The impact of nativity on uterine cancer survival in the public hospital system of Queens, New York.

OBJECTIVE: We studied cis-women with uterine cancer presenting to the two Public Hospitals in Queens, New York from 2006 to 2015 to examine the relationship between nativity (birthplace) and survival. METHODS: A retrospective review of tumor registries identified women diagnosed with uterine cancer between January 1, 2006, and December 31, 2015. Data from 259 women were available for this analysis. RESULTS: Most women were born outside the United States (US) (76% versus 24%). The majority of US-born women were black (68%). Seventy-seven women (30%) were born in Latin America, 76 in the Caribbean Islands (29%) and 44 in Asia/South Asia (17%). Most women presented with stage I/II disease (70%) and endometrioid/mucinous histology (68%) with no significant differences observed among nativity groups. Kaplan-Meier estimated survival curves stratified by birthplace demonstrated significant differences in survival distributions among the groups using the log-rank test (P < 0.0001). The most favorable survival curves were observed among all foreign-born women, whereas the least favorable survival was demonstrated in US-born women. Time to death was analyzed using the Cox proportional hazards model. Adjusting for age of diagnosis, insurance status, stage, and treatment modality, Latin American and Asia/South Asia birthplace was significantly associated with increased survival time. CONCLUSION: An immigrant health paradox was defined for foreign-born Latin American and Asian/South Asian women presenting to the two Public Hospitals of Queens, New York, as women born in these geographic regions were less likely to die at any given time compared to those born in the United States.

In Vivo and In Vitro Efficacy of Trastuzumab Deruxtecan in Uterine Serous Carcinoma.

Uterine serous carcinoma (USC) is a rare, biologically aggressive variant of endometrial cancer with a high recurrence rate and poor prognosis. HER2 overexpression (3+ positivity) by IHC and/or FISH ERBB2 gene amplification is detected in approximately one-third of patients with USC. Clinical trials incorporating trastuzumab with standard chemotherapy have recently demonstrated improved progression-free and overall survival in advanced-stage or recurrent USC that overexpresses HER2. However, a large number of patients with USC eventually developed resistance to trastuzumab. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody-drug conjugate with a topoisomerase I inhibitor payload recently approved by the Food and Drug Administration (FDA) for multiple tumor indications. Here, we investigated the in vitro and in vivo efficacy of T-DXd in primary USC cell lines and xenografts with different HER2 expression. T-DXd-induced cell growth suppression in HER2-overexpressing cell lines in vitro, increased early and late apoptosis as assessed by annexin and propidium iodide staining, and, similarly to trastuzumab, T-DXd-induced significant antibody-dependent cellular cytotoxicity in the presence of peripheral blood lymphocytes. While negligible activity was detected against USC cell lines with low HER2 expression, T-DXd demonstrated significant bystander killing against USC tumors with low/negligible HER2 when such cells were admixed with HER2 3+ tumor cells in vitro. T-DXd showed tumor growth suppression in in vivo USC PDX models that overexpress HER2 at 3+ levels, prolonging survival when compared with controls, with minimal toxicity. Future clinical trials are warranted in patients with USC failing trastuzumab treatment.

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment modality that aims to target the main site of tumor dissemination in ovarian cancer, the peritoneum, by combining the benefits of intraperitoneal chemotherapy with the synergistic effects of hyperthermia all during a single administration at the time of cytoreductive surgery. High-quality evidence currently only supports the use of HIPEC with cisplatin at the time of interval cytoreduction after neoadjuvant chemotherapy for stage III epithelial ovarian cancer. Many questions remain, including HIPEC's role at other timepoints in ovarian cancer treatment, who are optimal candidates, and specifics of HIPEC protocols. This article reviews the history of normothermic and hyperthermic intraperitoneal chemotherapy in ovarian cancer and evidence regarding HIPEC implementation and patient outcomes. Additionally, this review explores details of HIPEC technique and perioperative care, cost considerations, complication and quality of life data, disparities in HIPEC use, and unresolved issues.

The Poly (ADP-ribose) polymerase inhibitor olaparib and pan-ErbB inhibitor neratinib are highly synergistic in HER2 overexpressing epithelial ovarian carcinoma in vitro and in vivo.

INTRODUCTION: Ovarian cancer (OC) is associated with the highest gynecologic cancer mortality. The development of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical efficacy of the Poly (ADP-ribose) polymerase (PARP) inhibitor (olaparib) and the pan-ErbB inhibitor (neratinib) as single agents and in combination in ovarian cancer cell lines and xenografts with variable HER2 expression. METHODS: In vitro cell viability with olaparib, neratinib, and their combination was assessed using flow-cytometry based assays against a panel of OC primary cell lines with variable HER2 expression. Immunoblotting experiments were performed to elucidate the mechanism of activity and synergism. The in vivo antitumor activity of the olaparib/neratinib combination versus single agents was tested in HER2 positive xenograft OC models. RESULTS: HER2 + OC cell lines demonstrated higher sensitivity to olaparib and neratinib when compared to HER2 negative tumors (i.e., IC50: 2.06 ± 0.33 µM vs. 39.28 ± 30.51 µM, p = 0.0035 for olaparib and 19.42 ± 2.63 nM vs. 235.0 ± 165.0 nM, p = 0.0035 for neratinib). The combination of olaparib with neratinib was more potent when compared to single-agent olaparib or neratinib both in vitro and in vivo, and demonstrated synergy in all primary HER2 + OC models. Western blot experiments showed neratinib decreased pHER2/neu while increased Poly(ADP-ribose) (PAR) enzymatic activity; olaparib increased pHER2/Neu expression and blocked PAR activatio. Olaparib/neratinib in combination decreased both pHER2/Neu as well as PAR activation. CONCLUSION: The combination of olaparib and neratinib is synergistic and endowed with remarkable preclinical activity against HER2+ ovarian cancers. This combination may represent a novel therapeutic option for ovarian cancer patients with HER2+, homologous recombination-proficient tumors resistant to chemotherapy.

Ovarian and uterine carcinosarcomas are sensitive in vitro and in vivo to elimusertib, a novel ataxia-telangiectasia and Rad3-related (ATR) kinase inhibitor.

BACKGROUND: Carcinosarcoma of the ovary (OCS) and uterus (UCS) are rare highly aggressive malignancies. Ataxia-telangiectasia-and-Rad3-related (ATR) kinase and homologous recombination play a pivotal role in DNA damage repair. Homologous recombination deficiency (HRD) has been demonstrated in >30% of OCS/UCS. We investigated the preclinical activity of elimusertib, a selective ATR kinase inhibitor, against carcinosarcoma (CS) cell lines and xenografts. METHODS: Sensitivity to elimusertib was evaluated in vitro against nine whole exome-sequenced (WES) primary CS cell lines and in vivo against HRD CS xenografts. Western blots were performed to determine baseline ATR and p-ATR protein expression in CS, and ATR pathway downstream effectors and apoptosis markers in CS HRD cell lines after Elimusertib treatment. RESULTS: Out of the 9 CS cell lines, 3 harbored HRD and 6 homologous recombination proficient (HRP) features. Most of CS (i.e., 7/9 = 85%) were found to be sensitive to Elimusertib in vitro. Among the 5 primary CS cell lines with a high-grade pure serous epithelial component, HRD cell lines were more sensitive to elimusertib than HRP tumors (mean IC50 ± SEM HRD CS = 61.3 nM ±15.2 vs HRP = 361.6 nM ±24.4 (p = 0.01)). Baseline ATR and p-ATR protein expression was higher in HRD CS cell lines. Elimusertib showed tumor growth inhibition in HRD CS xenografts (p < 0.0001) and increased overall animal survival (p < 0.0001). Western blot demonstrated dose-dependent inhibition of ATR, p-ATR and its downstream effector p-CHK1, and a dose-dependent increase in caspase-3 expression. CONCLUSIONS: Elimusertib is preclinically active in vitro and in vivo against primary CS cell lines and xenografts, respectively. CS models harboring HRD or with pure/mixed endometrioid histology demonstrated higher sensitivity to ATR inhibition. Clinical trials with elimusertib in CS patients are warranted.

The impact of nativity on cervical cancer survival in the public hospital system of Queens, New York.

OBJECTIVE: We studied cervical cancer patients who presented to the Public Hospital System in ethnically-diverse Queens, New York from 2000 to 2010 with the purpose of examining the relationship between nativity (birthplace) and survival. METHODS: A retrospective review of tumor registries was used to identify patients diagnosed with cervical cancer between January 1, 2000 and December 31, 2010. Using electronic medical records, data from 317 patients were available for this analysis. RESULTS: The majority of patients were born outside the United States (US) (85.5% versus 14.5%). One hundred patients (31.5%) were born in Latin America, 105 in the Caribbean Islands (33.1%), 48 in Asia (15.1%), 8 in the South Asia (2.5%), 10 in Russia/Eastern Europe (3.2%) and 46 (14.5%) in the United States. Patients presented at varying stages of disease: 51.4% at stage I, 19.6% at stage II, 19.6% at stage III, and 8.5% at stage IV. Kaplan-Meier estimated survival curves stratified by birthplace demonstrated significant differences in survival distributions among the groups using the log-rank test (P<0.0001). The most favorable survival curves were observed among patients born in Latin America and Asia whereas the least favorable was demonstrated in US-born patients. Time to death was analyzed using the Cox proportional hazards model. Adjusting for age at diagnosis, insurance status, stage and treatment modality, nodal metastases and hydronephrosis, birthplace was significantly associated with survival time (P<0.0001). CONCLUSION: An immigrant health paradox was defined for foreign-born Latino and Asian patients presenting with cervical cancer to the Public Hospital System of Queens, New York as patients born in Latin America and Asia were less likely to die at any given time compared to those born in the United States.

Platinum (II) complex-nuclear localization sequence peptide hybrid for overcoming platinum resistance in cancer therapy.

Platinum therapy represents first line of treatment in many malignancies but its high systemic toxicity limits the therapeutic dosage. Herein, we report the synthesis of carboplatin-like complexes with azide and alkyne functional groups and the formation of a platinum (II) - nuclear localization sequence peptide (Pt-NLS) hybrid to improve the import of platinum (II) complexes directly into the cell's nucleus. The Pt-NLS hybrid successfully enters cells and their nuclei, forming Pt-induced nuclear lesions. The in vitro efficacy of Pt-NLS is high, superior to native carboplatin at the same concentration. The methodology used is simple and cost-effective and most importantly can easily be extended to load the Pt (II) onto other supports, opening new possibilities for enhanced delivery of Pt (II) therapy.

A critical re-appraisal of BRCA1 methylation studies in ovarian cancer.

A central challenge facing gynecologic oncology is achieving personalized care in ovarian cancer treatment. The current ovarian cancer classification scheme distinguishes tumors based on histopathologic subtype, grade, and surgical stage. Recent molecular investigations have highlighted distinguishing genetic features of certain tumors within a given category, and given the rapid pace of technologic advancement combined with plummeting costs for complete genomic sequencing this classification will markedly improve. Clinical studies have begun to explore the influence of currently known distinctions on the natural history of the disease, most recently with particular attention to the BRCA1 status of tumors. Mutations in the BRCA1 gene have long been known to increase a woman's risk of developing ovarian cancer. As has been shown, BRCA1-associated ovarian cancers may be associated with characteristic differences in therapeutic response and overall survival, and further defining these subsets may become instrumental in clinical decision-making. Therefore, given the eightfold difference (5-40%) in reported frequency of BRCA1 inactivation by methylation in the pioneering studies in the field, a critical re-appraisal of the literature, techniques, samples used, and interpretations of BRCA1 inactivation is warranted along with a review of the more recent and comprehensive molecular studies.

Caracterizaçäo morfométrica das lesöes do colo uterino relacionadas ao vírus da papilomatose humana / Morphometric characterization of cervix uteri lesions related to human papillomatosis virus

Este estudo é voltado para os seguintes aspectos ligados às lesSes cervicais relacionadas ao Vírus da Papilomatose Humana (VPH): 1) identificaçäo do vírus em tecido histologicamente normal; 2) diferenciaçäo morfométrica das alteraçSes induzidas pelo subtipo do VPH em condilomas, e 3) as diferenças morfométricas entre condiloma puro e Neoplasia Cervical Intraeptelial do Grau I (NIC I). Usamos o índice morfométrico núcleo/citoplasmático para as medidas da área, perímetro e máximo diâmetro, da célula e do núcleo celular. Quarenta e oito lâminas de biópsias cervicais foram estudadas e os achados, classificados dentro de três grupos: normal (22 casos), condiloma (20 casos) e NIC I (6 casos). A presença do DNA do VPH, detectada usando-se a metodologia da hibridizaçäo in situ, foi usada para estudar se o tecido histologicamente normal seria reconhecido como sendo infectado pelo VPH. Os casos de condiloma foram entäo comparados por meio de análise morfométrica para o subtipo do DNA do VPH por hibridizaçäo in situ, a fim de diferenciar os subtipos de VPH de baixo e alto risco. Os parâmetros foram avaliados por análise multivariada e demonstraram classificar corretamente todos os casos, exceto dois, com uma probabilidade posterior bastante elevada. Concluímos que os dados morfométricos foram úteis no diagnóstico diferencial entre as lesöes cervicais relacionadas ao VPH.