different protein expression patterns consistent with different functions.Conclusions: This study provides evidence that individual TP53 hotspot mutations have different impact on HGSOC patient outcomes and potentially TP53 function. Thus the status of particular TP53 aberrations could influence response to therapy and selection of therapeutic agents. [ABSTRACT FROM AUTHOR]

Most solid cancers are treated by surgical resections to reduce the burden of disease. Surgeons often face the challenge of detecting small areas of residual neoplasm after resection or finding small primary tumors for the initial resection. Intraoperative molecular imaging (IMI) is an emerging technology with the potential to dramatically improve cancer surgery operations by allowing surgeons to better visualize areas of neoplasm using fluorescence imaging. Over the last two years, two molecular optical contrast agents received U.S. Food and Drug Administration approval, and several more drugs are now on the horizon. Thus a conference was organized at the University of Pennsylvania to bring together oncologic surgeons from different specialties to discuss the current clinical status of IMI trials with a specific focus on phase 2 and phase 3 studies. In addition, phase 1 and experimental trials were also discussed briefly, to highlight other novel techniques. Our review summarizes the discussions from the conference and delves into the types of cancers discussed, different contrast agents in human trials, and the clinical value being studied. [ABSTRACT FROM AUTHOR]

OTL38 is a folate-indole-cyanine green-like conjugate to folate receptor alpha (FRa). The objectives of this prospective trial were to assess the safety and efficacy (sensitivity and positive predictive value (PPV)) of OTL38 for intraoperative imaging during epithelial ovarian cancer surgery. Patients with suspected ovarian cancer planned for cytoreductive surgery were eligible to receive OTL38. Near-infrared (NIR) imaging was used to visualize target lesions that were evaluated by two blinded pathologists. A modified intent to treat (mITT) population of lesions from all patients who received OTL38-NIR imaging, underwent surgery, and had at least one FRa + target lesion was used to determine sensitivity and PPV. Two generalized linear models, with and without random effects, were employed to estimate sensitivity and PPV. Forty-four patients were evaluated for safety, and 225 lesions from 29 patients (the mITT population) were evaluated for efficacy. When assuming no correlation of interlesional results within a patient, sensitivity was estimated at 85.93% (95% lower boundary CI = 81.19) and PPV at 88.14% (95% lower boundary CI = 83.59). When controlling for actual correlation of detection among multiple lesions within a single patient (a random effect), sensitivity was estimated at 97.97% (95% lower boundary CI = 87.75) and PPV at 94.93% (95% lower boundary CI = 86.13). A total of 48.3% [14/29, (95% CI 0.29–0.67)] of patients had at least one additional lesion detected by OTL38 alone. Eight patients had mild drug-related adverse events including infusion reaction, nausea, vomiting, and abdominal pain. OTL38-NIR was safe and efficacious in this phase II study regardless of folate expression levels and merits phase III evaluation. • OTL-38 binds preferentially to ovarian cancer tumors in this phase 2 study. • OTL-38-guided surgery was safe and detected additional ovarian cancer implants in half of subjects. • This study led to FDA support of a phase III trial NCT03180307. [ABSTRACT FROM AUTHOR]

This third biennial intraoperative molecular imaging (IMI) conference shows how optical contrast agents have been applied to develop clinically significant endpoints that improve precision cancer surgery. National and international experts on IMI presented ongoing clinical trials in cancer surgery and preclinical work. Previously known dyes (with broader applications), new dyes, novel nonfluorescence-based imaging techniques, pediatric dyes, and normal tissue dyes were discussed. Principal investigators presenting at the Perelman School of Medicine Abramson Cancer Center's third clinical trials update on IMI were selected to discuss their clinical trials and endpoints. Dyes that are FDA-approved or currently under clinical investigation in phase 1, 2, and 3 trials were discussed. Sections on how to move benchwork research to the bedside were also included. There was also a dedicated section for pediatric dyes and nonfluorescence-based dyes that have been newly developed. IMI is a valuable adjunct in precision cancer surgery and has broad applications in multiple subspecialties. It has been reliably used to alter the surgical course of patients and in clinical decision making. There remain gaps in the utilization of IMI in certain subspecialties and potential for developing newer and improved dyes and imaging techniques. [ABSTRACT FROM AUTHOR]

This study aimed to examine the factors affecting feasibility of optimal and complete secondary cytoreductive surgery (SCRS) and to characterise the prognostic factors that correlate with improved survival in patients who underwent SCRS. This is a retrospective single-institutional cohort study of patients who underwent SCRS for recurrent epithelial ovarian cancer (EOC). One hundred and forty-eight patients met inclusion criteria. Platinum sensitivity was associated with complete cytoreduction at SCRS. Factors associated with suboptimal cytoreduction (SOC) were age >55 years, serous histology, largest tumour implant size >4 cm, and SOC at primary surgery. Overall survival analysis showed significantly longer survival with complete cytoreduction compared to optimal and SOC. Surgical outcome of SCRS was an independent predictor of survival regardless of the outcome of primary cytoreduction. Location of the largest implant, DFI and timing of chemotherapy also impact on survival. [ABSTRACT FROM AUTHOR]

Oncogenic KRAS contributes to malignant transformation, antiapoptosis, and metastasis in multiple human cancers, such as lung, colon, and pancreatic cancers and melanoma. MicroRNAs (miRNAs) are endogenous 18- to 25-nucleotide noncoding small RNAs that regulate gene expression in a sequence-specific manner via the degradation of target mRNAs or inhibition of protein translation. In the present study, using array-based miRNA profiling in IMR90 and MCF10A cells expressing oncogenic KRAS, we identified that the expression of the microRNA 200 (mir-200) family was suppressed by KRAS activation and that this suppression was mediated by the transcription factors JUN and SP1 in addition to ZEB1. Restoration of mir-200 expression compromised KRAS-induced cellular transformation in vitro and tumor formation in vivo. In addition, we found that enforced expression of mir-200 abrogated KRAS-induced resistance to apoptosis by directly targeting the antiapoptotic gene BCL2. Finally, mir-200 was able to antagonize the epithelial-mesenchymal transition (EMT) driven by mutant KRAS. Collectively, our results suggest that repression of endogenous mir-200 expression is one of the important cellular responses to KRAS activation during tumor initiation and progression. [ABSTRACT FROM AUTHOR]

Objective Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Several factors prognostic for survival have been identified including the presence of certain lymphocyte markers. Tumor-infiltrating lymphocytes (TILs), particularly cytotoxic CD8 + TILs, have been shown to be most favorable for prognosis in ovarian cancer, although other immune cells including CD3 + T-cells, CD4 + T-cells, and B-cells have also demonstrated survival benefits. Although data for these markers exists, results are not uniform in the literature. Furthermore, other immunomodulatory protein markers that have been targeted in effective immunotherapies for other malignancies may prove to be favorable in ovarian cancer. Methods Here, extensive immunohistochemical analysis was performed on a tissue microarray, containing 135 ovarian cancer cases obtained during tumor debulking detecting 15 key lymphocyte markers such as CD3, CD4, and CD20, as well as activation and immunomodulatory molecules such as TIA-1 and PD-L1. Samples were analyzed for expression of markers in tumor islets or stroma and expression was correlated with overall survival, histotype, stage, age, debulking grade, and response to chemotherapy. Results Our results confirm the presence of CD8 + and CD20 + TILs is positively correlated with overall survival, with further multivariate modeling replicating that prognostic benefit. Additional markers of significant prognostic importance, including TIA-1, CD103 and HLA Class-II were also revealed. Conclusions Our results further support the vital role of cytotoxic T-cells in defense against ovarian cancer and reveals new questions as to the role of B-cells in tumor control as well as the potential benefits of immunotherapy involving other immune modulating molecules. [ABSTRACT FROM AUTHOR]

Objectives: To assess whether exposure to antibiotics (ABX) in the 90 days preceding initiation through the completion of first-line chemotherapy for epithelial ovarian carcinoma (EOC) is associated with decreased overall survival (OS) and truncated treatment-free interval (TFI), which we hypothesized. Methods: A retrospective cohort study of women with newly diagnosed stage III/IV EOC between 2009 to 2019 treated at a single institution was conducted. ABX exposure of >48 hours, timing with respect to chemotherapy initiation, and ABX class were captured. The association of ABX with TFI and OS was assessed with univariate and multivariable Cox proportional hazard models. Results: Of the 360 eligible women, 47% (n =170) were exposed to antibiotics, with 12% (n =46) receiving them only prior to first-line chemotherapy initiation, 23% (n =81) receiving them during chemotherapy, and 12% (n =43) receiving them before and during chemotherapy. Exposure to any ABX was associated with a decreased median OS (42.1 vs 60.0 months, HR: 1.33, 95% CI: 1.02-1.73, p=0.03) compared to no ABX. On subset analyses, ABX, specifically during chemotherapy, was associated with a decreased median OS (42.2 vs 60.0 months, HR: 1.46, 95% CI: 1.01-2.10). While exposure to ABX as a whole was not associated with TFI, receipt of ABX before chemotherapy was associated with a decreased TFI, with an HR of 1.76 (95% CI: 1.00-3.11, p=0.05), when compared to no ABX. Treatment with antibiotics against gram-positive organisms (GPO) with vancomycin, lin- cosamides, and macrolides was associated with worse OS (HR: 1.49, 95% CI: 1.01-2.20, p=0.049). In a multivariable analysis accounting for bowel surgery, exposure to granulocyte colony-stimulating factor, and IP chemo administration, exposure to ABX remained associated with an increased risk of death (HR: 1.38, 95% CI: 1.02-1.68, p=0.039). Conclusions: Patients with stage III/IV EOC exposed to ABX 90 days prior to chemotherapy had statistically significantly worse TFI compared to unexposed patients. In contrast, patients exposed to ABX during chemotherapy had worse OS compared to unexposed patients. Treatment with ABX targeting GPO decreased OS. Efforts to decrease the need for ABX, such as judicious prescription of ABX and implementation of perioperative infection prevention bundles, may offer an opportunity to increase survival in EOC. [ABSTRACT FROM AUTHOR]

Mitochondria provide energy for cells via oxidative phosphorylation. Reactive oxygen species, a byproduct of this mitochondrial respiration, can damage mitochondrial DNA (mtDNA), and somatic mtDNA mutations have been found in all colorectal, ovarian, breast, urinary bladder, kidney, lung, and pancreatic tumors studied. The resulting altered mitochondrial proteins or tumorassociated mitochondrial Ags (TAMAs) are potentially immunogenic, suggesting that they may be targetable Ags for cancer immunotherapy. In this article, we show that the RENCA tumor cell line harbors TAMAs that can drive an antitumor immune response. We generated a cellular tumor vaccine by pulsing dendritic cells with enriched mitochondrial proteins from RENCA cells. Our dendritic cell-based RENCA mitochondrial lysate vaccine elicited a cytotoxic T cell response in vivo and conferred durable protection against challenge with RENCA cells when used in a prophylactic or therapeutic setting. By sequencing mtDNA from RENCA cells, we identified two mutated molecules: COX1 and ND5. Peptide vaccines generated from mitochondrial-eneoded COX1 but not from ND5 had therapeutic properties similar to RENCA mitochondrial protein preparation. Thus, TAMAs can elicit effective antitumor immune responses, potentially providing a new immunotherapeutic strategy to treat cancer. [ABSTRACT FROM AUTHOR]

Summary The discovery of long non-coding RNA (lncRNA) has dramatically altered our understanding of cancer. Here, we describe a comprehensive analysis of lncRNA alterations at transcriptional, genomic, and epigenetic levels in 5,037 human tumor specimens across 13 cancer types from The Cancer Genome Atlas. Our results suggest that the expression and dysregulation of lncRNAs are highly cancer type specific compared with protein-coding genes. Using the integrative data generated by this analysis, we present a clinically guided small interfering RNA screening strategy and a co-expression analysis approach to identify cancer driver lncRNAs and predict their functions. This provides a resource for investigating lncRNAs in cancer and lays the groundwork for the development of new diagnostics and treatments. [ABSTRACT FROM AUTHOR]

Infiltration of cytotoxic T-lymphocytes in ovarian cancer is a favorable prognostic factor. Employing a differential expression approach, we have recently identified a number of genes associated with CD8+ T-cell infiltration in early stage ovarian tumors. In the present study, we validated by qPCR the expression of two genes encoding the transmembrane proteins GPC6 and TMEM132D in a cohort of early stage ovarian cancer patients. The expression of both genes correlated positively with the mRNA levels of CD8A, a marker of T-lymphocyte infiltration [Pearson coefficient: 0.427 (p = 0.0067) and 0.861 (p < 0.0001), resp.]. GPC6 and TMEM132D expression was also documented in a variety of ovarian cancer cell lines. Importantly, Kaplan-Meier survival analysis revealed that high mRNA levels of GPC6 and/or TMEM132D correlated significantly with increased overall survival of early stage ovarian cancer patients (p = 0.032). Thus, GPC6 and TMEM132D may serve as predictors of CD8+ T-lymphocyte infiltration and as favorable prognostic markers in early stage ovarian cancer with important consequences for diagnosis, prognosis, and tumor immunobattling. [ABSTRACT FROM AUTHOR]

Summary In a genome-wide survey on somatic copy-number alterations (SCNAs) of long noncoding RNA (lncRNA) in 2,394 tumor specimens from 12 cancer types, we found that about 21.8% of lncRNA genes were located in regions with focal SCNAs. By integrating bioinformatics analyses of lncRNA SCNAs and expression with functional screening assays, we identified an oncogene, f ocally a mplified l ncRNA on chromosome 1 ( FAL1 ), whose copy number and expression are correlated with outcomes in ovarian cancer. FAL1 associates with the epigenetic repressor BMI1 and regulates its stability in order to modulate the transcription of a number of genes including CDKN1A . The oncogenic activity of FAL1 is partially attributable to its repression of p21. FAL1 -specific siRNAs significantly inhibit tumor growth in vivo. [ABSTRACT FROM AUTHOR]

T-lymphocyte infiltration in ovarian tumors has been linked to a favorable prognosis, hence, exploring the mechanism of T-cell recruitment in the tumor is warranted. We employed a differential expression analysis to identify genes over-expressed in early stage ovarian cancer samples that contained CD8 infiltrating T-lymphocytes. Among other genes, we discovered that TTF1, a regulator of ribosomal RNA gene expression, and SMARCE1, a factor associated with chromatin remodeling were overexpressed in first stage CD8+ ovarian tumors. TTF1 and SMARCE1 mRNA levels showed a strong correlation with the number of intra-tumoral CD8+ cells in ovarian tumors. Interestingly, forced overexpression of SMARCE1 in SKOV3 ovarian cancer cells resulted in secretion of IL8, MIP1b and RANTES chemokines in the supernatant and triggered chemotaxis of CD8+ lymphocytes in a cell culture assay. The potency of SMARCE1-mediated chemotaxis appeared comparable to that caused by the transfection of the CXCL9 gene, coding for a chemokine known to attract T-cells. Our analysis pinpoints TTF1 and SMARCE1 as genes potentially involved in cancer immunology. Since both TTF1 and SMARCE1 are involved in chromatin remodeling, our results imply an epigenetic regulatory mechanism for T-cell recruitment that invites deciphering. [ABSTRACT FROM AUTHOR]

Patients with ovarian cancer are at high risk of tumor recurrence. Prediction of therapy outcome may provide therapeutic avenues to improve patient outcomes. Using reverse-phase protein arrays, we generated ovarian carcinoma protein expression profiles on 412 cases from TCGA and constructed a PRotein-driven index of OVARian cancer (PROVAR). PROVAR significantly discriminated an independent cohort of 226 high-grade serous ovarian carcinomas into groups of high risk and low risk of tumor recurrence as well as short-term and long-term survivors. Comparison with gene expression-based outcome classification models showed a significantly improved capacity of the protein-based PROVAR to predict tumor progression. Identification of protein markers linked to disease recurrence may yield insights into tumor biology. When combined with features known to be associated with outcome, such as BRCA mutation, PROVAR may provide clinically useful predictions of time to tumor recurrence. [ABSTRACT FROM AUTHOR]

The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1+CD8+ TIL can be, however, polyfunctional. PD-1+ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L. [Display omitted] • Ovarian islets are enriched in activated tumor-specific lymphocytes • Intraepithelial myeloid APC niches harbor polyfunctional TIL with increased fitness • TIL activation on αPD-1 depends on CD28 costimulation catered by myeloid APCs in situ • αPD-1 is enhanced in situ by αCTLA-4 through CD28 or by CD40L via APC activation Duraiswamy et al. characterize tumor-specific CD8+ lymphocytes infiltrating high-grade serous epithelial ovarian cancer and note their close association with intraepithelial myeloid APC niches in situ. Intraepithelial myeloid APC niches support tumor-infiltrating lymphocytes with CD28 costimulation in situ , sustaining antitumor immune attack and enabling response to PD-1 blockade. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction. [Display omitted] • CAR T cells under chronic antigen stimulation show hallmarks of T cell exhaustion • CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition • CAR T cells with NK-like transition were identified in patients after treatment • Unlike WT CAR T cells, ID3 and SOX4 knockout CAR T cells retain anti-tumor immunity Continuous antigen exposure drives CAR T cell exhaustion and promotes CD8+ T-to-NK-like T cell transition. Transcription factors ID3 and SOX4 are upregulated during CAR dysfunction and regulate genes associated with exhaustion, including NK receptors. Knocking out ID3 and SOX4 in CAR T cells slows dysfunction and improves anti-tumor immunity. [ABSTRACT FROM AUTHOR]

The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1+CD8+ TIL can be, however, polyfunctional. PD-1+ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L. [Display omitted] • Ovarian islets are enriched in activated tumor-specific lymphocytes • Intraepithelial myeloid APC niches harbor polyfunctional TIL with increased fitness • TIL activation on αPD-1 depends on CD28 costimulation catered by myeloid APCs in situ • αPD-1 is enhanced in situ by αCTLA-4 through CD28 or by CD40L via APC activation Duraiswamy et al. characterize tumor-specific CD8+ lymphocytes infiltrating high-grade serous epithelial ovarian cancer and note their close association with intraepithelial myeloid APC niches in situ. Intraepithelial myeloid APC niches support tumor-infiltrating lymphocytes with CD28 costimulation in situ , sustaining antitumor immune attack and enabling response to PD-1 blockade. [ABSTRACT FROM AUTHOR]

Purpose: Ovarian cancer, like most solid tumors, is in dire need of effective therapies. The significance of this trial lies in its promise to spearhead the development of combination immunotherapy and to introduce novel approaches to therapeutic immunomodulation, which could enable otherwise ineffective vaccines to achieve clinical efficacy.Rationale: Tumor-infiltrating T cells have been associated with improved outcome in ovarian cancer, suggesting that activation of antitumor immunity will improve survival. However, molecularly defined vaccines have been generally disappointing. Cancer vaccines elicit a modest frequency of low-to-moderate avidity tumor-specific T-cells, but powerful tumor barriers dampen the engraftment, expansion and function of these effector T-cells in the tumor, thus preventing them from reaching their full therapeutic potential. Our work has identified two important barriers in the tumor microenvironment: the blood-tumor barrier, which prevents homing of effector T cells, and T regulatory cells, which inactivate effector T cells. We hypothesize that cancer vaccine therapy will benefit from combinations that attenuate these two barrier mechanisms.Design: We propose a three-cohort sequential study to investigate a combinatorial approach of a new dendritic cell (DC) vaccine pulsed with autologous whole tumor oxidized lysate, in combination with antiangiogenesis therapy (bevacizumab) and metronomic cyclophosphamide, which impacts Treg cells.Innovation: This study uses a novel autologous tumor vaccine developed with 4-day DCs pulsed with oxidized lysate to elicit antitumor response. Furthermore, the combination of bevacizumab with a whole tumor antigen vaccine has not been tested in the clinic. Finally the combination of bevacizumab and metronomic cyclophosphamide in immunotherapy is novel. [ABSTRACT FROM AUTHOR]

Aim: To present the gastrointestinal (GI) complications associated with bevacizumab therapy and their findings on abdominal imaging studies. Methods: A computerized search identified 11 patients with GI complications of bevacizumab therapy on abdominal CT (n = 11) and fluoroscopic GI contrast studies (n = 4) who met our study criteria (including five patients with ovarian cancer, five with colon cancer, and one with cervical cancer). The medical records and imaging studies were reviewed to determine the clinical and radiographic findings in these patients. Results: All 11 patients had findings of GI perforation on CT, or CT and GI contrast studies. CT revealed a localized extraluminal collection containing gas, fluid, and/or contrast material in eight patients (73%) with focal perforation, and free abdominal air and fluid in three (27%) with free perforation The imaging studies also revealed seven fistulas, including two colovaginal, one rectovaginal, one enterocutaneous, one colocutaneous, one gastrocolic, and one colorectal fistula. Eight (73%) of the 11 patients died within 1 year of the development of GI perforation, and the perforation was felt to be the cause of death in four patients (36%). Conclusion: Abdominal CT and fluoroscopic GI contrast studies are useful imaging tests for the diagnosis of potentially life-threatening GI perforation as a complication of bevacizumab therapy. When GI perforation is detected on abdominal imaging studies, treatment with bevacizumab should immediately be discontinued. [ABSTRACT FROM AUTHOR]

The most cancer-specific biomarkers in blood are likely to be proteins shed directly by the tumor rather than less specific inflammatory or other host responses. The use of xenograft mouse models together with in-depth proteome analysis for identification of human proteins in the mouse blood is an under-utilized strategy that can clearly identify proteins shed by the tumor. In the current study, 268 human proteins shed into mouse blood from human OVCAR-3 serous tumors were identified based upon human vs. mouse species differences using a four-dimensional plasma proteome fractionation strategy. A multi-step prioritization and verification strategy was subsequently developed to efficiently select some of the most promising biomarkers from this large number of candidates. A key step was parallel analysis of human proteins detected in the tumor supernatant, because substantially greater sequence coverage for many of the human proteins initially detected in the xenograft mouse plasma confirmed assignments as tumor-derived human proteins. Verification of candidate biomarkers in patient sera was facilitated by in-depth, label-free quantitative comparisons of serum pools from patients with ovarian cancer and benign ovarian tumors. The only proteins that advanced to multiple reaction monitoring (MRM) assay development were those that exhibited increases in ovarian cancer patients compared with benign tumor controls. MRM assays were facilely developed for all 11 novel biomarker candidates selected by this process and analysis of larger pools of patient sera suggested that all 11 proteins are promising candidate biomarkers that should be further evaluated on individual patient blood samples. [ABSTRACT FROM AUTHOR]

Novel strategies for the therapy of recurrent ovarian cancer are warranted. We report a study of a combinatorial approach encompassing dendritic cell (DC)-based autologous whole tumor vaccination and anti-angiogenesis therapy, followed by the adoptive transfer of autologous vaccine-primed CD3/CD28-co-stimulated lymphocytes. Recurrent ovarian cancer patients for whom tumor lysate was available from prior cytoreductive surgery underwent conditioning with intravenous bevacizumab and oral metronomic cyclophosphamide, sequentially followed by (1) bevacizumab plus vaccination with DCs pulsed with autologous tumor cell lysate supernatants, (2) lymphodepletion and (3) transfer of 5 × 109 autologous vaccine-primed T-cells in combination with the vaccine. Feasibility, safety as well as immunological and clinical efficacy were evaluated. Six subjects received this vaccination. Therapy was feasible, well tolerated, and elicited antitumor immune responses in four subjects, who also experienced clinical benefits. Of these, three patients with residual measurable disease received outpatient lymphodepletion and adoptive T-cell transfer, which was well tolerated and resulted in a durable reduction of circulating regulatory T cells and increased CD8+ lymphocyte counts. The vaccine-induced restoration of antitumor immunity was achieved in two subjects, who also demonstrated clinical benefits, including one complete response. Our findings indicate that combinatorial cellular immunotherapy for the treatment of recurrent ovarian cancer is well tolerated and warrants further investigation. Several modifications of this approach can be envisioned to optimize immunological and clinical outcomes. [ABSTRACT FROM AUTHOR]

In human cancer, expression of the let-7 family is significantly reduced, and this is associated with shorter survival times in patients. However, the mechanisms leading to let-7 downregulation in cancer are still largely unclear. Since an alteration in copy-number is one of the causes of gene deregulation in cancer, we examined copy number alterations of the let-7 family in 2,969 cancer specimens from a high-resolution SNP array dataset. We found that there was a reduction in the copy number of let-7 genes in a cancer-type specific manner. Importantly, focal deletion of four let-7 family members was found in three cancer types: medulloblastoma (let-7a-2 and let-7e), breast cancer (let-7a-2), and ovarian cancer (let-7a-3/let-7b). For example, the genomic locus harboring let-7a-3/let-7b was deleted in 44% of the specimens from ovarian cancer patients. We also found a positive correlation between the copy number of let-7b and mature let-7b expression in ovarian cancer. Finally, we showed that restoration of let-7b expression dramatically reduced ovarian tumor growth in vitro and in vivo. Our results indicate that copy number deletion is an important mechanism leading to the downregulation of expression of specific let-7 family members in medulloblastoma, breast, and ovarian cancers. Restoration of let-7 expression in tumor cells could provide a novel therapeutic strategy for the treatment of cancer. [ABSTRACT FROM AUTHOR]

The RNA-binding protein LIN28A regulates the translation and stability of a large number of mRNAs as well as the biogenesis of certain miRNAs in embryonic stem cells and developing tissues. Increasing evidence indicates that LIN28A functions as an oncogene promoting cancer cell growth. However, little is known about its molecular mechanism of cell cycle regulation in cancer. Using tissue microarrays, we found that strong LIN28A expression was reactivated in about 10% (7.1-17.1%) of epithelial tumors (six tumor types, n = 369). Both in vitro and in vivo experiments demonstrate that LIN28A promotes cell cycle progression in cancer cells. Genome-wide RNA-IP-chip experiments indicate that LIN28A binds to thousands of mRNAs, including a large group of cell cycle regulatory mRNAs in cancer and embryonic stem cells. Furthermore, the ability of LIN28A to stimulate translation of LIN28A-binding mRNAs, such as CDK2, was validated in vitro and in vivo. Finally, using a combined gene expression microarray and bioinformatics approach, we found that LIN28A also regulates CCND1 and CDC25A expression and that this is mediated by inhibiting the biogenesis of let-7 miRNA. Taken together, these results demonstrate that LIN28A is reactivated in about 10% of epithelial tumors and promotes cell cycle progression by regulation of both mRNA translation (let-7-independent) and miRNA biogenesis (let-7-dependent). [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Vaginal dysplasia is associated with prior radiation therapy (RT) for gynecologic malignancies. We reviewed our institution''s experience with VAIN in patients who were treated with radiation therapy for a gynecologic malignancy. Methods: A retrospective review of patients treated for VAIN was performed. All cases of patients followed and treated for VAIN after radiation therapy were identified (n=10), along with a cohort of patients with VAIN who did not have radiation therapy (n=23). Results: Mean follow-up after initial diagnosis of VAIN was 37.6months (range: 12 to 72). Cytologic screening events after diagnosis of VAIN (n=105) showed that patients with prior RT were more than twice as likely to have recurrent dysplasia (OR 3.625, 95% CI=from 1.454 to 9.0376) after treatment. Of patients who recurred, the mean time to first recurrence was 12.3months in cases and 15.3months in controls, which was not statistically significant (p=0.31). Screening practices at our institution ranged from 3month to 12month intervals. 3 patients in the RT group and 1 patient in the control group developed invasive squamous cell cancer of the vagina. Conclusions: Vaginal dysplasia after radiation therapy is more refractory to treatment than dysplasia not associated with radiation therapy, more likely to recur after surgical and ablative therapy, and may also be more likely to progress to invasive cancer. These data support the need for further study to determine the optimal follow-up screening interval and whether aggressive surgical or ablative treatment stems disease progression in this clinical scenario. [Copyright &y& Elsevier]

Lysophosphatidic acid (LPA) is a naturally occurring phospholipid that exhibits pleiotrophic biological activities, ranging from rapid morphological changes to long-term cellular effects such as induction of gene expression and stimulation of cell proliferation and survival on a wide spectrum of cell types. LPA binds and activates distinct members of the Edg/LP subfamily of G protein-coupled receptors that link to multiple G proteins including G(i), G(q) and G(12/13) to elicit cellular responses. LPA plays a critical role as a general growth, survival and pro-angiogenic factor, in the regulation of physiological and pathophysiological processes in vivo and in vitro. Our previous work indicates that abnormalities in LPA metabolism and function in ovarian cancer patients may contribute to the initiation and progression of the disease. Thus, LPA could be a potential target for cancer therapy. This review summarizes evidence that implicates LPA in the pathophysiology of human ovarian cancer and likely other types of human malignancies. [Copyright &y& Elsevier]

Significance: Surgery is often paramount in the management of many solid organ malignancies because optimal resection is a major factor in disease-specific survival. Cancer surgery has multiple challenges including localizing small lesions, ensuring negative surgical margins around a tumor, adequately staging patients by discriminating positive lymph nodes, and identifying potential synchronous cancers. Intraoperative molecular imaging (IMI) is an emerging potential tool proposed to address these issues. IMI is the process of injecting patients with fluorescent-targeted contrast agents that highlight cancer cells prior to surgery. Over the last 5 to 7 years, enormous progress has been achieved in tracer development, near-infrared camera approvals, and clinical trials. Therefore, a second biennial conference was organized at the University of Pennsylvania to gather surgical oncologists, scientists, and experts to discuss new investigative findings in the field. Our review summarizes the discussions from the conference and highlights findings in various clinical and scientific trials. Aim: Recent advances in IMI were presented, and the importance of each clinical trial for surgical oncology was critically assessed. A major focus was to elaborate on the clinical endpoints that were being utilized in IMI trials to advance the respective surgical subspecialties. Approach: Principal investigators presenting at the Perelman School of Medicine Abramson Cancer Center's second clinical trials update on IMI were selected to discuss their clinical trials and endpoints. Results: Multiple phase III, II, and I trials were discussed during the conference. Since the approval of 5-ALA for commercial use in neurosurgical malignancies, multiple tracers and devices have been developed to address common challenges faced by cancer surgeons across numerous specialties. Discussants also presented tracers that are being developed for delineation of normal anatomic structures that can serve as an adjunct during surgical procedures. Conclusions: IMI is increasingly being recognized as an improvement to standard oncologic surgical resections and will likely advance the art of cancer surgery in the coming years. The endpoints in each individual surgical subspecialty are varied depending on how IMI helps each specialty solve their clinical challenges. [ABSTRACT FROM AUTHOR]