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.

Vesical clear cell adenocarcinoma of Müllerian origin treated conservatively with partial cystectomy.

A 71-year-old woman presented with an intravesical bladder mass found to be a clear cell adenocarcinoma of Müllerian origin with positive PAX-8 staining after transurethral resection. Partial cystectomy along with total hysterectomy were performed, and final pathology revealed no residual tumour and extensive endometriosis. She declined adjuvant therapy and was dispositioned to surveillance.

A phase 2 evaluation of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability.

BACKGROUND: Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter responses to ICIs is unclear. This article reports data from a prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI-H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential mechanisms of primary/secondary ICI resistance (NCT02899793). METHODS: Patients with measurable MSI-H/dMMR EC confirmed by polymerase chain reaction/immunohistochemistry were evaluated by WES and received 200 mg of pembrolizumab every 3 weeks for ≤2 years. The primary end point was the objective response rate (ORR). Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-five patients (24 evaluable) were treated. Six patients (25%) harbored Lynch/Lynch-like tumors, whereas 18 (75%) had sporadic EC. The tumor mutation burden was higher in Lynch-like tumors (median, 2939 mutations/megabase [Mut/Mb]; interquartile range [IQR], 867-5108 Mut/Mb) than sporadic tumors (median, 604 Mut/Mb; IQR, 411-798 Mut/Mb; P = .0076). The ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients (P = .024). The 3-year PFS and OS proportions were 100% versus 30% (P = .017) and 100% versus 43% (P = .043), respectively. CONCLUSIONS: This study suggests prognostic significance of Lynch-like cancers versus sporadic MSI-H/dMMR ECs for ORR, PFS, and OS when patients are treated with pembrolizumab. Larger confirmatory studies in ECs and other MSI-H/dMMR tumors are necessary. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI-H ECs. Oligoprogression in MSI-H/dMMR patients appears salvageable with surgical resection and/or local treatment and the continuation of pembrolizumab off study. Clinical studies evaluating separate MSI-H/dMMR EC subtypes treated with ICIs are warranted.

Femoral fracture in pregnancy: a case series and review of clinical management.

Femoral fractures in pregnancy are a rare complication, with an incidence of approximately 1%. Case reports and small trials leave perioperative obstetric management and route of delivery largely unclear. Three cases of femoral fracture are presented that occurred at 24, 30, and 31 weeks of gestation. The causes of femoral fracture were gunshot, motor vehicle collision, and fragility fracture. All fractures were surgically repaired, 1 utilizing neuraxial anesthesia and the others with general anesthesia. A 30-day postoperative course of low-molecular-weight heparin was prescribed, and all patients subsequently had vaginal deliveries. Femoral fractures in the viable pregnancy confer high maternal and fetal morbidity and mortality. Intraoperative fetal monitoring and postoperative anticoagulation should be considered, and vaginal delivery should not be contraindicated.

Pharmacokinetics and clinical response to single agent rucaparib in a dialysis dependent patient with BRCA associated breast and recurrent ovarian cancer.

A 56-year old woman with BRCA-associated breast cancer and recurrent ovarian cancer was treated with a poly (ADP-ribose) polymerase enzyme (PARP) inhibitor, rucaparib, in the setting of dialysis-dependence which required dose modification. Rucaparib trough levels were obtained before and after dialysis and a clinically significant disease response was appreciated.