Abstract Mast cells (MCs) constitute an important part of the tumor microenvironment (TME). However, their underlying mechanisms of activation within the TME remain poorly understood. Here we show ...that recapitulating cell-to-cell contact interactions by exposing MCs to membranes derived from a number of cancer cell types, results in MC activation, evident by the increased phosphorylation of the ERK1/2 MAP kinases and Akt, in a phosphatidylinositol 3-kinase dependent fashion. Activation is unidirectional since MC derived membranes do not activate cancer cells. Stimulated ERK1/2 phosphorylation is strictly dependent on the ecto enzyme CD73 that mediates autocrine formation of adenosine, and is inhibited by knockdown of the A3 adenosine receptor (A3R) as well as by an A3R antagonist or by agonist-stimulated down-regulation of the A3R. We also show that cancer cell mediated triggering upregulates expression and stimulates secretion of interleukin 8 from the activated MCs. These findings provide evidence for a novel mode of unidirectional crosstalk between MCs and cancer cells implicating direct activation by cancer cells in MC reprogramming into a pro tumorigenic profile.
Radiotherapy (RT) is our preferred modality for local palliation of metastatic soft tissue sarcoma (STS). A short and intense course of RT is usually needed for rapid palliation and local control of ...metastatic disease. Seventeen patients at a median age of 61 had symptomatic metastatic sarcoma and required rapid palliation. The symptoms related to the metastases were either pain or discomfort. All patients were treated by a short and intensive course of administration: 39 Gy were given in 13 fractions of 3 Gy/day, 5 times a week. Median follow-up period was 25 weeks. The treatment was well tolerated. Acute side effects included grade one skin toxicity. No wound complications were noted among those undergoing surgery. Late side effects included skin pigmentation and induration of irradiated soft tissues. Durable pain control was achieved in 12 out 15 cases treated for gross metastases. Tumor progression was seen in the 3 other cases within a period of two to nine months. Among 5 lesions which were irradiated as an adjunctive treatment following resection, no local recurrence was observed. The results of this series, although limited in size, point to the safety and feasibility of hypofractionated RT for palliation of musculoskeletal metastases from sarcoma
Abstract only
Background:
AL amyloidosis is a rare disorder characterized by organ infiltration of unstable misfolded light chain proteins. Diagnosis requires a high degree of suspicion, and cardiac ...involvement has poor outcomes. Anthracycline-based regimens are preferred for treating abdominal leiomyosarcoma (LMS) but pose a challenge in the presence of cardiac AL amyloidosis.
Case:
A 66-year-old male presented with bilateral leg edema and underwent evaluation for new heart failure. Echocardiography revealed preserved left ventricle ejection fraction (LVEF) with mild hypertrophy, increased interventricular septum thickness, and diastolic dysfunction. Due to concern for cardiac amyloidosis, the patient underwent nuclear scintigraphy scan, which was negative. Ongoing clinical suspicion prompted endomyocardial biopsy, which was positive for Congo Red staining, and serum studies revealed monoclonal lambda spike with increased free light chains. PET-CT was done to assess the lung nodule, revealing abdominal LMS. While Anthracycline is the drug of choice for LMS, its potential cardio-toxic effect in the presence of heart failure need be addressed. Treatment decisions involved a multidisciplinary team, resulting in bortezomib for AL amyloidosis, gemcitabine/paclitaxel for LMS, and symptomatic heart failure management.
Decision-making:
Anthracycline therapy was avoided due to potential cardiotoxicity. Daratumumab was added to expedite light chain reduction and minimize cardiotoxic effects. Individualized treatment considered the patient's clinical presentation and comorbidities.
Conclusion:
Diagnosing cardiac amyloidosis requires a high index of suspicion. Concurrent AL amyloidosis and LMS is extremely rare and presents a therapeutic dilemma, necessitating personalized management. Further research is needed to assess the potential cardio-toxic effect of anthracycline in the presence of cardiac AL amyloidosis.
Background
Diabetes mellitus (DM) is a highly prevalent chronic metabolic disorder. Although DM has been associated with immune dysfunction, the effect of DM on the efficacy of immunotherapy is ...unknown. This study aimed to evaluate the impact of DM on the efficacy of pembrolizumab in metastatic non–small cell lung cancer (NSCLC).
Methods
The authors reviewed the medical records of consecutive metastatic NSCLC patients treated with first‐line pembrolizumab either alone or in combination with chemotherapy at a single tertiary center. For validation, a computerized data from Maccabi Healthcare Services, a 2.5–million‐member state health service was used.
Results
Of the 203 eligible patients, 51 (25%) had DM. Patients with DM had a significantly shorter median progression‐free survival (PFS) (5.9 vs. 7.1 months, p = .004) and overall survival (OS) (12 vs. 21 months, p = .006). The shorter OS in diabetic patients was more pronounced when pembrolizumab was given alone (12 vs. 27 months, p = .03) than when combined with chemotherapy (14.3 vs. 19.4 months, p = .06). Multivariate analysis confirmed DM as an independent risk factor for shorter PFS (hazard ratio HR, 1.67; 95% confidence interval CI, 1.11−2.50, p = .01) and OS (HR, 1.73; 95% CI, 1.09−2.76, p = .02). In a validation cohort of 452 metastatic NSCLC patients, the time on pembrolizumab treatment was shorter in diabetic patients (p = .025), with only 19.6% of patients remaining on treatment at 12 months compared to 31.7% of the nondiabetic patients.
Conclusions
This study suggests immunotherapy is less beneficial in diabetic NSCLC patients. More work is needed to verify our findings and explore similar effects in other cancer entities.
One in four non–small cell lung cancer patients treated with pembrolizumab in our cohorts had diabetes mellitus. Patients with diabetes mellitus had a decreased progression‐free survival and overall survival compared to nondiabetic patients.
Purpose Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, thereby avoiding the generation of toxic metabolites. The PICASSO III trial compared doxorubicin ...plus palifosfamide with doxorubicin plus placebo in patients who had received no prior systemic therapy for metastatic soft tissue sarcoma. Patients and Methods Patients were randomly assigned 1:1 to receive doxorubicin 75 mg/m
intravenously day 1 plus palifosfamide 150 mg/m
/d intravenously days 1 to 3 or doxorubicin plus placebo once every 21 days for up to six cycles. The primary end point was progression-free survival (PFS) by independent radiologic review. Results In all, 447 patients were randomly assigned to receive doxorubicin plus palifosfamide (n = 226) or doxorubicin plus placebo (n = 221). Median PFS was 6.0 months for doxorubicin plus palifosfamide and 5.2 months for doxorubicin plus placebo (hazard ratio, 0.86; 95% CI, 0.68 to 1.08; P = .19). Median overall survival was 15.9 months for doxorubicin plus palifosfamide and 16.9 months for doxorubicin plus placebo (hazard ratio, 1.05; 95% CI, 0.79 to 1.39; P = .74). There was a higher incidence of grade 3 to 4 adverse events in the doxorubicin plus palifosfamide arm (63.6% v 50.9%) including a higher rate of febrile neutropenia (21.4% v 12.6%). Conclusion No significant difference in PFS was observed in patients receiving doxorubicin plus palifosfamide compared with those receiving doxorubicin plus placebo. The observed median PFS and overall survival in this large, international study can serve as a benchmark for future studies of doxorubicin in metastatic soft tissue sarcoma.
PDF
