Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking. METHODS: We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease-free survival, overall survival, and safety. RESULTS: In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease-free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed. CONCLUSIONS: Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann-La Roche; ALINA ClinicalTrials.gov number, NCT03456076.).

Specific IgE and Basophil Activation Test by Microarray: A Promising Tool for Diagnosis of Platinum Compound Hypersensitivity Reactions.

Drug hypersensitivity reactions (DHRs) to platinum-based compounds (PCs) are on the rise, and their personalized and safe management is essential to enable first-line treatment for these cancer patients. This study aimed to evaluate the usefulness of the basophil activation test by flow cytometry (BAT-FC) and the newly developed sIgE-microarray and BAT-microarray in diagnosing IgE-mediated hypersensitivity reactions to PCs. A total of 24 patients with DHRs to PCs (20 oxaliplatin and four carboplatin) were evaluated: thirteen patients were diagnosed as allergic with positive skin tests (STs) or drug provocation tests (DPTs), six patients were diagnosed as non-allergic with negative STs and DPTs, and five patients were classified as suspected allergic because DPTs could not be performed. In addition, four carboplatin-tolerant patients were included as controls. The BAT-FC was positive in 2 of 13 allergic patients, with a sensitivity of 15.4% and specificity of 100%. However, the sIgE- and BAT-microarray were positive in 11 of 13 DHR patients, giving a sensitivity of over 84.6% and a specificity of 90%. Except for one patient, all samples from the non-allergic and control groups were negative for sIgE- and BAT-microarray. Our experience indicated that the sIgE- and BAT-microarray could be helpful in the endophenotyping of IgE-mediated hypersensitivity reactions to PCs and may provide an advance in decision making for drug provocation testing.

Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial.

Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. Design, Setting, and Participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. Main Outcomes and Measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. Conclusions and Relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT04158440.

Platinum-based chemotherapy in metastatic prostate cancer: what possibilities?

Metastatic prostate cancer is a major health burden worldwide, necessitating the continuous development of effective treatment strategies. Androgen deprivation therapy remains the cornerstone of prostate cancer treatment, but novel approaches are needed for metastatic castration-resistant prostate cancer (mCRPC). Recent studies have highlighted the prevalence of mutations in DNA repair genes, including BRCA1 and BRCA2, in mCRPC patients, rendering them more susceptible to platinum-based chemotherapy and Poly (ADP-ribose) polymerase (PARP) inhibitors. Platinum-based chemotherapy, particularly in combination with taxanes, has demonstrated encouraging activity in mCRPC, as well as homologous recombination gene alterations have shown increased sensitivity to platinum compounds in these patients. The combination of platinum-based chemotherapy with PARP inhibitors represents a novel and potentially effective therapeutic strategy for this subgroup of patients. However, the optimal sequence of administering these agents and the potential for cross-resistance and cross-toxicities remain areas requiring further investigation. Prospective randomized studies are essential to elucidate the most effective treatment approach for this challenging patient population. This review aims to explore the potential of platinum-based chemotherapy in the context of prostate cancer, and more in detail in homologous recombination repair (HRR) mutated patients. We discuss the synergistic effects of combining platinum compounds with PARP inhibitors and the potential benefits of adopting specific therapeutic sequences.

Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer.

BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS: We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS: A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS: Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).

A state-of-art of underlying molecular mechanisms and pharmacological interventions/nanotherapeutics for cisplatin resistance in gastric cancer.

The fourth common reason of death among patients is gastric cancer (GC) and it is a dominant tumor type in Ease Asia. One of the problems in GC therapy is chemoresistance. Cisplatin (CP) is a platinum compound that causes DNA damage in reducing tumor progression and viability of cancer cells. However, due to hyperactivation of drug efflux pumps, dysregulation of genes and interactions in tumor microenvironment, tumor cells can develop resistance to CP chemotherapy. The current review focuses on the CP resistance emergence in GC cells with emphasizing on molecular pathways, pharmacological compounds for reversing chemoresistance and the role of nanostructures. Changes in cell death mechanisms such as upregulation of pro-survival autophagy can prevent CP-mediated apoptosis that results in drug resistance. Moreover, increase in metastasis via EMT induction induces CP resistance. Dysregulation of molecular pathways such as PTEN, PI3K/Akt, Nrf2 and others result in changes in CP response of GC cells. Non-coding RNAs determine CP response of GC cells and application of pharmacological compounds with activity distinct of CP can result in sensitivity in tumor cells. Due to efficacy of exosomes in transferring bioactive molecules such as RNA and DNA molecules among GC cells, exosomes can also result in CP resistance. One of the newest progresses in overcoming CP resistance in GC is application of nanoplatforms for delivery of CP in GC therapy that they can increase accumulation of CP at tumor site and by suppressing carcinogenic factors and overcoming biological barriers, they increase CP toxicity on cancer cells.

Efficacy of Nivolumab and Pembrolizumab in Platinum-sensitive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

BACKGROUND/AIM: This study evaluated the efficacy of nivolumab and pembrolizumab in treating platinum-sensitive recurrent or metastatic head and neck squamous cell carcinomas (R/M-HNSCC). PATIENTS AND METHODS: Platinum-sensitive patients with R/M-HNSCC were selected at Tokyo Medical University Hospital from May 1, 2017, to June 30, 2022. Patients with a history of treatment with nivolumab or pembrolizumab were included. Nivolumab was used in 21 cases and pembrolizumab in 15 cases. RESULTS: The median overall survival (OS) was 16.9 months in the nivolumab group and 19.2 months in the pembrolizumab group and no significant differences were observed between the two groups. The median progression-free survival (PFS) was 4.8 months in the nivolumab group and 9.3 months in the pembrolizumab group. No significant differences were observed between the two groups. The objective response rates (ORR) were 38% and 47% in the nivolumab and pembrolizumab groups, respectively. CONCLUSION: Nivolumab as well as pembrolizumab were found to be effective in platinum-sensitive patients with R/M-HNSCC. Nivolumab can be considered a potential treatment option for platinum-sensitive R/M-HNSCC in the future.

Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer.

BACKGROUND: Approximately 20% of patients with non-small-cell lung cancer (NSCLC) receive a diagnosis of stage III disease. There is no current consensus regarding the most appropriate treatment for these patients. METHODS: In this open-label, phase 2 trial, we randomly assigned patients with resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months. The primary end point was a pathological complete response (0% viable tumor in resected lung and lymph nodes). Secondary end points included progression-free survival and overall survival at 24 months and safety. RESULTS: A total of 86 patients underwent randomization; 57 were assigned to the experimental group and 29 were assigned to the control group. A pathological complete response occurred in 37% of the patients in the experimental group and in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI], 1.34 to 21.23; P = 0.02). Surgery was performed in 93% of the patients in the experimental group and in 69% in the control group (relative risk, 1.35; 95% CI, 1.05 to 1.74). Kaplan-Meier estimates of progression-free survival at 24 months were 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25 to 0.88). Kaplan-Meier estimates of overall survival at 24 months were 85.0% in the experimental group and 63.6% in the control group (hazard ratio for death, 0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients in the experimental group (19%; some patients had events of both grades) and 3 patients in the control group (10%). CONCLUSIONS: In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.).

Atomic-precise Pt2Cu4 cluster-based fluorescent sensor for rapid interleukin-6 detection.

Levonorgestrel protected Pt2Cu4 clusters were assembled with a polymer to prepare nanobeads (NBs) with intense red fluorescence. An immunofluorescence sensor based on Pt2Cu4NBs was established for the rapid and sensitive detection of interleukin-6 (IL-6) owing to its significance in inflammatory diseases, with a limit of detection of 42.66 pg mL-1. IL-6 spiked in serum was also accurately detected.

Cost-effectiveness analysis of niraparib maintenance therapy in Chinese patients with platinum-sensitive recurrent ovarian cancer.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of niraparib versus routine surveillance as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer in China. METHOD: A three-state partitioned survival model that adopted a lifetime horizon with a 4-week cycle length was developed. Efficacy data were derived from the NORA study. Cost and utility data were obtained from published studies and online databases. The cost and health outcomes were discounted at an annual rate of 5%. In this analysis, the primary outcomes included quality-adjusted life-year (QALY) and incremental cost-effectiveness ratio (ICER). The willingness-to-pay (WTP) thresholds were set at 1 to 3 times the gross domestic product per capita of China in 2022 ($12,741 to $38,233/QALY). Sensitivity analyses were conducted to verify the robustness of the model results. RESULTS: In the base-case analysis, niraparib was not found to be cost-effective, with an ICER of $42,888/QALY compared with routine surveillance at the WTP thresholds. One-way deterministic sensitivity analyses indicated that the ICER value was most sensitive to the cost of subsequent treatment in placebo group. The probabilistic sensitivity analysis suggested that at the WTP thresholds, the probability of niraparib being cost-effective was 2.9% to 50.1%. CONCLUSIONS: Niraparib improves the survival benefit of platinum-sensitive recurrent ovarian cancer patients. However, it seems to be less cost-effective, as it has higher costs than routine surveillance at the WTP thresholds. Reasonable dose reduction according to the patient's actual situation or lowering the price of niraparib can improve its cost-effectiveness.

Trichostatin A inhibits expression of the human SLC2A5 gene via SNAI1/SNAI2 transcription factors and sensitizes colon cancer cells to platinum compounds.

GLUT5, a key protein encoded by the SLC2A5 gene, is involved in the uptake of fructose from the intestine. Currently, with the increased consumption of this sugar and the associated increased incidence of obesity, diabetes and cancer, GLUT5 may represent an important molecular target in the prevention and treatment of these diseases. Here, we demonstrate that overexpression of the SNAI1 and SNAI2 transcription factors in cells expressing high levels of SLC2A5 mRNA reduced SLC2A5 gene expression. Furthermore, a histone deacetylase inhibitor, trichostatin A, which induces SNAI1 and SNAI2 expression, inhibits SLC2A5/GLUT5 expression and sensitizes colon cancer cells to cisplatin and oxaliplatin. This finding might have potential relevance for the development of therapeutic treatments aimed at modulating fructose transport or genes involved in this process for use with certain cancers.

Impact of Hydrophobic Chains in Five-Coordinate Glucoconjugate Pt(II) Anticancer Agents.

This study describes new platinum(II) cationic five-coordinate complexes (1-R,R') of the formula [PtR(NHC)(dmphen)(ethene)]CF3SO3 (dmphen = 2,9-dimethyl-1,10-phenanthroline), containing in their axial positions an alkyl group R (methyl or octyl) and an imidazole-based NHC-carbene ligand with a substituent R' of variable length (methyl or octyl) on one nitrogen atom. The Pt-carbene bond is stable both in DMSO and in aqueous solvents. In DMSO, a gradual substitution of dmphen and ethene is observed, with the formation of a square planar solvated species. Octanol/water partitioning studies have revealed the order of hydrophobicity of the complexes (1-Oct,Me > 1-Oct,Oct > 1-Me,Oct > 1-Me,Me). Their biological activity was investigated against two pairs of cancer and non-cancer cell lines. The tested drugs were internalized in cancer cells and able to activate the apoptotic pathway. The reactivity of 1-Me,Me with DNA and protein model systems was also studied using UV-vis absorption spectroscopy, fluorescence, and X-ray crystallography. The compound binds DNA and interacts in various ways with the model protein lysozyme. Remarkably, structural data revealed that the complex can bind lysozyme via non-covalent interactions, retaining its five-coordinate geometry.

Systemic therapy for advanced cervical cancer: Leveraging the historical threshold of overall survival.

Cervical cancer (CC) is a worldwide problem, especially in low- and middle-income countries, where patients are often diagnosed with locally advanced disease. Until recently, all chemotherapy drugs achieved low ORR and 12-month overall survival (12- month OS) for advanced CC after failure for platinum compounds. Advances in systemic therapy with immunotherapy, targeted therapy, and antibody-drug conjugates (ADC) have leveraged the 12-month OS limit. Recently, immunotherapy (pembrolizumab) has become the standard of care in first-line advanced CC combined with platinum and taxane and in second-line after platinum doublet failure.

High expression of CETN2 is associated with platinum resistance and poor prognosis in epithelial ovarian cancer.

PURPOSE: The poor prognosis of ovarian cancer is largely due to platinum resistance. It has been demonstrated that nucleotide excision repair (NER) involving centrin-2(CETN2) is connected to platinum resistance in ovarian cancer. The molecular mechanism of CETN2 in ovarian cancer and the mechanism affecting the outcome of chemotherapy are unknown. METHODS: The protein-protein interaction (PPI) network was mapped after obtaining the interacting proteins of CETN2, and the interacting genes were subjected to enrichment analysis. To examine the relationship between CETN2 and platinum resistance, gene microarray data and clinical data related to platinum resistance in ovarian cancer were downloaded. The possible signaling pathway of CETN2 was investigated by Gene set enrichment analysis (GSEA). Immune infiltration analysis was performed. Immunohistochemistry (IHC) and quantitative real-time PCR (QRT-PCR) were used to examine the expression of CETN2 in clinical samples in relation to the effectiveness of chemotherapy. The capacity of CETN2 to predict chemotherapy results was proven by receiver operating characteristic (ROC) curves after the construction of two prediction models, the logistic regression model and the decision tree model. The impact of CETN2 on prognosis was examined using the Kaplan-Meier technique. RESULTS: CETN2 was associated with NER, oxidative phosphorylation (OXPHOS) and cell cycle pathways in ovarian cancer drug-resistant samples. In clinical samples, CETN2 showed its possible correlation with immune infiltration. The protein expression level of CETN2 was significantly higher in platinum-resistant patients than that in platinum-sensitive patients, and the expression level had some predictive value for chemotherapy outcome, and high CETN2 protein expression was associated with poorer progression-free survival. CONCLUSIONS: CETN2 protein had a significant effect on ovarian cancer platinum sensitivity and prognosis, which may be related to the activation of NER, OXPHOS and cell cycle pathways upon CETN2 upregulation. Further research is necessary to determine the therapeutic application value of CETN2, which may be a new biomarker of chemoresponsiveness.

Induction of immunogenic cell death by novel platinum-based anticancer agents.

Traditional platinum-based anticancer drugs, led by cisplatin, play an important role in chemotherapy. However, the development of platinum compounds is limited due to serious toxicity and side effects. In recent years, studies have showed that immunogenic cell death (ICD) may be one of the potential action mechanisms of classical platinum drugs, such as oxaliplatin. This strategy combining chemotherapy and immunotherapy can effectively utilize the body's immune system to help platinum compounds to fight against tumors, and the dose can be appropriately reduced to limit toxic side effects. The induction of ICD by platinum compounds has become a research hotspot and one of the future development directions of metal drugs. Here, the progress of platinum compounds were collected and comprehensively summarized, their capacity of ICD induction and mechanism of action are exposed, providing reference for the design and synthesis of new anticancer platinum ICD inducers.

State of art in the chemistry of nucleoside-based Pt(II) complexes.

After the fortuitous discovery of the anticancer properties of cisplatin, many Pt(II) complexes have been synthesized, to obtain less toxic leads which could overcome the resistance phenomena. Given the importance of nucleosides and nucleotides as antimetabolites, studying their coordinating properties towards Pt(II) ions is challenging for bioorganic and medicinal chemistry. This review aims to describe the results achieved so far in the aforementioned field, paying particular attention to the synthetic aspects, the chemical-physical characterization, and the biological activities of the nucleoside-based Pt(II) complexes.

CUL4B increases platinum-based drug resistance in colorectal cancer through EMT: A study in its mechanism.

Platinum-based chemotherapy drugs play a very important role in the treatment of patients with advanced colorectal cancer, but the drug resistance of platinum-based chemotherapy drugs is an important topic that puzzles us. If we can find mechanisms of resistance, it will be revolutionary for us. We analysed the differential genes, core genes and their enrichment pathways in platinum-resistant and non-resistant patients through a public database. Platinum-resistant cell lines were cultured in vitro for in vitro colony and Transwell analysis. Tumorigenesis analysis of nude mice in vivo. Verify the function of core genes. Through differential gene and enrichment analysis, we found that CUL4B was the main factor affecting platinum drug resistance and EMT. Our hypothesis was further verified by in vitro drug-resistant and wild-type cell lines and in vivo tumorigenesis analysis of nude mice. CUL4B leads to platinum drug resistance in colorectal cancer by affecting tumour EMT.

Brief Research on the Biophysical Study and Anticancer Behavior of Pt(II) Complexes: Their DNA/BSA Binding, Molecular Docking, and Cytotoxic Property.

The potent bidentate carrier ligand 2-picolylamine (pic) has been used to synthesize Pt(II) complexes to know their bioactivity and anticancer property as reflected by PASS prediction software. The dichloro Pt(II) complex [Pt(pic)Cl2], Pt-1, and its hydrolyzed diaqua complex [Pt(pic)(OH2)2]2+, Pt-2, were synthesized. The thiol-containing Pt(II) complexes [Pt(pic)(l-cys)]+, Pt-3, and [Pt(pic)(L-ac-l-cy)]+, Pt-4, were synthesized from Pt-2, which was obtained from hydrolysis of Pt-1. Their biomolecular interactions with BSA and DNA were executed by spectroscopic methods, and their cytototoxic property was tested by the MTT assay. In vitro biomolecular interactions of Pt(II) complexes with BSA and DNA were investigated by different spectroscopic and viscosity measurement methods for their pharmacokinetic and pharmacodynamic importance. The conformational change of BSA in the presence of a drug candidate was studied by Förster resonance energy transfer calculation and synchronous and three-dimensional fluorescence spectroscopic studies. A theoretical approach on optimization structures, highest occupied molecular orbital-lowest unoccupied molecular orbital energy, global reactivity parameters, time-dependent density functional theory, and molecular docking with BSA and DNA was executed to strengthen and support the experimental observations. In vitro cytotoxic profiles of the complexes like the anticancer activity and their level of reactive oxygen species production were brought under consideration on A549 cancer cells and the normal human embryonic kidney cell line HEK-293. The cytotoxic property was compared with that of the recognized anticancer drug cisplatin.

Germline BRCA mutation carriers are more likely to undergo cytoreductive surgery for relapsed, platinum sensitive, ovarian cancer.

OBJECTIVE: BRCA mutations have been associated with improved outcomes in ovarian cancer patients. This study's objective was to compare the secondary cytoreduction surgery (SCS) rates among ovarian cancer patients by BRCA mutation status. METHODS: The study was retrospective and included platinum sensitive recurrent high grade serous ovarian cancer patients from one Canadian center and two Israeli centers from January 1999 to December 2018. Demographic and genetic data, tumor characteristics, patterns of recurrence and surgical and medical treatments were obtained from electronic charts. Patients were grouped according to BRCA mutation status. Logistic regression analyses were used to explore potential prognostic factors of secondary cytoreduction. RESULTS: 147 patients were enrolled, including 97 from Canada and 50 from Israel. Forty-seven patients (32%) had a BRCA mutation, including 39 (26.5%) germline mutations and 8 (5.5%) somatic mutations. Thirty-one patients (21.1%) underwent SCS. The rate of SCS was 33.3% among the germline BRCA mutation carriers and 15.7% among patients without germline BRCA mutation (p = 0.026). Predictors of secondary cytoreduction included germline BRCA mutation (OR = 2.5, p = 0.03), time to recurrence (OR = 1.004 per month, p < 0.001), absence of lymphatic recurrence (OR = 3.08, p = 0.013), three or fewer lesions at recurrence (OR = 36.74, p < 0.001) and absence of ascites (OR = 9.1, p = 0.034). After adjusting for the number of lesions at recurrence, no other variable remained a significant predictor. CONCLUSION: Germline BRCA mutation carriers are more likely to undergo secondary cytoreduction. This may be mediated in part by lower volume disease at recurrence. This observation should be considered when planning surveillance for these patients after first-line treatment.

A comparison of neoadjuvant therapies for gastroesophageal and gastric cancer on tumour resection rate: A network meta-analysis.

BACKGROUND: Gastric cancer is one of the most common malignancies around the world, and a variety of neoadjuvant chemotherapies with different drug combinations are available for the treatment. R0 resection refers to a microscopically negative margin on resection, where no gross or microscopic tumour remains in the primary tumour. We aimed to find evidence on the relative effectiveness of neoadjuvant therapies for patients with advanced gastroesophageal and gastric cancer on the R0 resection rate. METHODS: Relevant randomised controlled trials were searched using appropriate keywords in health-related databases. We performed network meta-analysis within a frequentist framework. The endpoint assessed was the R0 resection rate. We assessed consistency and transitivity assumptions that are necessary for network meta-analysis. This study only used data from published studies. The need for consent from participants was waived by the Ethics Review Committee of the International Medical University in Malaysia. RESULTS: Six randomised controlled trials involving 1700 patients were identified. A network plot was formed with five neoadjuvant regimens [DLX (pyrimidine analogue + platinum compounds + chemoradiotherapy), DELX (pyrimidine analogue + epipodophylllotoxins/etoposide + platinum compounds + chemoradiotherapy), ADL (anthracycline + pyrimidine analogue + platinum compounds), ADM (anthracycline+ pyrimidine analogue + anti-folate compounds) and LTX (platinum compounds + taxane + chemoradiotherapy)] and surgery alone for management of patients with advanced gastroesophageal and gastric cancer. Assumptions required for a network meta-analysis such as consistency ((global test: Chi2 (1): 3.71; p:0.054)), and the transitivity in accord to the characteristics of interventions considered in this review were not violated. In the network comparison, surgery alone has a lower R0 resection rate compared with LTX (OR 0.2, 95%CI:0.01, 0.38) or DLX (OR 0.48, 95%CI: 0.29, 0.79). LTX has higher resection rate compared with DLX (OR 2.47, 95%CI: 1.08 to 5.63), DELX (OR 106.0, 95%CI: 25.29 to 444.21), ADM (OR 5.41, 95%CI: 1.56 to 18.78) or ADL (OR 3.12, 95%CI: 1.27 to 7.67). There were wide or very wide CIs in many of these comparisons. Overall certainty of the evidence was low or very low. Further research in this field is very likely to have an important impact on our confidence in the R0 resection rates between LTX versus other neoadjuvant chemotherapy is likely to change the estimate. CONCLUSIONS: Findings suggest that overall quality of evidence on the relative effectiveness of neoadjuvant chemotherapies was low to very low level. Therefore, we are very uncertain about the true effect of neoadjuvant therapies in the R0 resection rate in patients with gastroesophageal and gastric cancer. Future well-designed large trials are needed. To recruit large samples in this field, multicountry trials are recommended. Future trials also need to assess treatment-related adverse events, and patients-centered outcomes such as health-related quality of life.