Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) experience in patients with recurrent low grade serous ovarian carcinoma (LGSOC): sub-cohort report of phase 1 clinical trial.

Introduction: Low grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer (OC) that is challenging to treat due to its relative chemoresistance. Given that LGSOC patients often recur in the peritoneal cavity, novel intraperitoneal (IP) chemotherapy should be explored. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a method that has demonstrated peritoneal disease control in cancers with peritoneal metastases. Methods: NCT04329494 is a US multicenter phase 1 trial evaluating the safety of PIPAC in recurrent ovarian, uterine, and GI cancers with peritoneal metastases. This analysis describes the outcomes of a sub-cohort of four LGSOC patients treated with IP cisplatin 10.5 mg/m2, doxorubicin 2.1 mg/m2 PIPAC q4-6 weeks. Primary endpoints included dose-limiting toxicities (DLT) and incidence of adverse events (AE). Secondary endpoints were progression free survival (PFS) and treatment response based on radiographic, intraoperative, and pathological findings. Results: Four patients with LGSOC were enrolled of which three were heavily pretreated. Median prior lines of therapy was 5 (range 2-10). Three patients had extraperitoneal metastases, and two patients had baseline partial small bowel obstructive (SBO) symptoms. Median age of patients was 58 (38-68). PIPAC completion rate (≥2 PIPACs) was 75%. No DLTs or Clavien-Dindo surgical complications occurred. No G4/G5 AEs were observed, and one G3 abdominal pain was reported. One patient had a partial response after 3 cycles of PIPAC and completed an additional 3 cycles with compassionate use amendment. Two patients came off study after 2 cycles due to extraperitoneal progressive disease. One patient came off study after 1 cycle due to toxicity. Median decrease in peritoneal carcinomatosis index between cycles 1 and 2 was 5.0%. Ascites decreased in 2 out of 3 patients who had ≥2 PIPACs. Median PFS was 4.3 months (1.7-21.6), median overall survival was 11.6 months (5.4-30.1), and objective response rate was 25%. Conclusion: PIPAC with cisplatin/doxorubicin is well tolerated in LGSOC patients without baseline SBO symptoms. IP response was seen in 2 out of 3 patients that completed ≥2 PIPAC cycles. Further study of PIPAC for patients with recurrent disease limited to the IP cavity and with no partial SBO symptoms should be considered.

SMARCA4 / BRG1 -deficient Uterine Neoplasm With Hybrid Adenosarcoma and Carcinoma Features: Expanding the Molecular-morphologic Spectrum of SMARCA4 -driven Gynecologic Malignancies.

SMARCA4 gene encodes BRG1 , a member of the SWItch/sucrose non-fermentable protein family involved in epigenetic transcriptional regulation of important cellular processes. In the uterine corpus, SMARCA4 / BRG1 deficiency is associated with a novel class of undifferentiated uterine sarcomas, characterized by younger age onset, rhabdoid histology, focal phyllodiform architecture, high-risk pathologic findings, and dismal prognosis. Herein, we report a case of a 34-year-old Asian woman with a SMARCA4 / BRG1 -deficient uterine tumor fulfilling the clinicopathologic features of an undifferentiated uterine sarcoma. However, the tumor exhibited several unique features that have not been previously emphasized, including (1) conspicuous phyllodiform architecture recapitulating conventional adenosarcoma, (2) rhabdoid tumor cells forming cords and keratin-positive cohesive epithelial islands, and (3) cooccurrence with a spatially distinct and discrete endometrial complex atypical hyperplasia from the rest of the proliferation. By immunohistochemistry, the tumor cells were diffusely positive for synaptophysin, whereas BRG1 was lost. Pertinent molecular findings included frameshift mutations in the SMARCA4 gene, mutations in histone modification and chromatin remodeling genes, including KMT2C , ARID1B , KAT6A , and NCOR1 , and mutations in Wnt signaling involving APC and CTNNB1 . Copy number gain in MDM2 and CDK4 were also identified. The tumor mutation burden was intermediate (6.8/MB) and it was microsatellite stable. On balance, our case exhibited morphologic and molecular features that overlap with (1) an undifferentiated uterine sarcoma, (2) an adenosarcoma with sarcomatous overgrowth, and (3) a mixed adenosarcoma and undifferentiated endometrial carcinoma. These hybrid features further expand the molecular-morphologic spectrum of SMARCA4 / BRG1 -deficient uterine neoplasms.

Oral Chronic Graft-versus-Host Disease in Post-Hematopoietic Stem Cell Transplant Patients Following SARS-CoV-2 Vaccination: Case Reports.

Patients receiving allogeneic hematopoietic stem cell transplant may experience graft-versus-host disease (GVHD) in which donor immune cells cause an immune reaction in host tissues. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines are highly effective in prevention of severe coronavirus-2019 (COVID-19) disease, but the vaccine can result in immune activation and GVHD. Herein, we report 4 cases of oral manifestations that may have been stimulated by COVID-19 or vaccination with Pfizer or Moderna vaccines. We believe this study is the first to report oral changes driven by an inflammatory/immune mechanism leading to oral symptomatic cGVHD. The clinical impact of this study is early recognition and appropriate management of oral symptomatic cGVHD following COVID-19 disease or SARS-CoV-2 vaccination.

CF33-hNIS-anti-PD-L1 oncolytic virus followed by trastuzumab-deruxtecan in a patient with metastatic triple negative breast cancer: a case study.

Prognosis of metastatic triple negative breast cancer (mTNBC) remains poor despite recent advances in therapeutic options. Trastuzumab deruxtecan (T-DXd) has shown promising efficacy in patients with human epidermal growth factor receptor 2 (HER2)-low breast cancer, which is defined by immunohistochemistry (IHC) 1+ or 2+ and lack of HER2 amplification by fluorescence in situ hybridization (FISH) testing. The purpose of the study is to evaluate the safety and initial evidence of efficacy of intratumoral administration of CF33-hNIS-anti-PD-L1 (CHECKvacc) against mTNBC. Oncolytic virus CHECKvacc intratumoral injection is currently undergoing investigation in patients with mTNBC as a single agent (NCT05081492). The patient was enrolled on the clinical trial CHECKvacc for the Treatment of Metastatic Triple Negative Breast Cancer, received a single dose of CHECKvacc, and discontinued the study due to lack of immediate response. We report a case of a patient with mTNBC who was heavily pretreated and presented with extensive dermal metastasis. Two dermal metastasis biopsies in 2021 showed HER2 0 by IHC. The patient received a single dose of CHECKvacc and discontinued the study due to lack of immediate response. Twenty-five days later, the patient received treatment with T-DXd, and her tumor regressed significantly. The patient's disease-free survival was 10 months (December 2021-October 2022). The sequential treatment with intratumoral injection of CHECKvacc followed by T-DXd may have significant clinical activity in select patients with heavily pretreated mTNBC. ClinicalTrials.gov NCT05081492.

BRCA germline mutations in multiethnic gynecologic patients: A 10-year retrospective analysis from a single cancer institute.

Histologic and genetic mutation information from racially and ethnically diverse populations is warranted to better inform future cancer predisposition and promote health equity. A single institutional, retrospective capture of patients with gynecologic conditions and genetic susceptibilities to malignant neoplasms of the breast or ovaries was performed. This was achieved with manual curation of the electronic medical record (EMR) from 2010-2020 with the use of ICD-10 code searches. Among 8983 consecutive women identified with gynecologic conditions, 184 were diagnosed with pathogenic/likely pathogenic (P/LP) germline BRCA (gBRCA) mutations. Median age was 54 (22-90). Mutations included insertion/deletion (majority frameshift, 57.4%), substitution (32.4%), large structural rearrangement (5.4%), and alteration in splice site/intronic sequence (4.7%). A total of 48% were non-Hispanic White, 32% Hispanic or Latino, 13% Asian, 2% Black, and 5% Other. The most common pathology was high grade serous carcinoma (HGSC, 63%), followed by unclassified/high grade carcinoma (13%). Additional multigene panels led to the detection of 23 additional BRCA-positive patients with germline co-mutations and/or variants of uncertain significance in genes functionally involved in DNA repair mechanisms. Hispanic or Latino and Asian individuals comprised 45% of patients with concomitant gynecologic condition and gBRCA positivity in our cohort, confirming that germline mutations are represented across racial and ethnic groups. Insertion/deletion mutations, the majority of which led to a frameshift change, occurred in approximately half of our patient cohort, which may have prognostic implication for therapy resistance. Prospective studies are needed to unravel the significance of germline co-mutations in gynecologic patients.

Medication-Related Osteonecrosis of the Jaw: Successful Medical Management of Complex Maxillary Alveolus with Sinus Involvement.

Medication-related osteonecrosis of the jaw (MRONJ) in cancer patients presents a considerable challenge in management. Current management is primarily based on interventions in a limited number of cases assessing a single approach. Medical management typically is reported to include antimicrobial therapy with or without surgery. Advances in the understanding of pathogenesis have led to the investigation of additional medical interventions for early-stage necrosis. We present 3 patients with advanced-stage MRONJ of the maxilla using combined medical modalities including antimicrobial therapy, photobiomodulation therapy, pentoxifylline, vitamin E, and synthetic parathyroid hormone. All patients had a good outcome and avoided surgical intervention. We also report biological and functional imaging that may assist in more effective diagnosis and management of MRONJ. The 3 patients reported suggest that combined medical management should be considered in all cases of MRONJ (including stage III) prior to determining if surgical intervention is required. Functional imaging with a technetium bone scan or positron emission tomography scan correlated with diagnosis and confirmed resolution in patients. We present 3 challenging MRONJ patients that were effectively managed with a combined medical and nonsurgical therapy that demonstrated good clinical outcomes avoiding surgical interventions.

Immunogenicity and efficacy of pembrolizumab and doxorubicin in a phase I trial for patients with metastatic triple-negative breast cancer.

Currently there is a limited understanding for the optimal combination of immune checkpoint inhibitor and chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC). Here we evaluate the safety, efficacy, and immunogenicity of a phase I trial for patients with mTNBC treated with pembrolizumab plus doxorubicin. Patients without prior anthracycline use and 0-2 lines of prior systemic chemotherapies received pembrolizumab and doxorubicin every 3 weeks for 6 cycles followed by pembrolizumab maintenance until disease progression or intolerance. The primary objectives were safety and objective response rate per RECIST 1.1. Best responses included one complete response (CR), five partial responses (PR), two stable disease (SD), and one progression of disease (PD). Overall response rate was 67% (95% CI 13.7%, 78.8%) and clinical benefit rate at 6 months was 56% (95% CI 21.2%, 86.3%). Median PFS was 5.2 months (95% CI 4.7, NA); median OS was 15.6 months (95% CI 13.3, NA). Grade 3-4 AEs per CTCAE 4.0 were neutropenia n = 4/10 (40%), leukopenia n = 2/10 (20%), lymphopenia n = 2/10 (20%), fatigue n = 2/10 (20%), and oral mucositis n = 1/10 (10%). Immune correlates showed increased frequencies of circulating CD3 + T cells (p = 0.03) from pre-treatment to cycle 2 day 1 (C2D1). An expansion of a proliferative exhausted-like PD-1 + CD8 + T cell population was identified in 8/9 patients, and exhausted CD8 + T cells were significantly expanded from pre-treatment to C2D1 in the patient with CR (p = 0.01). In summary, anthracycline-naïve patients with mTNBC treated with the combination of pembrolizumab and doxorubicin showed an encouraging response rate and robust T cell response dynamics.Trial registration: NCT02648477.

Phase I Trial of Ipatasertib Plus Carboplatin, Carboplatin/Paclitaxel, or Capecitabine and Atezolizumab in Metastatic Triple-Negative Breast Cancer.

BACKGROUND: This trial evaluated the safety and efficacy of ipatasertib in combination with carboplatin, carboplatin/paclitaxel, or capecitabine/atezolizumab in patients with metastatic triple-negative breast cancer (mTNBC). METHODS: Eligibility criteria were mTNBC, RECIST 1.1 measurable disease, no prior use of platinum for metastatic disease (Arms A and B), and no prior exposure to immune checkpoint inhibitor (Arm C). Primary endpoints were safety and RP2D. Secondary endpoints were progression-free survival (PFS), response rate, and overall survival. RESULTS: RP2D for Arm A (n = 10) was ipatasertib 300 mg daily, carboplatin AUC2, and paclitaxel 80 mg m-2 days 1, 8, and 15 every 28 days. RP2D for Arm B (n = 12) was ipatasertib 400 mg daily and carboplatin AUC2 days 1, 8, and 15 every 28 days. RP2D for Arm C (n = 6) was likely ipatasertib 300 mg 21 days on 7 days off, capecitabine 750 mg m-2, twice a day, 7 days on 7 days off, and atezolizumab 840 mg days 1 and 15 every 28 days. The most common (≥10%) grade 3-4 AEs at RP2D for Arm A (N = 7 at RP2D) were neutropenia (29%), diarrhea (14%), oral mucositis (14%), and neuropathy (14%); Arm B had diarrhea (17%) and lymphopenia (25%); and Arm C had anemia, fatigue, cognitive disturbance, and maculopapular rash (17% each). Overall responses at RP2D were 29% Arm A, 25% Arm B, and 33% Arm C. PFS was 4.8, 3.9, and 8.2 months for patients on Arms A, B, and C, respectively. CONCLUSIONS: Continuous dosing of ipatasertib with chemotherapy was safe and well-tolerated. Further study is warranted in understanding the role of AKT inhibition in treatment of TNBCs. TRIAL REGISTRATION: NCT03853707.

Hyperglycemia and Glycemic Variability Associated with Glucocorticoids in Women without Pre-Existing Diabetes Undergoing Neoadjuvant or Adjuvant Taxane Chemotherapy for Early-Stage Breast Cancer.

Glucocorticoids, which are administered with chemotherapy, cause hyperglycemia. Glycemic variability among breast cancer patients without diabetes is not well known. A retrospective cohort study was conducted involving early-stage breast cancer patients without diabetes who received dexamethasone prior to neoadjuvant or adjuvant taxane chemotherapy between August 2017-December 2019. Random blood glucose levels were analyzed, and steroid-induced hyperglycemia (SIH) was defined as a random glucose level of >140 mg/dL. A multivariate proportional hazards model was used to identify the risk factors of SIH. Out of 100 patients, the median age was 53 years (IQR: 45-63.5). A total of 45% of patients were non-Hispanic White, 28% Hispanic, 19% Asian, and 5% African American. The incidence of SIH was 67%, and glycemic fluctuations were highest in those with glucose levels of >200 mg/dL. Non-Hispanic White patients represented a significant predictor for time to SIH, with a hazard ratio of 2.5 (95% CI: 1.04, 5.95, p = 0.039). SIH was transient in over 90% of the patients, and only seven patients remained hyperglycemic after glucocorticoid and chemotherapy completion. Pretaxane dexamethasone-induced hyperglycemia was observed in 67% of the patients, with the greatest glycemic lability in those patients with blood glucose levels of >200 mg/dL. The non-Hispanic White patients had a higher risk of developing SIH.

Predicting Hyperglycemia Among Patients Receiving Alpelisib Plus Fulvestrant for Metastatic Breast Cancer.

BACKGROUND: Hyperglycemia is recognized as a common adverse event for patients receiving alpelisib but has been little studied outside of clinical trials. We report the frequency of alpelisib-associated hyperglycemia in a real-world setting and evaluate proposed risk factors. PATIENTS AND METHODS: We retrospectively identified patients with PIK3CA-mutated, hormone receptor-positive, metastatic breast cancer who initiated treatment with alpelisib plus fulvestrant between August 2019 and December 2021. Ordinal logistic regression evaluated 5 characteristics (diabetes, prediabetes, body mass index [BMI], age, and Asian ancestry) as independent risk factors for ALP-associated hyperglycemia grades 2-4. Risk of error from multiple hypothesis testing was controlled using the false discovery rate method. RESULTS: The study included n = 92 subjects, all but 1 female, mean age 59.9 (+11.9) years with 50% non-Hispanic White, 15% Hispanic/Latino, 13% Asian, 9% African/Black, and 13% other/unknown. In total 34% of patients had diabetes, 10% had pre-diabetes, and 56% had normoglycemia. Thirty-six percent were obese, 32% were overweight, 25% were normal weight, and 7% were lean. Frequency of grades 1-4 hyperglycemia in current subjects (64.1%) was similar to hyperglycemia reported in the SOLAR-1 trial (63.7%). Our subjects' risk of grades 2-4 hyperglycemia was independently increased by pre-existing diabetes (Odds ratio 3.75, 95% CI, 1.40-10.01), pre-diabetes (6.22, 1.12-34.47), Asian ancestry (7.10, 1.75-28.84), and each unit of BMI above 20 (1.17, 1.07-1.28). CONCLUSION: While receiving alpelisib, patients of Asian ancestry, as well as patients with pre-existing hyperglycemia and/or BMI above 20, should be closely monitored for hyperglycemia. The mechanism underlying the current association of alpelisib-associated hyperglycemia with Asian ancestry is independent of BMI and merits further study. The high incidence of hyperglycemia resulted in a change in practice to include consultation with a diabetes nurse educator or endocrinologist at the start of alpelisib.