The exercise in all chemotherapy trial.

BACKGROUND: Multiple international organizations have called for exercise to become standard practice in the setting of oncology care. The feasibility of integrating exercise within systemic chemotherapy has not been investigated. METHODS: Patients slated to receive infusion therapy between April 2017 and October 2018 were screened for possible inclusion. The study goal was to establish the acceptability and feasibility of embedding an exercise professional into the chemotherapy infusion suite as a method of making exercise a standard part of cancer care. The exercise prescriptions provided to patients were individualized according to results of brief baseline functional testing. RESULTS: In all, 544 patients were screened, and their respective treating oncologists deemed 83% of them to be medically eligible to participate. After further eligibility screening, 226 patients were approached. Nearly 71% of these patients (n = 160) accepted the invitation to participate in the Exercise in All Chemotherapy trial. Feasibility was established because 71%, 55%, 69%, and 63% of the aerobic, resistance, balance, and flexibility exercises prescribed to patients were completed. Qualitative data also supported the acceptability and feasibility of the intervention from the perspective of patients and clinicians. The per-patient cost of the intervention was $190.68 to $382.40. CONCLUSIONS: Embedding an exercise professional into the chemotherapy infusion suite is an acceptable and feasible approach to making exercise standard practice. Moreover, the cost of the intervention is lower than the cost of other common community programs. Future studies should test whether colocating an exercise professional with infusion therapy could reach more patients in comparison with not colocating. LAY SUMMARY: Few studies have tested the implementation of exercise for patients with cancer by embedding an exercise professional directly into the chemotherapy infusion suite. The Exercise in All Chemotherapy trial shows that this approach is both acceptable and feasible from the perspective of clinicians and patients.

Prognostic Value of DNA Damage Response Genomic Alterations in Relapsed/Advanced Urothelial Cancer.

BACKGROUND: DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear. MATERIALS AND METHODS: We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. RESULTS: DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03-4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31-0.8; p = .003). CONCLUSIONS: Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression. IMPLICATIONS FOR PRACTICE: Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.

Moving Synergistically Acting Drug Combinations to the Clinic by Comparing Sequential versus Simultaneous Drug Administrations.

Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. Protein kinase B (AKT) is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 (mitotic inhibitor kinase) seems to have potential to make AKT-based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine these agents sequentially, enabling the use of existing phase I clinical trial toxicity data. Therefore, a rapid preclinical approach is needed to evaluate whether simultaneous or sequential drug treatment has maximal therapeutic efficacy, which is based on a mechanistic rationale. To develop this approach, melanoma cell lines were treated with AKT inhibitor AZD5363 [4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide] and WEE1 inhibitor AZD1775 [2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one] using simultaneous and sequential dosing schedules. Simultaneous treatment synergistically reduced melanoma cell survival and tumor growth. In contrast, sequential treatment was antagonistic and had a minimal tumor inhibitory effect compared with individual agents. Mechanistically, simultaneous targeting of AKT and WEE1 enhanced deregulation of the cell cycle and DNA damage repair pathways by modulating transcription factors p53 and forkhead box M1, which was not observed with sequential treatment. Thus, this study identifies a rapid approach to assess the drug combinations with a mechanistic basis for selection, which suggests that combining AKT and WEE1 inhibitors is needed for maximal efficacy.

Acoustic separation of circulating tumor cells.

Circulating tumor cells (CTCs) are important targets for cancer biology studies. To further elucidate the role of CTCs in cancer metastasis and prognosis, effective methods for isolating extremely rare tumor cells from peripheral blood must be developed. Acoustic-based methods, which are known to preserve the integrity, functionality, and viability of biological cells using label-free and contact-free sorting, have thus far not been successfully developed to isolate rare CTCs using clinical samples from cancer patients owing to technical constraints, insufficient throughput, and lack of long-term device stability. In this work, we demonstrate the development of an acoustic-based microfluidic device that is capable of high-throughput separation of CTCs from peripheral blood samples obtained from cancer patients. Our method uses tilted-angle standing surface acoustic waves. Parametric numerical simulations were performed to design optimum device geometry, tilt angle, and cell throughput that is more than 20 times higher than previously possible for such devices. We first validated the capability of this device by successfully separating low concentrations (∼100 cells/mL) of a variety of cancer cells from cell culture lines from WBCs with a recovery rate better than 83%. We then demonstrated the isolation of CTCs in blood samples obtained from patients with breast cancer. Our acoustic-based separation method thus offers the potential to serve as an invaluable supplemental tool in cancer research, diagnostics, drug efficacy assessment, and therapeutics owing to its excellent biocompatibility, simple design, and label-free automated operation while offering the capability to isolate rare CTCs in a viable state.

Prognosis and treatment of non-metastatic primary and secondary breast angiosarcoma: a comparative study.

BACKGROUND: Breast angiosarcoma is a rare malignancy with limited publications confined to small retrospective case reviews and case reports. Knowledge of this disease is limited because information from previous studies is insufficient and inconsistent. METHODS: We obtained data from the Surveillance, Epidemiology, and End Results Program for non-metastatic primary and secondary breast angiosarcoma, and performed analysis to determine clinicopathological characteristics and estimate their associations with overall survival (OS). RESULTS: Median age was 50-54 years in primary breast angiosarcoma and 70-74 years in secondary breast angiosarcoma, while median OS was 93 and 32 months, respectively. Age, tumor grade and tumor spread were associated with poor survival outcomes. Compared with primary breast angiosarcoma, patients with secondary breast angiosarcoma had a "nominal" increased death risk (HR = 1.89, 95% CI, 1.43-2.50, p < 0.001), which was driven by older age and more aggressive tumor phenotype at presentation. Mastectomy was associated with worse OS compared with breast conservative surgery (BCS) (adjHR = 2.47, 95% CI, 1.29-4.74) in primary angiosarcoma patients. Adjuvant radiation was associated with worse OS in secondary angiosarcoma patients (adjHR =1.77, 95% CI, 1.01-3.12). CONCLUSIONS: There is a "nominal" increased death risk in secondary breast angiosarcoma due to advanced clinicopathological features. Both BCS and mastectomy are feasible in primary and secondary angiosarcoma if R0 can be achieved. Routine radiation in unselected breast angiosarcoma should be cautious because there is no survival benefit in primary AS and appeared to be associated with a worse OS in secondary AS.

An interstitial deletion within 9p21.3 and extending beyond CDKN2A predisposes to melanoma, neural system tumours and possible haematological malignancies.

Familial atypical multiple mole melanoma syndrome (FAMMM) is characterised by dysplastic naevi, malignant melanoma and pancreatic cancer. Given that large deletions involving CDKN2A (cyclin-dependent kinase inhibitor 2A) account for only 2% of cases, we describe a family that highlights the co-occurrence of both melanoma and neural system tumours to aid clinical recognition and propose a management strategy. A patient with multiple neurofibromas was referred with a provisional diagnosis of neurofibromatosis type 1 (NF1). Prior molecular testing, though, had failed to identify an NF1 mutation by sequencing and multiplex ligation-dependent probe amplification. His family history was significant for multiple in situ/malignant melanomas at young ages and several different cancers reminiscent of an underlying syndrome. A search of the Familial Cancer Database, FaCD Online, highlighted several families with cutaneous melanoma and nervous system tumours who were subsequently identified to have large deletions spanning CDKN2A Although sequencing of CDKN2A and TP53 failed to identify a mutation, a heterozygous CDKN2A deletion was identified by targeted array comparative genomic hybridisation (CGH). Whole-genome oligonucleotide array CGH and SNP analysis identified an interstitial deletion of at least 1.5 Mb within 9p21.3 and spanning approximately 25 genes. Identification of the underlying molecular abnormality permits predictive testing for at-risk relatives. Given the young cancer diagnoses, a surveillance regimen was developed and a clinical team organised for ongoing management so that genetic testing could be offered to both adults and minor children. Surveillance recommendations addressed cancer risks associated with FAMMM, and other cancers exhibited by this family with a large contiguous gene deletion.

Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: A Systematic Review and Two-Step Meta-Analysis.

BACKGROUND: Platinum-based neoadjuvant chemotherapy has been shown to improve survival outcomes in muscle-invasive bladder cancer patients. We performed a systematic review and meta-analysis to provide updated results of previous findings. We also summarized published data to compare clinical outcomes of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) versus gemcitabine and cisplatin/carboplatin (GC) in the neoadjuvant setting. METHODS: A meta-analysis of 15 randomized clinical trials was performed to compare neoadjuvant chemotherapy plus local treatment with the same local treatment alone. Because no randomized trials have investigated MVAC versus GC in the neoadjuvant setting, a meta-analysis of 13 retrospective studies was performed to compare MVAC with GC. RESULTS: A total of 3,285 patients were included in 15 randomized clinical trials. There was a significant overall survival (OS) benefit associated with cisplatin-based neoadjuvant chemotherapy (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96). A total of 1,766 patients were included in 13 retrospective studies. There was no significant difference in pathological complete response between MVAC and GC. However, GC was associated with a significantly reduced overall survival (HR, 1.26; 95% CI, 1.01-1.57). After excluding carboplatin data, GC still seemed to be inferior to MVAC in OS (HR, 1.31; 95% CI, 0.99-1.74), but the difference was no longer statistically significant. CONCLUSION: These results support the use of cisplatin-based combination neoadjuvant chemotherapy in muscle-invasive bladder cancer. Although GC and MVAC had similar treatment response rates, the different survival outcome observed in this study requires further investigation. IMPLICATIONS FOR PRACTICE: Platinum-based neoadjuvant chemotherapy (NCT) has been shown to improve survival outcomes in muscle-invasive bladder cancer (MIBC) patients, but the optimal neoadjuvant regimen has not been established. Methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and gemcitabine and cisplatin/carboplatin (GC) are two of the most commonly used chemotherapy regimens in modern oncology. In this two-step meta-analysis, an updated and more precise estimate of the survival benefit of cisplatin-based NCT in MIBC is provided. This study also demonstrated that MVAC might have superior overall survival compared with GC (with or without carboplatin data) in the neoadjuvant setting. The findings suggest that NCT should be standard care in MIBC, and MVAC could be the preferred neoadjuvant regimen.

Palliative effect of capecitabine and cetuximab for refractory metastatic squamous cell carcinoma of the perineum in epidermodysplasia verruciformis.

A teenage girl presented with multiple warty skin lesions and had a diagnosis of epidermodysplasia verruciformis made several years later. Later in life she presented with an extensive SCC in situ in her gluteal crease that was surgically resected with wide margins. Despite this treatment, the lesion recurred with extension onto her lower back. Biopsies at the time confirmed SCC in situ of the perianal tissue and invasive SCC above her gluteal cleft.

Current and future trials of targeted therapies in cutaneous melanoma.

In order to effectively treat melanoma, targeted inhibition of key m-echanistic events regulating melanoma development such as cell proliferation, survival, angiogenesis and invasion or metastasis needs to be accomplished. The Mitogen Activated Protein Kinase (MAPK) pathway has been identified as a key player in melanoma development making this cascade an important therapeutic target. However, identification of the ideal pathway member to therapeutically target for maximal clinical benefit remains a challenge. In normal cells, the MAPK pathway relays extracellular signals from the cell membrane to the nucleus via a cascade of phosphorylation events, which promote cancer development. Dysregulation of the MAPK pathway occurs frequently in many human cancers including melanoma. Mutations in the B-RAF and RAS genes, genetic or epigenetic modifications are the key aberrations observed in this signaling cascade. Constitutive activation of this pathway causes oncogenic transformation of cells by promoting cell proliferation, invasion, metastasis, migration, survival and angiogenesis. This review provides an overview of (a) key members of MAPK signaling regulating melanoma development; (b) key proteins which can serve as biomarkers to assess disease progression; (c) the clinical efficacy of various pharmacological agents targeting MAPK pathway; (d) current clinical trials evaluating downstream targets of the MAPK pathway; (e) issues associated with pharmacological agents such as drug resistance, induction of cancers; and finally (e) various strategies overcoming drug resistance.

Group-led creative writing and behavioural health in cancer: a randomised clinical trial.

BACKGROUND: Cancer diagnosis can adversely affect mental well-being and overall clinical outcome. We evaluated the efficacy of a group-led creative writing workshop (CWW) on mood in patients with cancer prospectively. METHODS: We conducted a single-institution phase II study. Sixty adult patients with cancer (any type or stage) were randomised 2:1 to CWW (4×CWW sessions, bimonthly over 8 weeks) versus active control (AC) (independent writing at home with the help of a book, four sessions, bimonthly over 8 weeks). The total study duration was 6 months with a follow-up of up to 3 months. PRIMARY OBJECTIVE: changes in overall mood, depression and anxiety symptoms before and after intervention in both arms. Emotional Thermometer Scale (ETS) was used to assess changes in patients' mood. Additionally, the Patient Health Questionnaire (PHQ)-9 and General Anxiety Disorder Scale (GAD)-7 were used to evaluate depression and anxiety symptoms. RESULTS: Of 50 evaluable patients (CWW 34, AC 17), 26 patients in the CWW arm attended at least one class and 19 attended at least four classes. Patients in CWW had significant immediate improvement in the overall ETS (post vs preclass scores; p<0.0001, 95% CI -4.31 to -2.47). Four of the five subscale ETS scores were significantly lower for the CWW arm: distress (p=0.0346, 95% CI -2.6 to -0.1), anxiety (p=0.0366, 95% CI -4.1 to -0.2), depression (p=0.0441, 95% CI -3.9 to -0.1) and anger (p=0.0494, 95% CI -3.3 to 0). No significant differences were seen in the AC arm. No significant differences were observed in the PHQ-9 or the GAD-7 scores. CONCLUSION: CWW had a positive effect on mood based on ETS scores, suggesting a potential therapeutic benefit among patients with cancer.

Avelumab in Combination with Eribulin Mesylate in Metastatic Urothelial Carcinoma: BTCRC GU-051, a Phase 1b Study.

BACKGROUND: Patients with metastatic urothelial carcinoma (mUC) have poor prognosis, so further development of novel combinations for these patients is needed. OBJECTIVE: To assess the safety and efficacy of eribulin mesylate (eribulin) with avelumab in mUC. DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, phase 1b study in which patients with mUC who were cisplatin-ineligible and treatment-naïve or platinum-resistant were treated with eribulin and avelumab. A 3 + 3 design was used. The study was prematurely terminated because the free study drug became unavailable, but we performed extended follow-up for patients enrolled in the study. INTERVENTION: Patients received eribulin 1.1 mg/m2 plus avelumab 10 mg/kg on days 1 and 15 in every 28-d cycle in cohort 0, or eribulin 1.4 mg/m2 plus avelumab 10 mg/kg on days 1 and 15 in every 28-d cycle in cohort +1. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objectives were to determine the maximum tolerated dose (MTD) of eribulin with avelumab and assess the objective response rate. A key secondary endpoint was to assess efficacy by evaluating the disease control rate. Exploratory endpoints included PD-1 expression on T cells in peripheral blood and in tumor cells, and tumor DNA sequencing. RESULTS AND LIMITATIONS: A total of six patients were enrolled in the MTD group (n = 3 in cohort 0 and n = 3 in cohort +1). No dose-limiting toxicity (DLT) was observed in cohort 0, whereas two DLT events were observed in cohort +1. Two patients in cohort 0 had a partial response that was durable, with one patient having a durable response for 7.8 mo. Disease control was observed in 4/6 patients (66.7%). Owing to the early termination, MTD could not be determined. CONCLUSIONS: While early termination of this trial precludes any definitive conclusions, the combination of eribulin and avelumab shows promise in mUC. We observed that treatment was better tolerated and efficacious at lower doses of eribulin. Further research is warranted for this combination in mUC. PATIENT SUMMARY: We evaluated different doses of eribulin (a chemotherapy drug) in combination with a fixed dose of avelumab (an antibody used to treat several different cancers) in a small group of patients with metastatic cancer of the urinary tract. The lower dose of eribulin was easier to tolerate and the combination had an anti-cancer effect. This trial is registered at ClinicalTrials.gov as NCT03502681.

Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice.

Tyrosine kinase is a key enzyme activity utilized in many intracellular messaging pathways. Understanding the role of particular tyrosine kinases in malignancies has allowed for the design of tyrosine kinase inhibitors (TKIs), which can target these enzymes and interfere with downstream signaling. TKIs have proven to be successful in the treatment of chronic myeloid leukemia, renal cell carcinoma and gastrointestinal stromal tumor, and other malignancies. Scattered reports have suggested that these agents appear to affect blood glucose (BG). We retrospectively studied the BG concentrations in diabetic (17) and nondiabetic (61) patients treated with dasatinib (8), imatinib (39), sorafenib (23), and sunitinib (30) in our clinical practice. Mean declines of BG were dasatinib (53 mg/dL), imatinib (9 mg/dL), sorafenib (12 mg/dL), and sunitinib (14 mg/dL). All these declines in BG were statistically significant. Of note, 47% (8/17) of the patients with diabetes were able to discontinue their medications, including insulin in some patients. Only one diabetic patient developed symptomatic hypoglycemia while on sunitinib. The mechanism for the hypoglycemic effect of these drugs is unclear, but of the four agents tested, c-kit and PDGFRß are the common target kinases. Clinicians should keep the potential hypoglycemic effects of these agents in mind; modification of hypoglycemic agents may be required in diabetic patients. These results also suggest that inhibition of a tyrosine kinase, be it c-kit, PDGFRß or some other undefined target, may improve diabetes mellitus BG control and it deserves further study as a potential novel therapeutic option.

Effects of commercially available soy products on PSA in androgen-deprivation-naïve and castration-resistant prostate cancer.

OBJECTIVE: No standard therapeutic option exists for men with prostate cancer who have failed local therapy, have no gross metastatic disease, and whose only manifestation of disease is a rising prostate-specific antigen (PSA) level. Soy products are able to affect PSA kinetics in some men with prostate cancer, and this effect has been attributed to the decreased expression of the androgen receptor and other mechanisms. METHODS: We treated 10 men with rising PSA levels after radical prostatectomy and salvage radiotherapy with commercially available soy products. Scans revealed no gross metastatic disease. Three men also had been receiving androgen-deprivation therapy (ADT) and had rising PSA levels that were consistent with castration-resistant (CR) disease. We reported the results of this modality on PSA levels, PSA kinetics, and the duration of PSA response. RESULTS: Responses occurred in 4 of 7 (57%) patients with ADT-naïve disease and 1 of 3 (33%) patients with CR disease. The median duration of treatment response was 24 months. The overall clinical benefit, therefore, was noted in 5 of 10 (50%) patients. Therapy was well tolerated. CONCLUSIONS: Our findings are fairly congruent with what has been described in the literature on the use of this modality in prostate cancer. We used commercially available soy products. We also show that soy can provide benefit in CR prostate cancer. Our clinical experience suggests that soy supplementation using commercially available soy products can have durable beneficial effects on PSA levels and PSA kinetics in some men with prostate cancer.

Medical Service Use and Charges for Cancer Care in 2018 for Privately Insured Patients Younger Than 65 Years in the US.

Importance: Currently, there are limited published data regarding resource use and spending on cancer care in the US. Objective: To characterize the most frequent medical services provided and the associated spending for privately insured patients with cancer in the US. Design, Setting, and Participants: This cohort study used data from the MarketScan database for the calendar year 2018 from a sample of 27.1 million privately insured individuals, including patients with a diagnosis of the 15 most prevalent cancers, predominantly from large insurers and self-insured employers. Overall societal health care spending was estimated for each cancer type by multiplying the mean total spending per patient (estimated from MarketScan) by the number of privately insured patients living with that cancer in 2018, as reported by the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Analyses were performed from February 1, 2018, to July 8, 2021. Exposures: Evaluation and management as prescribed by treating care team. Main Outcomes and Measures: Current Procedural Terminology and Healthcare Common Procedure Coding System codes based on cancer diagnosis code. Results: The estimated cost of cancer care in 2018 for 402 115 patients with the 15 most prevalent cancer types was approximately $156.2 billion for privately insured adults younger than 65 years in the US. There were a total of 38.4 million documented procedure codes for 15 cancers in the MarketScan database, totaling $10.8 billion. Patients with breast cancer contributed the greatest total number of services (10.9 million [28.4%]), followed by those with colorectal cancer (3.9 million [10.2%]) and prostate cancer (3.6 million [9.4%]). Pathology and laboratory tests contributed the highest number of services performed (11.7 million [30.5%]), followed by medical services (6.3 million [16.4%]) and medical supplies and nonphysician services (6.1 million [15.9%]). The costliest cancers were those of the breast ($3.4 billion [31.5%]), followed by lung ($1.1 billion [10.2%]) and colorectum ($1.1 billion [10.2%]). Medical supplies and nonphysician services contributed the highest total spent ($4.0 billion [37.0%]), followed by radiology ($2.1 billion [19.4%]) and surgery ($1.8 billion [16.7%]). Conclusions and Relevance: This analysis suggests that patients with breast, colorectal, and prostate cancers had the greatest number of services performed, particularly for pathology and laboratory tests, whereas patients with breast, lung, lymphoma, and colorectal cancer incurred the greatest costs, particularly for medical supplies and nonphysician services. The cost of cancer care in 2018 for the 15 most prevalent cancer types was estimated to be approximately $156.2 billion for privately insured adults younger than 65 years in the US.

Postoperative chemotherapy and radiation improve survival following cardiac sarcoma resection.

OBJECTIVE: Cardiac sarcoma represents a rare and aggressive form of cancer with a paucity of data to produce outcome-driven evidence-based guidelines. Current surgical management consists of resection with postoperative therapy (chemotherapy, radiation, or both) offered on a selective, individualized basis. This study was designed to determine whether postoperative therapy was associated with improved overall survival after resection. METHODS: The National Cancer Database was used to identify patients with cardiac sarcoma between 2004 and 2015. Patient characteristics were stratified by treatment (surgical, nonsurgical, and none), and treatment was analyzed by stage. Overall survival, assessed with Kaplan-Meier methodology, was compared between patients who received postoperative therapy and those who did not following resection. Multivariable survival modeling using a Weibull model identified risk factors associated with survival while controlling for confounders. RESULTS: The study included 617 patients diagnosed with cardiac sarcoma. Only 24% (149/617) of patients were diagnosed with early-stage disease. Angiosarcoma represented 48% (298/617) of cases and was the most commonly identified histologic subtype. 60% (372/617) underwent surgical resection and 58% (216/372) of those patients were treated with postoperative therapy. Following surgery, median survival was more than doubled for patients treated with postoperative therapy (19 months vs 8 months, P = .026). However, 5-year overall survival was similar between the groups. Multivariable analysis confirmed an improvement in survival with postoperative therapy (hazard ratio, 0.68; 95% confidence interval, 0.51-0.91, P = .009). CONCLUSIONS: Postoperative therapy is associated with better median survival following resection of cardiac sarcoma. However, at 5 years, the difference in overall survival is not statistically significant.

Radiotherapy and Receptor Tyrosine Kinase Inhibition for Solid Cancers (ROCKIT): A Meta-Analysis of 13 Studies.

Background: We hypothesized that the addition of receptor tyrosine kinase inhibitors (RTKis, e.g., lapatinib, erlotinib, cetuximab, bevacizumab, panitumumab) to radiotherapy-based treatment for solid tumors does not increase overall survival but may increase toxicity. Methods: Population, Intervention, Control, Outcome, Study Design; Preferred Reporting Items for Systematic Reviews and Meta-Analyses; and Meta-analysis of Observational Studies in Epidemiology methods were used to identify prospective randomized studies including patients with solid tumor cancers treated with radiotherapy with or without RTKis. Extracted variables included use of radiotherapy vs chemoradiotherapy, RTKi type (antibody vs small molecule), outcomes, and toxicities. The primary endpoint was overall survival; the secondary endpoint was grade 3+ toxicity. Random-effects meta-analyses were performed for each outcome measure. All statistical tests were 2-sided. Results: A total of 405 studies met the initial search criteria, of which 13 prospective randomized trials of radiotherapy with or without RTKi met the inclusion criteria, encompassing 5678 patients. The trials included cancers of the head and neck (6 trials, 3295 patients), esophagus (3 trials, 762 patients), lung (2 trials, 550 patients), and brain (2 trials, 1542 patients). Three studies evaluated a small molecule and radiotherapy in 949 patients, and 10 studies evaluated antibodies and radiotherapy in 4729 patients. The addition of RTKis to radiotherapy-based treatment did not improve overall survival (hazard ratio = 1.02, 95% confidence interval = 0.90 to 1.15, P = .76) but increased grade 3+ toxicity (relative risk = 1.18, 95% confidence interval = 1.06 to 1.33, P = .009). Conclusions: The addition of RTKis to radiotherapy does not improve survival and worsens toxicity.

Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity.

PURPOSE: Increased ß-adrenergic receptor (ß-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly ß2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective ß-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma. PATIENTS AND METHODS: A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months. RESULTS: Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders. CONCLUSIONS: Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.

Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma.

PURPOSE: Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma. PATIENTS AND METHODS: Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery. RESULTS: A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2-43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5-85.8], with a 43% (95% CI: 27.3-60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively). CONCLUSIONS: Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133.

Epstein Barré virus-negative diffuse large B-cell lymphoma in an HIV-infected man with a durable complete remission on highly active antiretroviral therapy alone.

We report a unique case of a human immunodeficiency virus (HIV)-infected man with Epstein-Barré virus (EBV) negative diffuse large B-cell lymphoma (DLBCL) that responded solely to highly active antiretroviral therapy (HAART). Our patient presented with a retroperitoneal mass, high viral load, CD4 288 and began therapy with HAART with marked improvement of symptoms. The patient declined chemotherapy since he felt better after HAART, and rescanning at that time demonstrated marked improvement of the lymphoma on HAART alone. Viral load became undetectable, CD4 450 by 8 weeks. By 6 months, the patient had a complete remission verified by positron emission tomography/computed tomography (PET/CT) and has remained in remission to date on HAART alone. We postulate that HIV infection directly precipitated the lymphoma.