Effective Therapy Regimens Research Articles

Tinea capitis, caused by Microsporum canis (felineum) : literature review and clinical cases

According to statistics, tinea capitis remains the main mycological problem in childhood. The spectrum of causative agents of tinea capitis varies depending on the continent. In epidemiological terms, the pathogenic fungus Microsporum canis (felineum)absolutely predominates on the Eurasian continent. A significant problem in the diagnosis and, in particular, in the treatment of microsporia are cases of the disease in very young children: we estimate this most problematic age from 1 to 18 months. Microsporia in children under the age of 1 year is the most relevant in pediatric clinical mycology due to the limited arsenal of topical and systemic medications approved at this age. The clinical case presented in this article demonstrates an example of successful treatment of scalp microsporia in a 7-month-old child who had contraindications to systemic therapy. It should be noted that the duration of treatment in this case was almost 4 months, while the most effective therapy regimens, including systemic drugs, lead to the elimination of pathogenic fungus from the foci on the scalp within 30–45 days.

Silibinins and curcumin as promising ligands against mutant cystic fibrosis transmembrane regulator protein

Cystic Fibrosis Transmembrane Regulator (CFTR) is a significant protein that is responsible for the movement of ions across cell membranes. The cystic fibrosis (CF) occur due to the mutations in the CFTR gene as it produces the dysfunctional CFTR protein. The sequence of CFTR protein as a target structure was retrieved from UniProt and PDB database. The ligands selection was performed through virtual screening and top 3 ligands choose out of 65 ligands silibinins, curcumin, demethoxycurcumin were selected with a reference drug Trikafta (R*). According to docking, ADMET analyses, the natural ligands (Silibinins and Curcumin) displayed best binding energy, pharmacokinetic and free toxicity than other natural compounds and reference drug (R*). An MD simulation for 200 ns was also established to ensure that natural ligands (Silibinins and Curcumin) attached to the target protein favorably and dynamically, and that protein–ligand complex stability was maintained. It is concluded that silibinins and curcumins have a better capacity to decrease the effect of mutant CFTR protein through improved trafficking and the restoration of original function. In conclusion, in silico studies demonstrate the potential of silibinins and curcumin as therapeutic agents for cystic fibrosis, particularly for the D614G mutated protein. Their ability to increase CFTR function while reducing cellular stress and inflammation, together with their favorable safety profile and accessibility could make them valuable additions to cystic fibrosis treatment options. Further experimental and clinical validation will be required to fully realize their potential and include them into effective therapy regimens.

Determinants of resistance and response to melanoma therapy.

Metastatic melanoma is among the most enigmatic advanced cancers to clinically manage despite immense progress in the way of available therapeutic options and historic decreases in the melanoma mortality rate. Most patients with metastatic melanoma treated with modern targeted therapies (for example, BRAFV600E/K inhibitors) and/or immune checkpoint blockade (for example, anti-programmed death 1 therapy) will progress, owing to profound tumor cell plasticity fueled by genetic and nongenetic mechanisms and dichotomous host microenvironmental influences. Here we discuss the determinants of tumor heterogeneity, mechanisms of therapy resistance and effective therapy regimens that hold curative promise.

Weekly paclitaxel, carboplatin and cetuximab (PCC) combination followed by nivolumab in platinum-sensitive recurrent and /or metastatic squamous cell carcinoma of head and neck: a retrospective analysis from two institutions in India

Background: First line (1L) TP-Ex-like regimen followed by 2nd-line (2L) immunotherapy represents one of the standards of care in platinum-sensitive recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN). We report our experience from 2 tertiary care institutions of India. Methods: This is a retrospective analysis of consecutive patients of platinum-sensitive R/M SCCHN treated with 1L weekly paclitaxel, carboplatin, and cetuximab (PCC) regimen followed by cetuximab maintenance (if non-progressive) or 2L nivolumab or oral metronomic chemotherapy (OMCT) on progression. Overall response rates (ORR), progression-free survival after 1L and 2L (PFS-1 & PFS-2), overall survival (OS), and safety were evaluated. Results: The study included 54 patients; median age 56.5 years; 89% men; 11% had cardiac dysfunction; 13% had renal dysfunction. After 1L PCC, ORR was 59.3%; median PFS-1 was 7.031 months; 61% had progression; 35% were treated with nivolumab and 18% with OMCT. The ORR was 26.3% (nivolumab) and 10% (OMCT). Median PFS-2 was 6.5 months (nivolumab) and 2 months (OMCT). The median OS was 15.01 months (entire cohort), 20.6 months (nivolumab), and 7 months (OMCT). Grade III/IV adverse events on PCC included neutropenia (31.4%), anaemia (35.1%), thrombocytopenia (7.4%), febrile neutropenia (11.1%), and skin reaction (16.6%); no Grade-III/IV treatment-related toxicities on 2L. Conclusions: 1L weekly PCC is an effective regimen for palliative therapy of platinum- sensitive R/MSCCHN with an acceptable toxicity profile. The addition of 2L nivolumab on progression further improves the outcomes.

Comparative host transcriptomics as a tool to identify candidate biomarkers for immune reactions in leprosy using meta-analysis.

Background Leprosy is no longer considered an imprecation, as an effective multidrug therapy regimen is available worldwide for its cure. However, its diverse clinical manifestations sometimes involve acute inflammatory reactions. These complications result in irreversible nerve damage, neuritis and anatomical deformities that emerge before, during the treatment or after the completion of treatment. Reversal reaction (Type-I) and erythema nodosum leprosum (Type-II) are the leprosy reactions generally seen in patients with lepromatous and borderline forms of leprosy. At present, there is no accurate diagnostic test available to detect these leprosy reactions. Objectives To identify potential biomarkers indicative of Type-I and Type-II leprosy reactions that could help in their early diagnosis. Methods and Results Host-transcriptomics investigations have been utilised in this study to decipher a correlation between host-gene expression-based biomarkers and exacerbation of leprosy reactions. We present a comparative analysis of publicly available host transcriptomics datasets (from Gene Expression Omnibus) related to leprosy reactions. Individual datasets were analysed and integration of results was carried out using meta-analysis. Common differentially expressed genes (DEGs) were identified using the frequentist and Bayesian ratio association test methods. We have identified several genes - ADAMTS5, ADAMTS9, IFITM2, IFITM3, KIRREL, ANK3, CD1E, CTSF, DOCK9 and KRT73 to name a few - which can serve as potential biomarkers for Type-II reaction. Similarly, ACP5, APOC1, CCL17, S100B, SLC11A1 among others may likely serve as biomarkers for Type-I reaction. Limitations The number of datasets related to leprosy reactions found after the systematic search is less (n = 4) and may limit the accuracy of identified biomarker genes. This could be resolved by including more studies in the data analysis. Conclusion We provide a comprehensive list of gene candidates which could be prioritised further in research focusing on immune reactions in leprosy, as they are likely important in understanding its complexities and could be useful in its early diagnosis.

Prognostic significance of real-world (RW) recurrence patterns after resection or ablation of early-stage hepatocellular carcinoma (HCC): Insights from the US Medicare population.

e16241 Background: The prognosis after curative-intent resection or ablation of early-stage HCC remains poor, largely due to high rates of recurrence. We aimed to characterize real-world recurrence patterns and determine whether the timing of recurrence was associated with overall survival (OS). Methods: Patients (pts) with early-stage HCC who underwent resection and/or ablation were identified from the SEER-Medicare database (2010-2019). Pts who received liver transplant were excluded. A proxy for recurrence was defined as the receipt of new HCC treatments (surgery, locoregional therapy, systemic therapy) or a secondary malignant neoplasm claim (excluding liver). Pseudo-recurrence dates were assigned to pts without recurrence to match the distribution of time between initial resection/ablation and recurrence in the recurrence cohort, to avoid immortal time bias. Early vs late recurrence was defined as occurring within 1 year vs after 1 year of initial resection/ablation. Primary outcome was OS as measured both from the time of recurrence/pseudo-recurrence and initial resection/ablation. Results: 1,146 eligible pts with early-stage HCC were identified. 63% were male, mean age was 74 yrs, and initial therapy was resection (39%), ablation (50%), or both (11%). 736 (64%) experienced recurrence. Among them, 53% received ablation, 37% surgery, and 11% received both. Median OS from recurrence or pseudo-recurrence was 22 months (mo) vs 67 mo (p < 0.001) for pts with vs without recurrence, respectively. When measured from resection/ablation date, median OS was 39 mo vs 83 mo (p < 0.001). After adjusting for relevant demographic and clinico-pathologic factors, including type of index therapy, in a multivariable Cox regression model, recurrence remained significantly associated with an increased risk of death (hazard ratio [HR]: 2.24; 95% CI: 1.85-2.71; p < 0.001). Among pts who recurred, 380 (52%) had early recurrence and 356 (48%) had late recurrence. Median OS from recurrence was 17 mo vs 30 mo (p < 0.001) for early vs late recurrence, respectively, and 23 mo vs 63 mo when measured from resection/ablation The adjusted HR for the risk of death associated with early recurrence was 1.39 (95% CI: 1.14-1.68; p < 0.001) compared to late recurrence. Other significant prognostic factors associated with reduced OS included larger tumor size ( > = 5cm), greater extent of disease, and poor differentiation (grade III and above). Conclusions: In this study among US Medicare pts, early recurrence within one year after curative-intent treatment of early-stage HCC was significantly associated with decreased OS compared to pts who recur later or without recurrence. This highlights the need for developing and utilizing effective adjuvant therapy regimens to delay or avoid recurrence.

Abstract PO1-02-09: Efficacy of breast conserving treatment of minimal residual tumors after neoadjuvant therapy for breast cancer

Abstract Background. Determining the most effective drug therapy regimens is one of the top priorities in the individualization of the treatment of patients with breast cancer (BC). Achievement of pathological complete response (pCR) is important prognostic factor, and used as the surrogate primary end point in many clinical trials. According to the literature, the achievement of pCR after neoadjuvant systemic treatment (NST) in breast cancer varies from 30 to 70%. Patients who do not achieve pCR require post-neoadjuvant treatment, even when reaching minimal size of residual tumors. Initially, primary minimal tumors are characterized by high survival rates, which are proved by international and domestic studies. It is required to clarify the survival rates in the presence of a minimal residual tumor (ypT < 10mm) after neoadjuvant systemic therapy and to compare with primary minimal forms of breast cancer (pT1a-b N0M0), characterized by the most favorable prognosis. Objective. Improvement of the effectiveness of treatment of residual minimal forms (ypT1a-b) of BC after NST. Determination of the correlation between the schemes of NST and the rates of tumor response based on the results of postoperative pathological reports including RCB scale. Methods. The study included 602 patients aged 18–65 years with early and locally advanced I–IIIC stage T1-3N1-3M0 breast cancer,who underwent complex or combined treatment. This study included patients treated at the N.N. Petrov National Medical Research Center of Oncology from 2015 to 2021 Conclusion. After reaching a complete pathomorphological response of the tumor to NST (RCB 0), the 5-year disease-free (DFS) and overall (OS) survival rates (DFS – 78.5%; OS 90.4%) were inferior to the survival rates of patients with primary minimal breast cancer (pT1ab N0M0) [DFS – 86.4%; OS – 98.6%]. Neoadjuvant chemotherapy regimens that allow achieving a pathological complete response in triple-negative and HER2- positive breast cancer have been defined. An assessment of adverse factors that affect the effectiveness of breast conserving treatment and correlate with a deterioration in overall survival was performed. Results. Our data analysis revealed that the survival rates (DFS and OS) of patients with minimal residual tumor after neojuvant systemic therapy were not comparable with those in the group of patients with primary minimal breast cancer. Data analysis revealed the most effective combinations of drugs expressed in the rates of pathomorphological response according to the RCB scale. An assessment of adverse factors that affect the effectiveness of organ-preserving treatment and correlate with a deterioration in overall survival was performed. Citation Format: Roman Pesotsky, Vladimir Semiglazov, Petr Krivorotko, Tengiz Tabagua, Konstantin Zernov, Alexander Emelyanov, Viktoria Mortada, Nikolay Amirov, Daria Ulrikh, Valerii Levchenko, Yana Bondarchuk, Diana Enaldieva, Nestan Bekkeldieva, Konsantin Zirov, Sergey Yerechshenko, Vladislav Evseev, Kirill Rychagov, Sergey Novikov, Maria Kazantseva, Larisa Gigolaeva, Elena Zhiltsova, Denis Nesterov, Olga Ivanova, Tatiana Semiglazova. Efficacy of breast conserving treatment of minimal residual tumors after neoadjuvant therapy for breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-02-09.

Abstract 1810: Development of new phthalic hydrazide scaffold for potent TNKS inhibitors

Abstract Tankyrase 1 and 2 (TNKS1/2) catalyze post-translational modifications of target proteins through poly-ADP-ribosylation. Inhibition of TNKS stabilizes AXIN and induces β-catenin degradation in adenomatous polyposis coli (APC)-mutated colorectal cancer (CRC) cells. Therefore, TNKS emerges as a therapeutic target for APC mutant CRC, and there is a critical need for drug development against it. Tankyrase 1 and 2 (TNKS1/2) catalyze the post-translational modification of target proteins through poly-ADP-ribosylation. Their inhibition stabilizes AXIN and induces β-catenin degradation. Therefore, TNKS is a therapeutic target for APC mutant colorectal cancer (CRC), and there is a need for drug development against it. However, reported TNKS inhibitors have serious limitations in that they cause intestinal toxicity. To address these issues and enhance efficacy, we synthesized 60 compounds based on the tetrahydrophthalazine scaffold using protein structure modeling-Al technology. Using an in vitro TNKS1 and TNKS2 enzyme assay and derivatizing Hit compounds, we confirmed that TI-61987 significantly inhibits TNKS enzyme activity at low nanomolar levels. TI-61987 stabilized AXIN2, reduced active β-catenin, and downregulated β-catenin target genes in COLO320DM, APC-mutated CRC cells. Additionally, TI-61987 exhibited excellent anticancer effects not only in COLO320DM cells but also in in vivo xenograft mouse models. Our findings demonstrate that TI-61987 is a therapeutic candidate targeting TNKS for the treatment of APC-mutated CRCs, and this anticancer drug may represent an effective therapy regimen for APC-mutated CRCs. Citation Format: Hwani Ryu, Hye-Ran Seo, Ju Han Lee, Kyu Myung Lee, Jiyeon Ahn. Development of new phthalic hydrazide scaffold for potent TNKS inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1810.

Sex differences in the effectiveness and tolerability of dolutegravir plus rilpivirine as a switch strategy in people living with HIV.

Dolutegravir + rilpivirine (DTG + RPV) is an effective antiretroviral therapy regimen approved in clinical guidelines as a switch therapy for virologically suppressed people with HIV. Our study aimed to compare the effectiveness and tolerability of DTG + RPV in women and men in real-world clinical practice. This was a retrospective analysis of treatment-experienced people with HIV from a large HIV unit who switched to DTG + RPV. We analysed treatment effectiveness, rates of adverse events and discontinuation, and metabolic changes after 48 weeks of treatment. HIV-RNA levels <50 copies/mL were analysed at 48 weeks using both intention-to treat analysis (where missing data were interpreted as failures) and per-protocol analysis (excluding those with missing data or changes due to reasons other than virological failure). Outcomes were compared between women and men based on sex at birth. A total of 307 patients were selected (71 women and 236 men). No transgender people were included. At baseline, women had lived with HIV infection and received antiretroviral therapy for longer than men (23.2 vs 17.4 years and 18.9 vs 14.2 years, respectively). In the intention-to-treat analysis, 74.6% (95% confidence interval [CI] 63.4-83.3%) of women and 83.5% (95% CI 78.2-87.7) of men had HIV-RNA <50 copies/mL. In the per-protocol analysis, 96.4% (95% CI 87.7-99) of women and 99% (95% CI 98.9-99.7) of men had HIV-RNA levels <50 copies/mL. Two women and two men had HIV-RNA >50 copies/mL at 48 weeks. Discontinuation due to adverse events was more frequent in women than in men: 12.7% vs 7.2% (p < 0.02). Neuropsychiatric and gastrointestinal events were the most frequently reported. A median (interquartile range) weight gain of 1.9 kg (0-4.2) in women and 1.2 kg (-1-3.1) in men was reported (median of differences between baseline visit and week 48); the remaining changes in metabolic parameters were neutral. DTG + RPV exhibited good and similar virological effectiveness in women and men in real-world settings. However, poorer tolerability and more treatment interruptions were observed in women.

Chemotherapy-induced cognitive impairment in breast cancer survivors: A systematic review of studies from 2000 to 2021.

Studies have indicated that apart from enhancing patient survival, chemotherapy has adverse side effects on the psychological, social, and cognitive functions of breast cancer survivors. This study was conducted to understand chemotherapy's impact on breast cancer survivors' cognitive functions. Our study is a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We searched English databases, including PubMed/MEDLINE, PsycINFO, and Web of Science, and Persian databases, such as Irandoc and Elmnet, using Persian keywords of cancer, breast cancer, chemotherapy, cognitive functions, executive functions, and neuropsychological functions. Two reviewers independently evaluated the full text of the articles according to predefined criteria. Among the 937 available studies, 26 were selected based on the inclusion and exclusion criteria, of which 17 (65%) were longitudinal and 9 (35%) were cross-sectional. The findings indicated a significant relationship between the use of chemotherapy and cognitive impairments, most notably attention, working and short-term memory, and executive functions. However, the studies differed in their findings regarding the long-term persistence of cancer-related cognitive impairment (CRCI), which could be due to the wide range of tools used, different methods to measure cognitive functions, and the difference in the sample size of the studies. Chemotherapy, affecting cortical and subcortical brain structures, causes a set of cognitive impairments that can lead to impairments in social responsibility acceptance, daily functioning, and quality of life of women. Therefore, rigorous and extensive research design is required to understand the causes and consequences of CRCI using standardized and sensitive measures of cognitive functions. Specifically, studies comparing the effects of different chemotherapy regimens on cognition and potential mechanisms and/or moderators of CRCI would be instrumental in designing more effective therapy regimens and evaluating the efficacy and cost-effectiveness of cognitive rehabilitation and supportive care programs.

Present Strategy and Tactics of Antibacterial Therapy for Hospital Infections: Lessons Learned from the COVID-19 Pandemic

A significant increase in sales of antibacterial drugs in pharmacies and their purchases by medical institutions of the Russian Healthcare System was observed against the background of the past pandemic of a novel coronavirus infection in Russia. Microbiological monitoring that was carried out at City Clinical Hospital No. 67 named after. L. A. Vorokhobov (Moscow) in 2020–2021, revealed a pressing problem — primarily gram-negative bacteria, with a predominance of multidrug-resistant (MDR) strains, were isolated from patients with healthcare-associated infections (HAIs). As shown by pharmacoeconomic studies conducted by the authors, the cost of one course of targeted antibacterial therapy for HAI in this case could increase by 6–12 times compared to a similar course of therapy in the absence of both MDR strains and XDR strains of hospital pathogens. In order to achieve a reduction in the cost of antibacterial therapy developed and used by the authors, in addition to the development of effective antibacterial therapy regimens for HAIs caused by MDR/XDR pathogens, another study was carried out as a continuation of the work on creating and improving biotherapy regimens for HAIs, namely the development of personalized phage therapy regimens for patients with hospital-acquired pneumonia caused by MDR bacterial strains. Based on the data obtained, the concept of a personalized approach to phage therapy of various nosological forms of HAIs caused by hospital-acquired MDR pathogens in patients of a multidisciplinary hospital was proposed and tested. As a result of this approach, the effectiveness of phage therapy for various nosological forms of HAIs caused by MDR and XDR strains of hospital pathogens in City Clinical Hospital No. 67 named after. L. A. Vorokhobov increased by 30%, and the effectiveness of the initial antibiotic regimen was 70%. The economic effect of the combination of antibiotic therapy and phage therapy («booster therapy») amounted to 3,000,000 rubles, compared with the use of antibiotics alone in the treatment of patients with HAIs caused by MDR/XDR strains of hospital pathogens.

Impact of radiological and pathological splenic vein involvement in patients with resectable pancreatic body or tail cancer.

Several studies have reported a negative impact on survival associated with splenic vessel involvement, especially splenic artery (SpA) involvement, in patients diagnosed with pancreatic body or tail cancer. However, there is limited research on splenic vein (SpV) involvement. Therefore, we aimed to elucidate the significance of splenic vessel involvement, especially SpV involvement, in patients with resectable pancreatic body or tail cancer. Between January 2007 and December 2021, 116 consecutive patients underwent distal pancreatectomies for pancreatic body or tail cancer. Among them, this study specifically examined 88 patients with resectable pancreatic body or tail cancer to elucidate prognostic factors using a multivariable Cox proportional analysis. The Kaplan-Meier method evaluated the impact of SpV involvement in terms of both radiological and pathological aspects and the efficacy of neoadjuvant therapy. Higher pre-operative carcinoembryonic antigen levels, larger tumour size, pathological SpV invasion, and non-completion of adjuvant therapy were identified as independent poor prognostic factors for overall survival (OS) and recurrence-free survival (RFS). Additionally, patients with radiological SpV encasement had significantly worse prognoses in terms of OS (p = 0.039) and RFS (p < 0.001). The sensitivity and specificity of multidetector-row computed tomography for detecting pathological SpV invasion were 81.0% and 61.2%, respectively. However, the prognostic impact of neoadjuvant therapy could not be determined, regardless of radiological SpV involvement. Radiological and pathological SpV involvement is a poor prognostic factor for patients with resectable pancreatic body or tail cancer. New innovative treatments and effective neoadjuvant therapy regimens are required for patients with SpV involvement.

Effectiveness and Tolerability of Dual Therapy with Dolutegravir Plus Darunavir/cobicistat in Treatment-Experienced Patients with HIV: A 144-Week Follow-Up.

A dual regimen with dolutegravir plus cobicistat-boosted darunavir (DTG+DRV/c) is a promising alternative for patients with human immunodeficiency virus (HIV) with resistance or intolerance to nucleoside reverse transcriptase inhibitors, especially those with a history of treatment failure. We included all treatment-experienced patients with HIV who switched to the DTG+DRV/c regimen at a tertiary university hospital. We assessed the regimen's effectiveness, safety, and tolerability through serial laboratory data and clinical findings. The primary endpoint was the proportion of patients with plasma HIV-RNA levels <50 copies/mL at week 144 post-switch. The secondary endpoints were safety and tolerability assessments. Our retrospective analysis involved 40 patients. The leading reasons for switching to DTG+DRV/c were treatment failure in 17 patients (42.5%), simplification after multiple previous regimens in 15 (37.5%), and adverse drug reactions in 8 (20.0%). Among the 17 patients in the treatment failure group, we observed enhanced viral suppression and improved CD4+ T-cell counts after initiating the dual regimen. In the non-treatment failure group (23 patients), viral suppression and CD4+ T-cell levels were consistently maintained. No significant alterations in renal function, liver function, glucose levels, or lipid profiles were observed post-switch. High tolerability was observed, with 34/40 patients (85.0%) responding well to the regimen. However, six patients discontinued treatment before reaching the 144-week mark. Our findings confirm that DTG+DRV/c is an effective and well-tolerated switch therapy regimen for treatment-experienced patients with HIV, with sustained benefits observed for up to 144 weeks of follow-up. This regimen showed adaptability across different patient groups and demonstrated virological and immunological improvements, particularly in patients with a history of treatment failure.

Array-based specific classification of bacterial species via hydrophilic/hydrophobic biosensors

The early detection of bacterial species plays a crucial role in patient prognosis and the development of effective therapy regimens. This study introduces an accessible and promising fluorescent sensor array...

Outcome and treatment-related adverse events of combined immune checkpoint inhibition with flipped dosing in a real-world cohort of 79 patients with metastasized melanoma

IntroductionCombined immune checkpoint inhibition (ICI) with ipilimumab and nivolumab is a widely used treatment regimen for metastatic melanoma with non-resectable metastases. Nevertheless, the standard dose of ipilimumab 3 mg/kg bw and nivolumab 1 mg/kg bw is associated with a high rate of treatment-related adverse events (trAEs) (59% grade 3–4). In the CheckMate 511 study, it could be shown that flipped dosing with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw resulted in a significant reduction of trAE.MethodsWe have also used this regimen in the clinical setting and report the trAE, progression-free survival, and overall survival for 79 patients with metastatic melanoma who started combined ICI in the flipped dosing between March 2019 and April 2020.Resultsin total, 40 patients started first-line, 50% of whom had an elevated lactate dehydrogenase level at baseline. The disease control rate of these patients was 50%. The 2-year overall survival rate 67%. Moreover, 33% of the patients suffered grade 3 or 4 treatment related adverse events. DiscussionThe results of our study correspond very well to the results of the CheckMate 511 study (2-year OS: 65%, grade 3-4 immune-related side effects: 35%). Combined ICI with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw seems to be an equally effective but better-tolerated therapy regimen for metastasized melanoma patients, also in a real-world cohort.

Prospective Efficacy of Two Cycles Toripalimab Plus Induction Chemotherapy in T4 or N3 Locoregionally Advanced Nasopharyngeal Carcinoma: A Retrospective and Mechanistic Study

Gemcitabine-cisplatin (GP) as the most commonly used induction chemotherapy is the standard first-line systemic treatment for advanced nasopharyngeal carcinoma. However, the toxicity of three cycles induction chemotherapy following on chemoradiotherapy remains a pertinent issue. Additional monoclonal antibody against human programmed death-1 (PD-1) has shown promising efficacy in recurrent or metastatic nasopharyngeal carcinoma. In this study, we compared three cycles of gemcitabine and cisplatin as classical induction chemotherapy with two cycles of induction chemotherapy plus toripalimab, and then both groups treated with the similar concurrent chemoradiotherapy. Patients with locoregionally advanced nasopharyngeal carcinoma staging T4 or N3 were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1-3), administered every 3 weeks for three cycles, or GP combined with toripalimab (at a dose of 240mg) for two cycles. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety. A total of 60 patients were included in the trial (30 patients in the toripalimab combined induction chemotherapy group and another 30 in the standard-therapy group). Among 60 patients evaluable for response assessment after induction therapy, all patients had overall response in combined group, including 10 patients (30%) with complete response (CR) in the primary tumor site. 21 patients (70%) were evaluated as partial response (PR) in the standard induction chemotherapy, and another 9 patients were assessed as SDa. At a median follow-up of 27.6 months, the 6-months, 1-, 2-year recurrence-free survival was 100% vs 86.7%, 100% vs 80%, 93% vs 70% in the toripalimab combined induction chemotherapy group and standard-therapy group (stratified hazard ratio for recurrence or death, 0.62; 95% confidence interval [CI], 0.38 to 0.87; P = 0.001). Overall survival at 2 years was 93.3% and 100%, respectively (stratified hazard ratio for death, 0.53; 95% CI, 0.29 to 0.79). The incidence of acute adverse events of grade 3 or 4 was 76.8% in the standard-induction chemotherapy group and 56% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 10.2% in the induction chemotherapy group and 10.4% in the combined-therapy group. Two cycles of toripalimab combined with induction chemotherapy of and CCRT shows excellent distant metastatic control with acceptable safety, which is a new promising and effective systemic therapy regimen for high-risk of metastatic NPC patients.

Weekly paclitaxel, carboplatin and cetuximab (PCC) combination followed by nivolumab in platinum-sensitive recurrent and /or metastatic squamous cell carcinoma of head and neck: a retrospective analysis from two institutions in India

Background: First line (1L) TP-Ex-like regimen followed by 2nd-line (2L) immunotherapy represents one of the standards of care in platinum-sensitive recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN). We report our experience from 2 tertiary care institutions of India. Methods: This is a retrospective analysis of consecutive patients of platinum-sensitive R/M SCCHN treated with 1L weekly paclitaxel, carboplatin, and cetuximab (PCC) regimen followed by cetuximab maintenance (if non-progressive) or 2L nivolumab or oral metronomic chemotherapy (OMCT) on progression. Overall response rates (ORR), progression-free survival after 1L and 2L (PFS-1 &amp; PFS-2), overall survival (OS), and safety were evaluated. Results: The study included 54 patients; median age 56.5 years; 89% men; 11% had cardiac dysfunction; 13% had renal dysfunction. After 1L PCC, ORR was 59.3%; median PFS-1 was 7.031 months; 61% had progression; 35% were treated with nivolumab and 18% with OMCT. The ORR was 26.3% (nivolumab) and 10% (OMCT). Median PFS-2 was 6.5 months (nivolumab) and 2 months (OMCT). The median OS was 15.01 months (entire cohort), 20.6 months (nivolumab), and 7 months (OMCT). Grade III/IV adverse events on PCC included neutropenia (31.4%), anaemia (35.1%), thrombocytopenia (7.4%), febrile neutropenia (11.1%), and skin reaction (16.6%); no Grade-III/IV treatment-related toxicities on 2L. Conclusions: 1L weekly PCC is an effective regimen for palliative therapy of platinum- sensitive R/MSCCHN with an acceptable toxicity profile. The addition of 2L nivolumab on progression further improves the outcomes.

Molecular tumor board and theranostics

Clinical oncology is currently undergoing a period of unprecedented change. Targeted therapy, and subsequently immunotherapy, has revolutionized the clinical course and outcome of many patients with solid cancer. Clinical oncology is inseparable from molecular oncology, the development of which is interconnected. Molecular tumor research proposes the most precise, effective and lesser toxic antitumor therapy regimen is an extremely urgent clinical task, especially in life-threatening and resistant to other types of treatment cases of cancer. Modern technologies of genomic and postgenomic studies, as well as molecular imaging methods (positron and single photon emission computed tomography, PET and SPECT, respectively) make it possible not only to assess the metabolic and receptor status of tumor foci, but also to select the optimal therapeutic tactics as a key to the lock. In the clinical practice of oncology, there is an increasing need for molecular tumor board (MTB). Published real clinical experience with MTB-recommended treatment regimens based on the molecular geno-transcriptomic profile of the tumor indicates better relapse-free and overall patient survival compared to treatment prescribed by a physician without taking into account the molecular profile of the tumor. More experience is needed and randomized controlled clinical trials are needed for more solid and evidence-based conclusions. However, there is no doubt that the MTB is a powerful tool for the development of precision personalized oncology.

Патогенетическая, симптоматическая и саногенетическая терапия острых респираторных инфекций

The Advisory Board dedicated the treatment of acute respiratory infections (ARI) was held in Moscow on June 17, 2023. In addition to pathogenetic and symptomatic approaches to the therapy of these diseases, the focus of experts' attention was on means and methods for the immune system effective functioning and sanogenesis – a complex of protective and adaptive processes aimed at restoring of the body self-regulation. During the discussion of modern approaches to the ARI treatment and the prevention of their complications in children, the importance of choice of effective and safe therapy regimens with implementation of multi-component medicines with a low content of active substances having an evidence base, including RCTs, and successful long-term experience in the world was emphasized. The consolidated opinion of experts about possible ARI treatment algorithms in children is formulated. Key words: children, acute respiratory infection (ARI), sanogenesis, immune response, inflammation, rhinitis, Engistol, Viburcol, Euphorbium compositum, Nasentropfen C

Stenotrophomonas maltophilia Bacteremia: From Diagnosis to Treatment.

There are many difficulties in diagnosing and treating Stenotrophomonas maltophilia bacteremia. In this study, we aimed to evaluate "true" and "false-positive bacteremia" and assess mortality risk factors and the impact of different treatment regimens. Hospitalized adult patients with S. maltophilia-positive blood cultures were assessed by a two-stage analysis. First, the clinical significance of blood cultures was assessed, and patients were divided into "true" and "false-positive bacteremia" groups. Then, excluding false positives, we analyzed the antimicrobial regimens and the factors associated with 28-day mortality in true bacteremia cases performing univariate and multivariate analyses. The study included 127 out of 138 patients with S. maltophilia bacteremia. True bacteremia was identified in 51.2% and false-positive bacteremia in 48.8% of patients. In the true bacteremia group, hypotension, nosocomial bacteremia, concomitant infections, a source of bacteremia, two positive blood culture sets, and 28-day mortality were more common. The 28-day mortality was 50.7% among true bacteremia cases. In multivariate analysis, age and solid tumor were the independent predictors of 28-day mortality. Early effective antimicrobial therapy and different antimicrobial regimens, including trimethoprim-sulfamethoxazole (SXT), fluoroquinolones (FQs), and tigecycline (TGC), did not have any significant impact on survival. Patients with S. maltophilia bacteremia should first be assessed regarding clinical significance. Clinical findings, the presence of multiple positive blood culture sets and the primary sources of bacteremia are useful parameters while discriminating true from false-positive bacteremia. Patients with advanced age and solid tumors should be followed carefully in terms of mortality. Antimicrobial regimens, including SXT, FQs, or TGC, can be preferred in patients with S. maltophilia bacteremia considering antimicrobial resistance and adverse effects or toxicity.