Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxiarepressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients.
Recently, a human/mouse chimeric monoclonal antibody, rituximab, has been successfully used to treat cases of B-cell non-Hodgkin's lymphoma and some autoimmune diseases. However, several viral infections related to rituximab have been reported in the literature, but were not well characterized. To further investigate this topic, relevant English language studies were identified through Medline. There were 64 previously reported cases of serious viral infection after rituximab treatment. The median age of the cases was 61 years (range: 21 - 79). The median time period from the start of rituximab treatment to viral infection diagnosis was 5.0 months (range: 1 - 20). The most frequently experienced viral infections were hepatitis B virus (HBV) (39.1%, n = 25), cytomegalovirus infection (CMV) (23.4%, n = 15), varicella-zoster virus (VZV) (9.4%, n = 6), and others (28.1%, n = 18). Of the patients with HBV infections, 13 (52.0%) died due to hepatic failure. Among the 39 cases that had viral infections other than HBV, 13 died due to these specific infections. In this study, about 50% of the rituximab-related HBV infections resulted in death, whereas this was the case in only 33% of the cases with other infections. Close monitoring for viral infection, particularly HBV and CMV, in patients treated with rituximab should be recommended.
Increased serum cTnT level can be detected in the early stages of anthracycline therapy and it is associated with diastolic dysfunction of the left ventricle. Therefore, serum cTnT level could be a useful measure for early detection of anthracycline-induced cardiotoxicity.
See Appendix for individual names.Background: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. Patients and methods:In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8 mg/kg loading dose, then 6 mg/kg every 3 weeks (q3w)] and pertuzumab (840 mg loading dose, then 420 mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results:Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nabpaclitaxel in 65; 7 discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%).Conclusions: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile.ClinicalTrials.gov: NCT01572038.
Coronavirus disease 2019 (COVID-19) is expected to significantly affect cancer patients due to adverse outcomes with COVID-19 and disruptions in cancer care. Another important point is the stress and anxiety burden of COVID-19, which could affect quality of life. Patient education is vital due to the vulnerability of the topic to disinformation. To determine the areas needing improvements in patient education, and coping with stress, the burden of the problem should be pictured. From this point, we aimed to assess the perspectives and fears of cancer patients about COVID-19 with resources of COVID-19 knowledge with a questionnaire. A total of 250 adult cancer patients applied to the outpatient chemotherapy unit of Hacettepe University Cancer Center between May 27, 2020, and June 9, 2020, invited to answer a questionnaire of 13 multiple-choice questions with a return rate of 78% (195/250). Most patients acquired their knowledge about COVID-19 from television (91.9%). Social media were the second most common source of knowledge (43.8%) with a predilection in younger patients, nonsmokers, targeted therapy-or immunotherapy-treated patients, and breast cancer patients (>65 vs. <65 years of age, p = 0.057; nonsmoker vs. ever-smoker, p = 0.036; targeted therapy and immunotherapy vs. chemotherapy, p = 0.004; breast cancer vs. other cancers, p = 0.019). The percentage of patients seeing the information about COVID-19 as adequate (38.9%) or inadequate (35.1%) was similar. More than 90% of the patients had a moderate to severe degree of COVID-19 fear. In addition, 27.6% of patients had false knowledge of glove using as a protective measure for COVID-19. More than half of the patients had another wrong knowledge as the need for the supplements for COVID-19 protection. A significant percentage of patients (84.7%) expected some level of disruption in oncological care with the expectation of a moderate-to-severe disruption was more common in the advanced-stage patients (p = 0.026). In our experience, most cancer patients had a significant degree of fear about both infecting COVID-19 and the disruption of cancer care by COVID-19. A significant amount of our patients had wrong information about the protection necessities, which denotes the need for better patient education about COVID-19.
Rituximab maintenance therapy has emerged as an effective treatment for low-grade lymphomas. No major acute or cumulative toxicities were observed in patients receiving rituximab maintenance therapy compared with observation arms in clinical trials. However, B-cells are completely depleted throughout the maintenance period and even longer, which may render patients at high risk for infections. Several infections related to rituximab have been reported in the literature. Yet it is not clear whether rituximab maintenance therapy increases the infectious complications or not. To further investigate this topic, we have performed a systematic review and meta-analysis of randomised controlled trials (RCT). The meta-analysis of five RCTs showed that rituximab maintenance therapy significantly increased the relative risk of both infection and neutropenia in patients with lymphoma. On the basis of the available evidence, patients who received rituximab maintenance treatment have higher risk of neutropenia and infection than those who did not. Previously treated patients particularly with fludarabine containing regimens are more susceptible to infectious complications and require extended vigilance.
Doxorubicin may result in arrhythmias both in early and late periods of treatment. These arrhythmias are rarely life threatening.
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