Tumor alkalization therapy: misconception or good therapeutics perspective? - the case of malignant ascites.

Tumor acidity has been identified as a key factor in promoting cancer progression, metastasis, and resistance. Tumor alkalization therapy has emerged as a potential strategy for cancer treatment. This article provides preclinical and clinical evidence for tumor alkalization therapy as a promising cancer treatment strategy. The potential of tumor alkalization therapy using sodium bicarbonate in the treatment of malignant ascites was studied. The concept of intraperitoneal perfusion with an alkalizing solution to increase the extracellular pH and its antitumor effect were explored. The significant extension in the overall survival of the Ehrlich ascites carcinoma mice treated with sodium bicarbonate solution compared to those treated with a sodium chloride solution was observed. In the sodium bicarbonate group, mice had a median survival of 30 days after tumor cell injection, which was significantly (p<0.05) different from the median survival of 18 days in the sodium chloride group and 14 days in the intact group. We also performed a case study of a patient with ovarian cancer malignant ascites resistant to previous lines of chemotherapy who underwent intraperitoneal perfusions with a sodium bicarbonate solution, resulting in a significant drop of CA-125 levels from 5600 U/mL to 2200 U/mL in and disappearance of ascites, indicating the potential effectiveness of the treatment. The preclinical and clinical results obtained using sodium bicarbonate perfusion in the treatment of malignant ascites represent a small yet significant contribution to the evolving field of tumor alkalization as a cancer therapy. They unequivocally affirm the good prospects of this concept.

Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients.

Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcinomas arising in BRCA1 mutation carriers almost always carry alterations of the TP53 gene thus providing an opportunity to address this question. The analysis of consecutive BC patients treated by NACT revealed a higher pCR rate in BRCA1-driven vs. BRCA1-wildtype BCs (13/24 (54%) vs. 29/192 (15%), p < 0.0001). Twelve pre-/post-NACT tissue pairs obtained from BRCA1 mutation carriers were available for the study. While TP53 mutation was identified in all chemonaive tumors, droplet digital PCR (ddPCR) analysis of the post-NACT tumor bed revealed the persistence of this alteration in all seven pCR-non-responders but in none of five pCR responders. Eleven patients provided to the study post-NACT tissue samples only; next-generation sequencing (NGS) analysis revealed mutated TP53 copies in all six cases without pCR but in none of five instances of pCR. In total, TP53 mutation was present in post-NACT tissues in all 13 cases without pCR, but in none of 10 patients with pCR (p < 0.000001). Therefore, the lack of visible tumor cells in the post-NACT tumor bed is indeed a reliable indicator of the complete elimination of transformed clones. Failure of ultrasensitive methods to identify patients with minimal residual disease among pCR responders suggests that the result of NACT is a categorical rather than continuous variable, where some patients are destined to be cured while others ultimately fail to experience tumor eradication.

Management and Treatment of Non-small Cell Lung Cancer with MET Alteration and Mechanisms of Resistance.

OPINION STATEMENT: MET-driven tumors are a heterogenous group of non-small cell lung cancers (NSCLC) with activating mutations. Pathologic activation of MET can be achieved with increased number of gene copies overexpression, or decreased protein degradation through several mechanisms, including mutations, amplifications, or fusions. Besides its role as primary driver, MET activation might also mediate resistance to kinase inhibitors in NSCLC with various other actionable alterations. While checkpoint inhibitors have modest efficacy in MET-driven tumors, several approaches of targeted blockade are available. Among them the most promising are small tyrosine kinase inhibitors, antibody-drug conjugates, and bispecific antibodies. Unfortunately, resistance is virtually inevitable. Resistance to small kinase inhibitors might be mediated by kinase domain mutations or activation of shunting cascades. Various resistance mechanisms might be present in one patient, making it overcoming an unresolved problem.

The emergence of hypervirulent blaNDM-1-positive Klebsiella pneumoniae sequence type 395 in an oncology hospital.

Fifteen hypermucoviscous isolates (13 blaNDM-1-positive) obtained from 11 oncology patients were analyzed by whole genome sequencing, and selected isolates were assessed in a murine model of sepsis. ST395/K2 isolates harboring rmpA, rmpA2, peg-344, aerobactin, enterobactin, yersiniabactin, type I fimbriae, etc. displayed maximal virulence in the mouse lethality assay (LD50 = 102 CFU). ST147/K20 isolates lacking yersiniabactins were relatively less virulent (LD50 = 104 CFU), ST395/K2 isolates lacking rmpA, rmpA2, peg-344, and aerobactin, but harboring yersiniabactin demonstrated minimal virulence (LD50 = 105 CFU). Isolates represent various paths and stages of evolution directed towards convergence of multidrugresistant classical Klebsiella pneumoniae and hypervirulent K. pneumoniae.

Lack of Response to Vemurafenib in Melanoma Carrying BRAF K601E Mutation.

Vemurafenib has been developed to target common BRAF mutation V600E. It also exerts activity towards some but not all rare BRAF substitutions. Proper cataloguing of drug-sensitive and -insensitive rare mutations remains a challenge, due to low occurrence of these events and inability of commercial PCR-based diagnostic kits to detect the full spectrum of BRAF gene lesions. We considered the results of BRAF exon 15 testing in 1872 consecutive melanoma patients. BRAF mutation was identified in 1,090 (58.2%) cases. While drug-sensitive codon 600 substitutions constituted the majority of BRAF gene lesions (V600E: 962 [51.4%]; V600K: 86 [4.6%]; V600R: 17 [0.9%]), the fourth common BRAF allele was K601E accounting for 9 (0.5%) melanoma cases. The data on BRAF inhibitor sensitivity of tumors with K601E substitution are scarce. We administered single-agent vemurafenib to a melanoma patient carrying BRAF K601E mutation as the first-line treatment. Unfortunately, this therapy did not result in a tumor response. Taken together with already published data, this report indicates lack of benefit from conventional BRAF inhibitors in patients with BRAF K601E mutated melanoma.