Case report: The activity of multi-kinase VEGF inhibitor, Pazopanib, in metastatic undifferentiated round cell sarcomas harboring EWSR1::CREM fusion: clinicopathological series of two cases and literature review.

Soft tissue sarcomas harboring EWSR1::CREM fusion are rare and challenging to treat. Pazopanib, a multi-tyrosine kinase inhibitor, is FDA-approved for advanced soft tissue sarcomas, but predictive biomarkers for its efficacy remain unidentified. We conducted a study on > 240,000 neoplasms submitted to Caris Life Sciences (Phoenix, AZ) to detect rearrangements using whole transcriptome sequencing. Two sarcoma-experienced, board-certified pathologists performed histological reviews, and treatment/outcome information was collected. Among the identified cases (n = 18), we observed a diverse range of sarcoma and other cancers, including an intracranial myxoid mesenchymal tumor, mesothelioma, hyalinizing clear cell carcinomas of the head and neck, clear cell sarcomas, and undifferentiated round cell sarcomas, as well as histologically malignant tumors with epithelioid morphology. Notably, two undifferentiated, metastatic, abdominal round cell sarcoma cases treated with pazopanib demonstrated significant sustained partial response and clinical benefit. To explore the genetic factors associated with the efficacy of pazopanib in these cases, next-generation sequencing and fluorescence in situ hybridization were analyzed for alterations in the tumors. The genomic analysis provided compelling evidence confirming the presence of EWSR1::CREM fusion in both cases, with no other pathogenic gene variants or copy number alterations detected. These cases demonstrate the potential of Pazopanib as a promising therapeutic option for patients with EWSR1::CREM fusion-positive soft tissue sarcomas, including metastatic undifferentiated round cell sarcomas. The sustained clinical benefit and partial responses observed in these cases warrant further research to validate these findings and explore the wider utility of Pazopanib in this rare and challenging subset of soft tissue sarcomas. Case studies: Case 1: A 49-year-old man presented with abdominal pain, weight loss, and chronic cough. A computed tomography (CT) of the chest, abdomen, and pelvis showed multiple lung nodules and masses and a right rectus mass that was biopsied and revealed an undifferentiated round cell sarcoma with a rare fusion EWSR1-CREM. No additional pathogenic gene variants or copy number alterations were detected. He received neoadjuvant chemotherapy with three cycles of Vincristine, Adriamycin, and Ifosfamide (VAI) and seven cycles of Vincristine/Irinotecan and Temodar (VIT). After cycle 7 of VIT, he had surgical resection of the abdominal mass and received radiation for lung metastasis. He completed 13 cycles of VIT after which he presented with progression of disease and switched to monotherapy with Pazopanib. At the time of this analysis he had stable disease for 28 months. Case 2: A 75-year-old woman presented with pelvic pain and new onset constipation. CT abdomen showed a large pelvic mass and intraperitoneal tumor spread. Exploratory laparotomy revealed a ruptured pelvic mass and a small bowel tumor. Both tumors were proved to be high-grade, poorly differentiated sarcoma. Genomic analysis demonstrated an EWSR1::CREM fusion but no other pathogenic gene variants or copy number alterations. She was treated initially for a primitive neuroectodermal tumor (PNET) with four cycles of Vincristine/Adriamycin/Cytoxan/Olaratumab but declined additional chemotherapy after progression. Two years later, she presented with recurrent abdominal mass and received one cycle of Temodar/Irinotecan, then she began Pozapanib and underwent palliative radiation to the entire pelvis. She has been on Pazopanib for 23 months with stable disease.

Comparison of PARPi efficacy according to homologous recombination deficiency biomarkers in patients with ovarian cancer: a systematic review and meta-analysis.

BACKGROUND: Mutations in the BRCA1/2 (BRCA) genes are associated with response to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). In addition, there are different homologous recombination deficiency (HRD) biomarkers available in clinical practice [e.g., genome-wide loss-of-heterozygosity (gLOH) and myChoice® score] that identify patients who can benefit from PARPi. Inconsistencies in biomarkers used in PARPi clinical trials make it challenging to identify clinically relevant predictive biomarkers. This study aims to compare clinically available HRD biomarkers in terms of benefits from PARPi. METHODS: We performed database search for phase II or III randomized clinical trials comparing PARPi versus chemotherapy, and meta-analysis using generic inverse variance and a Random Effects model. Patients were classified according to their HRD status: (I) BRCAm (patients with BRCA mutation of germline or somatic origin); (II) non-BRCA HRD [patients BRCA wild-type (wt) with another HRD biomarker-gLOH or myChoice®]; and (III) homologous recombination proficiency (HRP) (BRCAwt and without HRD biomarkers). From those that were BRCAwt, we compared myChoice®+ with gLOH-high. RESULTS: Five studies (3,225 patients) analyzing PARPi in first line setting were included. Patients with BRCAmut had progression-free survival (PFS) with hazard ratio (HR) 0.33 [95% confidence interval (CI): 0.30-0.43]; patients with non-BRCA HRD had a PFS HR 0.49 (95% CI: 0.37-0.65), and patients with HRP had a PFS HR 0.78 (95% CI: 0.58-1.03). Eight studies (5,529 patients) with PARPi including first line and recurrence settings were included. BRCAmut had PFS HR 0.37 (95% CI: 0.30-0.48), BRCAwt & HRD 0.45 (95% CI: 0.37-0.55) and HRP 0.70 (95% CI: 0.57-0.85). Patients with BRCAwt & myChoice® ≥42 had PFS HR 0.43 (95% CI: 0.34-0.56), similar to patients with BRCAwt & gLOH-high with PFS HR 0.42 (95% CI: 0.28-0.62). CONCLUSIONS: Patients with HRD derived significantly more benefit from PARPi when compared to patients with HRP. The benefit of PARPi in patients with HRP tumors was limited. Careful cost-effectiveness analysis, and alternative therapies or clinical trial enrollment should strongly be considered for patients with HRP tumors. Among patients with BRCAwt, a similar benefit was found in patients with gLOH-high and those myChoice®+. The clinical development of further HRD biomarkers (e.g., Sig3) may help identify more patients who benefit from PARPi.

Osteogenic Sarcoma of the Head and Neck: Is Chemotherapy Needed?

OPINION STATEMENT: Head and neck osteosarcoma (HNOS) is a rare subtype of sarcoma that most commonly arises in the mandible or maxilla. Treatment for HNOS typically involves a multidisciplinary and multimodal approach depending on the size, grade, and histological subtype. Surgery by sarcoma-experienced head and neck surgeons and orthopedic oncologists remains a crucial component of treatment in all subtypes of HNOS, particularly for those with low-grade histology, which can be treated definitively with surgical resection if negative margins are obtained. Negative surgical margins are of utmost prognostic importance, and neoadjuvant or adjuvant radiation should be considered in patients with positive (or anticipated positive) margins/residual postoperative disease. Current data favors the use of (neo)adjuvant chemotherapy in patients with high-grade HNOS to improve overall survival but must be individualized to weigh benefits and risks of the short- and long-term effects of treatment. Our center uses a multidisciplinary treatment plan and notes anecdotal improvement in treatment outcomes with a combined surgical and ifosfamide-containing chemotherapeutic approach with radiotherapy for local control if positive margins. Large volume cohorts and adequate randomized control trials assessing the efficacy of chemotherapy in HNOS are scant and additional research and multi-institutional collaboration are needed to study polychemotherapeutic and radiation treatment regimens and outcomes more adequately.

Response in BRCA1 mutation carrier with metastatic pancreatic adenocarcinoma treated with FOLFIRINOX.

A woman in her 50s previously treated for early-stage breast cancer, parotid mucoepidermoid carcinoma and Caroli's disease was diagnosed with stage IV pancreatic ductal adenocarcinoma (PDAC) metastatic to the liver and was found to harbour a BRCA1 germline mutation. She had palliative chemotherapy, initially with 5-fluorouracil, leucovorin, irinotecan and oxaliplatin, and then FOLFIRI and capecitabine, achieving a sustained near-complete response for at least 86 months. Chemotherapy was eventually discontinued when she was diagnosed with a tongue squamous cell carcinoma. Despite withholding systemic therapy, she has maintained a durable response. This is the first report in the English literature showing a sustained duration of response in a patient with PDAC and BRCA1 germline mutation.

A Unique Case of Pyruvate Carboxylase Deficiency.

Pyruvate carboxylase (PC) converts pyruvate to oxaloacetate, which is an important step in gluconeogenesis. Pyruvate carboxylase deficiency (PCD) is a rare inherited metabolic disorder characterized by movement disorders, neurologic disturbances, hypoglycemia, lactic acidosis, hyperammonemia, and elevated levels of pyruvate and alanine in plasma. The prognosis for PCD is poor. Most children die within the first six months of life, and those who survive longer have neurological damage and mental disability. This is due to the accumulation of lactic acid and toxic components in the blood. Here we describe the case of a 21-month-old male presenting with abnormal movements and new-onset seizures. His family history is relevant because of parental consanguinity. A genetic analysis showed a novel mutation, homozygous c. 2630A>G (p. Gln877Arg) variant, in the PC gene, a mutation not previously described in the English literature.

Babesiosis: Appreciating the Pathophysiology and Diverse Sequela of the Infection.

Babesiosis is a blood-borne disease found mainly in the United States caused by a parasitic piroplasm. While most infections are mild to moderate in immunocompetent hosts, life-threatening complications can occur in those with significant comorbidities like congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD). There is sparse literature discussing the complications of Babesia microti infection or the pathophysiology and management thereof. A literature review was conducted to consolidate the current knowledge about the disease, pathophysiology, and proposed management of all potential complications based on risk factors and other clinical information. A MeSH cross-references strategy was employed in PubMed using the search terms "babesia" and "babesiosis" and the established associated conditions, and the search expanded to increase capture. Only papers written in the English language and discussing human subjects in the North American patient population were included. The initial search yielded 315 papers and, after applying the inclusion/exclusion criteria, a final number of 18 was reviewed. The various complications and pathophysiology thereof are then discussed according to organ system. Babesia is a subversive parasite associated with a variety of conditions. We hope a better appreciation of all potential presentations and complications will help clinicians manage this increasingly common zoonosis and reduce adverse effects. More research is recommended into the pathophysiology and prevention of complications following this and other tick-borne illnesses.