Melatonin and Metformin Failed to Modify the Effect of Dacarbazine in Melanoma.

LESSONS LEARNED: Melatonin did not increase the efficacy of systemic chemotherapy in melanoma. Metformin did not increase the efficacy of systemic chemotherapy in melanoma. BACKGROUND: Current data support the possibility of antitumor activity of melatonin and metformin. METHODS: From March 2014 to December 2016, 57 patients with disseminated melanoma received dacarbazine (DTIC) 1,000 mg/m2 on day 1 of a 28-day cycle, either as monotherapy (first group) or in combination with melatonin 3 mg p.o. daily (second group) or metformin 850 mg two times a day p.o. daily (third group) as the first-line of chemotherapy. The primary endpoint was objective response rate (ORR). Secondary endpoints were time to progression (TTP), overall survival (OS), immunologic biomarkers, and quality of life. RESULTS: ORR was 7% and did not differ among the treatment groups. Median TTP was 57, 57, and 47 days, respectively, in the first, second, and third groups (р = .362). Median OS was 236, 422, and 419 days, respectively (p = .712). Two patients from the combinations groups showed delayed response to therapy. The increase of CD3+ CD4+ HLA-DR+ lymphocytes (p = .003), CD3+ CD8+ HLA-DR+ (p = .045), CD3+ CD8+ lymphocytes (p = .012), CD4+ CD25high CD127low lymphocytes (p = .029), and overall quantity of lymphocytes (p = .021) was observed in patients with clinical benefit. CONCLUSION: No benefit was found in either combination over DTIC monotherapy. Delayed responses in melatonin and metformin combination groups were registered. The increase of lymphocyte subpopulations responsible for antitumor immune response demonstrates the immune system's potential involvement in clinical activity.

Breast cancer sensitivity to neoadjuvant therapy in BRCA1 and CHEK2 mutation carriers and non-carriers.

Breast carcinomas caused by inheritance of cancer-predisposing germ-line mutations have specific bioclinical features. This study aimed to analyze the efficacy of conventional cytotoxic treatment in BRCA1 and CHEK2 mutation carriers and non-carriers. The study included 415 Russian breast cancer patients aged 50 years or younger, who were subjected to various standard schemes of neoadjuvant therapy. The choice of therapy was done without the knowledge of the mutations status, because DNA testing was performed retrospectively using the archival tissue samples. 19 BRCA1 (4.6%) and 8 CHEK2 (1.9%) heterozygous genotypes were identified. BRCA1 mutation carriers achieved pathological complete response more frequently than non-carriers [6/19 (31.6%) vs. 46/388 (11.9%), p = 0.024]; this effect was limited to women treated by anthracycline-based therapy without taxanes [5/9 (55.6%) vs. 28/247 (11.3%), p = 0.002] and was not observed in any of 7 BRCA1 carriers receiving taxane-containing regimens. CHEK2 heterozygotes did not experience pathological complete response and showed lower frequency of objective clinical responses as compared to mutation non-carriers [4/8 (50%) vs. 333/388 (85.5%), p = 0.020]; the efficacy of neoadjuvant therapy was particularly poor in CHEK2 carriers receiving anthracyclines without taxanes. This study provides evidence for distinct sensitivity of BRCA1 and CHEK2 mutation-driven breast carcinomas to standard chemotherapeutic schemes.

Delays in diagnosis and treatment of breast cancer: a multinational analysis.

BACKGROUND: Reducing treatment delay improves outcomes in breast cancer. The aim of this study was to determine factors influencing patient- and system-related delays in commencing breast cancer treatment in different countries. METHODS: A total of 6588 female breast cancer patients from 12 countries were surveyed. Total delay time was determined as the sum of the patient-related delay time (time between onset of the first symptoms and the first medical visit) and system-related delay time (time between the first medical visit and the start of therapy). RESULTS: The average patient-related delay time and total delay time were 4.7 (range: 3.4-6.2) weeks and 14.4 (range: 11.5-29.4) weeks, respectively. Longer patient-related delay times were associated with distrust and disregard, and shorter patient-related delay times were associated with fear of breast cancer, practicing self-examination, higher education level, being employed, having support from friends and family and living in big cities. The average system-related delay time was 11.1 (range: 8.3-24.7) weeks. Cancer diagnosis made by an oncologist versus another physician, higher education level, older age, family history of female cancers and having a breast lump as the first cancer sign were associated with shorter system-related delay times. Longer patient-related delay times and higher levels of distrust and disregard were predictors of longer system-related delay times. CONCLUSIONS: The delay in diagnosis and treatment of breast cancer remains a serious problem. Several psychological and behavioural patient attributes strongly determine both patient-related delay time and system-related delay time, but their strength is different in particular countries.

The significance of upfront autologous stem cell transplantation for high-intermediate/high-risk stage IV diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common (30%-35%) type of B-cell lymphoma. Only about 60% of all newly diagnosed advanced-stage DLBCL can be completely treated with x6 R-CHOP. High-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation in the first remission (upfront auto-HSCT) can serve as an option to improve a prognosis in these patients. AIMS: This trial aimed to improve prognosis in DLBCL by upfront auto-HSCT. METHODS AND RESULTS: A group of 105 patients: DLBCL NOS, age 18-65, stage IV, IPI ≥2, CR/PR after x6 R-CHOP/DA-EPOCH-R from 2010 to 2019 at NMRC of Oncology named after N.N.Petrov of MoH of Russia was retrospectively analyzed. The HSCT group included patients with upfront HDCT followed by auto-HSCT (n = 35). The control group included patients with non-invasive follow-up after induction (n = 70). Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), response rate and relapse rate. The 3-year OS (p = .013) and 3-year PFS (p = .033) were significantly higher in the HSCT group. The 3-year OS was decreased by the occurrence of relapse (p ≤ .001) and weight loss (B-symptom) (p = .04). DEL was the negative prognostic factor for 3-year PFS in all patients (p = .001) and control group (p = .001). DA-EPOCH-R significantly increased the 3-year PFS (p = .041). CONCLUSION: Upfront HDCT followed by auto-HSCT can increase 3-year OS and PFS and improve prognosis in DLBCL NOS, age 18-65, stage IV, IPI ≥2 patients.

Evaluation of Colon-Specific Plasma Nanovesicles as New Markers of Colorectal Cancer.

PURPOSE: Developing new and efficient approaches for the early diagnosis of colorectal cancer (CRC) is an important issue. Circulating extracellular nanovesicles (ENVs) present a promising class of cancer markers. Cells of well-differentiated adenocarcinomas retain the molecular characteristics of colon epithelial cells, and the ENVs secreted by these cells may have colon-specific surface markers. We hypothesize that an increase in the number of ENVs carrying colon-specific markers could serve as a diagnostic criterion for colorectal cancer. EXPERIMENTAL DESIGN: Potential colon-specific markers were selected based on tissue-specific expression profile and cell surface membrane localization data. Plasma was collected from CRC patients (n = 48) and healthy donors (n = 50). The total population of ENVs was isolated with a two-phase polymer system. ENVs derived from colon epithelium cells were isolated using immune-beads with antibodies to colon-specific markers prior to labelling with antibodies against exosomal tetraspanins (CD63 and CD9) and quantification by flow cytometry. RESULTS: The number of ENVs positive for single colon cancer markers was found to be significantly higher in the plasma of CRC patients compared with healthy donors. The efficacy of detection depends on the method of ENV labelling. The diagnostic efficacy was estimated by ROC analysis (the AUC varied between 0.71 and 0.79). The multiplexed isolation of colon-derived ENVs using immune-beads decorated with antibodies against five markers allowed for a further increase in the diagnostic potency of the method (AUC = 0.82). CONCLUSIONS: ENVs derived from colon epithelium may serve as markers of differentiated CRC (adenocarcinomas). The composition of ligands used for capturing colon-derived ENVs and their method of labelling are critical for the efficacy of this proposed diagnostic approach.

Novel PD-1 inhibitor prolgolimab: expanding non-resectable/metastatic melanoma therapy choice.

BACKGROUND: Prolgolimab is an IgG1 anti-PD-1 (programmed cell death protein 1) monoclonal antibody containing the Fc-silencing 'LALA' mutation. We assessed the efficacy and safety of two dosing regimens of prolgolimab in patients with advanced melanoma in a multicenter open-label parallel-arm phase II trial (MIRACULUM). We present the final analysis after 1 year of follow-up and additional efficacy results from 2 years of follow-up. METHODS: Patients with advanced cutaneous or non-cutaneous melanoma, including stable brain metastasis, without autoimmune disease and who underwent no prior targeted therapy, anti-PD-(L)1 or anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) therapy were randomly assigned (1:1) to receive prolgolimab in 2 dosing regimens, 1 mg/kg every 2 weeks (arm 1) or 3 mg/kg every 3 weeks (arm 2), until disease progression or intolerable toxicity. Randomisation was stratified based on performance status (Eastern Cooperative Oncology Group 0 or 1), lactate dehydrogenase levels (elevated or normal) and prior systemic therapy (naive or previously treated). The primary outcome was the objective response rate, assessed as per immune-related Response Evaluation Criteria in Solid Tumours by independent central review. The hypothesis that each dosing regimen of prolgolimab has an overall response rate >28% was tested independently for each study arm comprising all patients who received at least one dose of prolgolimab. Exploratory assessment of efficacy, including subgroup analysis, at 2 years of follow-up was not specified in the protocol. This study is registered withClinicalTrials.gov(NCT03269565). RESULTS: Between August 2017 and March 2018, 126 patients with advanced melanoma were enrolled. At main 1-year data cut-off, the median follow-up was 13.8 and 14.5 months in arm 1 and 2, respectively. An objective response was observed in 38.1% of patients (arm 1) and in 28.6% (arm 2). Grade III-IV treatment-related adverse events occurred in 12.7% and 3.2% of patients in arm 1 and 2, respectively. For exploratory efficacy analysis, the median follow-up was 25.4 and 25.7 months in arm 1 and 2, respectively. The 2-year progression-free survival was 33.3% in arm 1 and 30.2% in arm 2, and the 2-year overall survival was 57.1% and 46.0%, respectively. CONCLUSIONS: The MIRACULUM study met its primary end-point in both the study arms. Prolgolimab showed significant antitumour activity and a manageable safety profile in patients with advanced melanoma.