The Clinical and Economic Implications of Different Treatment Pathways for Patients with Rapidly Recurrent Malignant Pleural Effusion.

BACKGROUND: Malignant pleural effusion (MPE) is a common cancer complication. Clinical and economic implications of different recurrent MPE treatment pathways have not been fully evaluated. RESEARCH QUESTION: What clinical outcomes, complications, healthcare resource use, and costs are associated with various rapidly recurrent MPE treatment pathways? STUDY DESIGN AND METHODS: This retrospective cohort study using Surveillance, Epidemiology and End Results Medicare data (2011-2015) included patients aged 66-90 with rapidly recurrent MPE. Rapid recurrence was defined as receipt of a second pleural procedure within 14 days of the first thoracentesis including non-definitive repeated thoracentesis, or a definitive treatment option including chest tube, indwelling pleural catheter (IPC), or thoracoscopy. RESULTS: Among 8,378 patients with MPE, 3,090 (36.9%) had rapidly recurrent MPE (mean [SD] age 75.9 [6.6], 45.6% male, primary cancer 62.9% lung and 37.1% other). Second pleural procedures were non-definitive thoracentesis (62.3%), chest tube (17.1%), IPC (13.2%), or thoracoscopy (7.4%). A third pleural procedure was more frequently required if the second pleural procedure was non-definitive thoracentesis vs. chest tube, IPC, or thoracoscopy (70.3% vs. 44.1% vs. 17.9% vs. 14.4%, respectively). The mean number of subsequent pleural procedures over the patient's lifetime varied significantly among the procedures (1.74, 0.82, 0.31, and 0.22 for patients receiving thoracentesis, chest tube, IPC, and thoracoscopy, respectively; P < .05). Average total costs following the second pleural procedure to death adjusted for age at primary cancer diagnosis, race, year of second pleural procedure, Charlson Comorbidity Index, cancer stage at primary diagnosis, and time from primary cancer diagnosis to diagnostic thoracentesis were lower with IPC ($37,443; P < .0001) or chest tube ($40,627; P = .004) vs. thoracentesis ($47,711). Patients receiving thoracoscopy ($45,386; P = .5) had similar costs to patients receiving thoracentesis. INTERPRETATION: Early definitive treatment was associated with fewer subsequent procedures and lower costs in rapidly recurrent MPE.

To Quiesce or Senesce, That Is the Question for Dedifferentiated Liposarcoma.

Dedifferentiated liposarcoma (DDLPS) has an appealing therapeutic target due to its CDK4 amplification on chromosome 12q. The understanding of geroconversion from quiescent cells to senescent cells defines a patient's response to CDK4 inhibitors. This new observation will inform not only the ongoing phase III clinical trial of abemaciclib, but all future clinical trials in DDLPS. See related article by Gleason et al., p. 703.

COL1A1::PDGFB fusion-associated uterine sarcoma and response to Imatinib: A case report.

Uterine sarcomas are rare neoplasms of the uterus, some of which are associated with distinctive gene fusions. COL1A1::PDGFB fusion uterine sarcoma is a recently described entity that shares the same genetic alteration as dermatofibrosarcoma protuberans. These uterine sarcomas have a nonspecific spindle cell sarcoma appearance and are CD34 positive by immunohistochemistry. Accurate diagnosis relies on identification of the characteristic fusion by molecular genetic methods. The importance of diagnosing this entity lies in its potential response to targeted therapy with imatinib, a tyrosine kinase inhibitor successfully used in dermatofibrosarcoma protuberans, but only one prior case of COL1A1::PDGFB fusion uterine sarcoma treated with imatinib has been reported. Here, we describe a case of COL1A1::PDGFB fusion uterine sarcoma with response to imatinib after recurrence, with a brief review of this rare tumor.

The Midwest Sarcoma Trials Partnership: Bridging Academic and Community Networks in a Collaborative Approach to Sarcoma.

The treatment of sarcoma necessitates a collaborative approach, given its rarity and complex management. At a single institution, multidisciplinary teams of specialists determine and execute treatment plans involving surgical, radiation, and medical management. Treatment guidelines for systemic therapies in advanced or nonresectable soft tissue sarcoma have advanced in recent years as new immunotherapies and targeted therapies become available. Collaboration between institutions is necessary to facilitate accrual to clinical trials. Here, we describe the success of the Midwest Sarcoma Trials Partnership (MWSTP) in creating a network encompassing large academic centers and local community sites. We propose a new model utilizing online platforms to expand the reach of clinical expertise for the treatment of advanced soft tissue sarcoma.

Relapsed Synovial Sarcoma: Treatment Options.

OPINION STATEMENT: Synovial sarcoma (SS) is a fusion-driven subtype of sarcoma that is a more chemo-sensitive subtype of soft tissue sarcoma. While chemotherapy options are currently standard of care, our fundamental understanding of the biology of SS is driving new therapies. We will review the current standard of care, as well as the current therapies showing promise in a clinical trial. It is our hope that by encouraging participation in clinical trials, the fundamental therapies available for SS will change the current treatment paradigm.

The Impact of TSC-1 and -2 Mutations on Response to Therapy in Malignant PEComa: A Multicenter Retrospective Analysis.

BACKGROUND: Perivascular epithelioid cell neoplasms (PEComas) are a diverse family of mesenchymal tumors with myomelanocytic differentiation that disproportionately affect women and can be associated with tuberous sclerosis (TS). Although mTOR inhibition is widely used as first-line treatment, it is unclear what genomic alterations exist in these tumors and how they influence the response to therapy. METHODS: This was a multicenter study conducted at five sites within the US. The data were collected from 1 January 2004 to 31 January 2021. We conducted a retrospective analysis to identify PEComa patients with next-generation sequencing (NGS) data and compared outcomes based on mutations. RESULTS: No significant differences in survival were identified between TSC-1 and TSC-2 mutated PEComa or TSC-1/-2 versus other mutations. No significant difference was seen in progression-free survival (PFS) after first-line therapy between mTOR inhibition versus other systemic therapies. CONCLUSIONS: We were unable to detect differences in survival based on genomic alterations or PFS between mTOR inhibition versus other systemic therapies. Future studies should seek to identify other drivers of TSC-1/-2 silencing that could predict response to mTOR inhibition.

Systemic Treatment of Soft Tissue Sarcomas in the Geriatric Population.

OPINION STATEMENT: As the population ages, there will be an increase in the incidence and prevalence of soft tissue sarcoma (STS) within the geriatric population. As this disease disproportionately affects older adults, the percentage of adults >65 years old is expected to increase in the coming years. Geriatric patients are often more vulnerable to disease-related symptoms and have more difficulty tolerating treatment-related side effects. While there are no formal existing guidelines to direct the care of this geriatric patient population, it is of utmost importance to consider each patients' fitness and co-morbidities when selecting treatment plans. This review focuses on the current state of research of older adults with advanced or metastatic soft tissue sarcoma, highlighting the lack of representation of this patient population in clinical trials. Given that chronological age does not necessarily equate to physiologic age, integration of comprehensive geriatric and quality of life assessments is needed in the care of geriatric patients to help guide therapeutic decisions.

The clinical utility of next-generation sequencing for bone and soft tissue sarcoma.

Background: Sarcomas are a rare and heterogeneous tumor group composed of a variety of histologic subtypes. Targeted next-generation sequencing (NGS) of bone and soft tissue sarcomas is a nascent field with limited evidence for its use within clinical practice. Therefore, further research is needed to validate NGS in sarcoma and assess the clinical utility of these techniques with the hope of improving treatment options.Methods: Comprehensive molecular profiling with NGS was performed on 136 tumors (116 soft tissue, 20 bone) using two commercial vendors. Patient records were retrospectively reviewed, and the clinical impact of NGS-related findings were qualitatively analyzed to determine actionable mutations and number of changes in treatment.Results: The median age was 55.0 years (IQR 42-67 years), and most patients were non-metastatic at presentation (80.9%, n = 110). Prior to performing NGS, 72.1% (n = 98) were treated with a mean 1.1 ± 1.2 lines of systemic chemotherapy. NGS identified 341 putative alterations with at least one mutation present in 89.7% (n = 122) of samples. In a subset of 111 patients with available TMB data, 78.7% (n = 107) had a low (<6 m/Mb) mutational burden. Among all 136 cases, 47.1% (n = 64) contained clinically actionable alterations, and 12 patients had a change in medical treatment based on NGS. Those who underwent a treatment change all had metastatic or recurrent disease; three of these patients experienced a clinical benefit.Conclusion: Most bone and soft tissue sarcomas harbor at least one genetic alteration, and it appears a sizeable number of tumors contain mutations that are clinically actionable. While a change in treatment based off NGS-related findings occurred in 12 cases, three patients experienced a clinical benefit. Our data provide further proof-of-concept for NGS in sarcoma and suggest a clinical benefit may be observed in select patients.

Truly Man's Best Friend: Canine Cancers Drive Drug Repurposing in Osteosarcoma.

While metastatic osteosarcoma is rare in humans, it is the most common bone tumor found in any breed of dog. Given the genetic similarities between canine and human osteosarcomas, canine clinical trials allow for rapid testing and drug repurposing at a speed that cannot be achieved using patients with osteosarcoma. See related article by Regan et al., p. 662.

Phase II study of dacarbazine given with modern prophylactic anti-emetics and growth factor support to patients with metastatic, resistant soft tissue, and bone sarcoma.

Historically, administration of dacarbazine to sarcoma patients was limited by frequent treat-ment-related nausea/vomiting and neutropenia. These toxicities are now largely preventable with contemporary antiemetics and growth factor support. In this single-arm, phase II study, dacarbazine 850 mg/m2 was given on day 1 of each 3-week cycle until disease progression or intolerance with prophylactic serotonin-3 receptor, neurokinin-1 antagonists, corticosteroids, and pegfilgrastim. Coprimary endpoints included clinical benefit rate (CBR), and any grade of nausea/vomiting and/or grade 3-4 neutropenia. With a sample size of 80 patients, >24 patients with clinical benefit would indicate that the CBR exceeds the historical (<20%) [Power 0.80; alpha 0.05]. In addition, we hypothesized that the rates of nausea/vomiting would be 27% and grade 3-4 neutropenia would be 1% (historical: 90% and 36%, respectively) [power 0.95; alpha 0.05]. The CBR was 30% (24 patients: PR-2 and stable-22). The rate of nausea/vomiting was 37.5% (31 patients) and grades 3-4 neutropenia was 10% (8 patients). Median time-to-progression was 8.1 weeks (95% CI 8-9.7) and median overall survival was 35.8 weeks (95% CI 26.2-55.4). PET scans demonstrated no association with response. Modern prophylactic anti-emetics and pegfilgrastim given with dacarbazine reduced the rates of treatment related nausea/vomiting and serious neutropenia.

Impact of tissue-based genomic profiling on clinical decision making in the management of patients with metastatic breast cancer at academic centers.

BACKGROUND: Genomic profiling can identify targetable mutations; however, the impact of tissue-based genomic profiling on clinical decision making for patients with metastatic breast cancer has not been well characterized. METHODS: Patients with stage IV breast cancer who had undergone genomic profiling between 7/2013 and 3/2015 were identified at three academic cancer centers. Genomic analysis was determined to have impacted clinical decision if (A) a patient was enrolled onto a genotype-matched clinical trial or (B) prescribed off-label an FDA-approved therapy targeting an identified mutation. The frequency of mutated genes was determined. RESULTS: A total of 117 patients with stage IV breast cancer were identified. Median age was 46 (25-75). Fifty-three patients (45%) had ER-positive/HER2-negative disease, 50 (43%) had ER-negative/HER2-negative disease, and 14 (12%) had ER-any/HER2-positive disease. Median number of previous therapies received prior to genomic profiling was 2 (range 0-15), and median follow-up after testing was obtained after 5.8 months (range 0-24.4 months). Commercial reports indicated that 85 (73%) patients had at least one mutation targetable by an FDA-approved medication, and 112 (96%) patients had at least one clinical trial available; however, clinical management was only affected in 11 patients (9%). The most frequent mutations observed were those in TP53, FGF, PI3KCA, MYC, ZNF, FGFR, CCND, ARID1A, GATA3, and MAP; frequencies of these mutations varied by clinical subtype. CONCLUSIONS: Tumor genomic profiling affected clinical management in a minority of patients with metastatic breast cancer, thus these data do not support the routine use of genomic profiling outside of a clinical trial.

Rituximab-induced remission in a woman with coexisting rheumatoid arthritis and nephrotic syndrome.

We describe a patient with rheumatoid arthritis who presented with nephrotic syndrome which was not related neither to drug therapy nor to amyloidosis. Renal biopsy revealed membranous glomerulonephritis. The patient was treated with three cycles of rituximab with complete resolution of the clinical and laboratory evidence of nephrosis. The following report discusses this unusual presentation and clinical response.

Bortezomib-cyclophosphamide-dexamethasone (VCD) versus bortezomib-thalidomide-dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis.

Three-drug induction regimens have become the standard of care in newly diagnosed transplant-eligible multiple myeloma patients. Two frequently used protocols are bortezomib, cyclophosphamide and dexamethasone (VCD) and bortezomib, thalidomide and dexamethasone (VTD). Comparisons between the two are lacking. The present study aimed to identify the differences in response rate and toxicity between the two regimens. Databases were searched using the terms 'VTD' or 'VCD' and 'induction regimens for newly diagnosed multiple myeloma'. Prospective trials evaluating initial response in transplant eligible patients were included. The main outcome measures were response rates and adverse events. Eight clinical trials were eligible for analysis. Overall 672 patients were treated with either VCD (n = 157) or VTD (n = 515) as induction therapy. Patients treated with VTD presented with a significantly higher complete/near complete response (34% vs. 6%, P = 0·002) as well as a higher very good partial response rate or better, following induction therapy (62% vs. 27%, P < 0·0001). Although grade 3-4 neurotoxicity was more frequent during VTD therapy (11% vs. 6%, P = 0·057), a higher incidence of overall grade 3-4 adverse events was found in the VCD-treated patients (74% vs. 51%, P < 0·001). VTD induction therapy may be superior in achieving deeper response rate following induction therapy, and is better tolerated.