Second-line Regimens Research Articles

Current trends in <i>Helicobacter pylori</i> eradication therapy

According to the Maastricht VI consensus, the triple therapy (PPI + clarithromycin + amoxicillin) and bismuth-based quadruple therapy (PPI + bismuth + tetracycline + metronidazole) are considered and may be proscribed empirically as first-line regimens in the regions with low clarithromycin resistance rates (<15%). In the regions with high clarithromycin resistance rates (> 15%), as well as in the regions with unknown resistance to this antibacterial agent, it is recommended to use classical quadruple therapy with bismuth drugs as the main choice and quadruple therapy without bismuth drugs (“simultaneous” or “concomitant”) as an alternative. The second-line regimens of empiric choice (when antimicrobial susceptibility testing is not available) include fluoroquinolone-based quadruple therapy (PPI + levofloxacin + amoxicillin + bismuth) or fluoroquinolone-based triple therapy (PPI + levofloxacin + amoxicillin) and bismuth-based quadruple therapy. The Maastricht VI consensus regulates the use of rifabutin-based triple therapy (PPI + amoxicillin + rifabutin) as a “rescue” therapy, if the above ET schemes are ineffective and there is no possibility to conduct an antimicrobial susceptibility test. In its latest clinical guidelines, the Russian Gastroenterological Association (RGA) recommends with a view to achieving maximum treatment efficiency during classic triple ET and levelling the risk of further progression of clarithromycin resistance in Russia to take additional measures to increase its effectiveness (detailed instruction of a patient and control over strict adherence to the prescribed regimen, prolonging the course up to 14 days; prescribing PPI at increased dose twice a day; the latest generation PPIs (rabeprazole and esomeprazole); adding bismuth tripotassium dicitrate (240 mg 2 times a day) to the standard triple therapy; adding cytoprotector rebamipide (100 mg 3 times a day) to the standard triple therapy; adding a probiotic with proven efficacy to the standard triple therapy within controlled studies).

Risk assessment of first-line treatment failure in untreated HIV patients in Northwestern Federal District of the Russian Federation

The HIV infection epidemic in Russia continues to evolve, and HIV infection cases have been registered in all territorial entities of the Russian Federation. 2021 Treatment coverage was 82.2% and 56.4% individuals under dispensary observation and living with diagnosed HIV infection. 79.9% receiving ART subjects were shown to achieve undetectable viral load. Highly active antiretroviral therapy (HAART) currently represents a combination of three (less frequently four) antiretroviral drugs targeting pathways involved in various stages of HIV replication in vivo. Treatment failure is a problem facing doctors and patients using HAART. The most common cause of therapeutic failure is the development of HIV drug resistance. The emergence of resistance is associated with processes involving mutation occurring in the viral genome influenced by evolutionary factors. Therefore, it is important clinically and programmatically to learn more about the rate of first-line treatment failure, the rate of switching to a second-line ART regimen, and to identify patients at risk to develop strategies for preventing development of further failure cases. The study was aimed at analyzing ineffectiveness of first-line ART therapy in patients in Northwestern Federal District of the Russian Federation. Materials and methods. Sequencing reactions were performed using the AmpliSens HIV Resist-Seq. Assembly of consensus sequences from fragments obtained during sequencing was carried out using Unipro UGENE software. Isolate genotyping was performed using the MEGA-X software with the Neighbor-joining algorithm. Results. The HIV pol genes in 239 patients with first-line ART failure and 100 nave patients were sequenced; all sequences genotyped as HIV-1 subsubtype A6. According to analysis, 82% of patients had at least one significant mutation associated with drug resistance for the corresponding viral subtype. In total, we encountered 87 different drug resistance mutations. Conclusion. We have shown increased proportion of patients with first-line ART failure among all patients with treatment failure. The main cause for such changes is probably related to the prevalence of primary drug resistance, estimated here at 8%. Specific differences were found between drug resistance mutation profiles in patients without suppressed viral load and patients with virological breakthrough. The overall results of the study indicate a need to diagnose and characterize HIV drug resistance prior to initiation of therapy in order to avoid ineffective first-line antiretroviral treatment.

Acute inflammatory reaction during anti-angiogenesis therapy combined with immunotherapy as a possible indicator of the therapeutic effect: Three case reports and literature review.

The posterior line treatment of unresectable advanced or metastatic gastrointestinal (GI) tumors has always been a challenging point. In particular, for patients with microsatellite stable (MSS)/mismatch repair proficient (pMMR) 0GI tumors, the difficulty of treatment is exacerbated due to their insensitivity to immune drugs. Accordingly, finding a new comprehensive therapy to improve the treatment effect is urgent. In this study, we report the treatment histories of three patients with MSS/pMMR GI tumors who achieved satisfactory effects by using a comprehensive treatment regimen of apatinib combined with camrelizumab and TAS-102 after the failure of first- or second-line regimens. The specific contents of the treatment plan were as follows: apatinib (500 mg/d) was administered orally for 10 days, followed by camrelizumab (200 mg, ivgtt, day 1, 14 days/cycle) and TAS-102 (20 mg, oral, days 1-21, 28 days/cycle). Apatinib (500 mg/d) was maintained during treatment. Subsequently, we discuss the possible mechanism of this combination and review the relevant literature, and introduce clinical trials on anti-angiogenesis therapy combined with immunotherapy.

Abstract 2685: Synergistic antitumor effect of oncolytic virus and cytotoxic chemotherapy in gastric cancer

Abstract Introduction: The prognosis of advanced gastric cancer is extremely poor, and the development of novel effective treatment is necessary. Currently, platinum-based, fluoropyrimidine-based, and paclitaxel-based combinations are accepted worldwide as established first-line and second-line drug regimens. Pexa-Vec (pexastimogene devacirpvec; JX-594) engineered from the Wyeth vaccine strain has emerged as attractive oncolytic virotherapy in cancer treatment. Pexa-Vec demonstrated oncolytic, immunotherapeutic, and tumor vascular disrupting mechanisms of action. The aim of this study is to investigate the combination efficacy of JX-594 with paclitaxel in human gastric cancer cell lines and to identify potential biomarkers of oncolytic virotherapy. Method: The anti-proliferative activities of paclitaxel and JX-594 were performed using 49 human gastric cancer cell lines, and YCC-32 was selected for sensitive to JX-594 and resistance to paclitaxel. YCC-32 was treated with JX-594 and paclitaxel, alone and in combination. Cytotoxicity was evaluated by MTT assay. Compusyn and Combenefit software was used to evaluate synergistic efficacy. In addition, the synergism effect was evaluated in the xenograft mouse model in vivo. Tumors were implanted by subcutaneous injection of 5 x 106 YCC-32 cells into the right flank of nude mice. When tumors reached >100mm3, mice were treated with either PBS, 1 x 107 plaque-forming units (pfu) of JX-594 by intratumoral (IT), 5mg/kg paclitaxel by intraperitoneal (IP) injection, or combination every 7 days. Result: Cytopathic effect of Pexa-Vec and paclitaxel was observed in YCC-32 gastric cancer cell line. IC50 (half maximal inhibitory concentration) of JX-594 and paclitaxel were 0.0089 MOI and 7.021ng/ml in YCC-32 cell. JX-594 and paclitaxel in YCC-32 was used to assess the synergism of the two drugs in a dose-dependent manner. In YCC-32 cell line, in combination with JX-594 0.01 MOI and paclitaxel 7ng/ml had CI (combination index) value had 0.69, suggesting synergism. To assess the potential therapeutic benefit of combining JX-594 with paclitaxel in vivo, we employed YCC-32 xenograft models and observed the antitumor effects of JX-594, paclitaxel, and their combination. Paclitaxel, JX-594, and their combination reduced tumor growth compared to control at 64.1%, 59.2%, and 19.1% for YCC-32 xenografts. This result suggests that combined treatment with JX-594 and paclitaxel significantly enhanced tumor growth inhibition compared to monotherapy. Conclusion: Combination with JX-594 and paclitaxel showed enhanced antitumor effects in vitro and in vivo. This study shows combination synergism and provides a promising approach to combination therapy with an oncolytic virus on gastric cancer. For future research, additional studies on other gastric cancer cell lines and investigation of mechanisms are needed. Citation Format: Jee Hung Kim, YeLin Kim, Youkeun Shin, Dagyo Oh, Woo Sun Kwon, Tae Soo Kim, Namhee Lee, Keunhee Oh, Hyun Cheol Chung, Hei-Cheul Jeung, Sun Young Rha. Synergistic antitumor effect of oncolytic virus and cytotoxic chemotherapy in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2685.

Immunotherapy in oncogynaecology

Immune checkpoint inhibitors have deeply changed treatment paradigm of many tumor types, notably by providing long-term remissions, even in the metastatic setting. These immunotherapies aim to restore T-cells activity against tumour cells, in particular via the inhibition of PD1/PD-L1 interaction. As for lung or renal carcinomas, and melanomas, the management of endometrial and uterine cervical cancers has been disrupted by PD1/PD-L1 inhibitors efficacy. In locally advanced or metastatic cervical carcinomas, the combination of platinum-based chemotherapy with pembrolizumab demonstrated improved overall and progression-free survival in all subgroups of patients, and became the new standard of care. Regarding endometrial cancers, while single-agent immunotherapies have shown very limited activity in an unselected population, dostarlimab and pembrolizumab have been associated with remarkable antitumor activity in case of microsatellite instability (dMMR/MSI), detected in around 30% of patients. Finally, in endometrial cancer that has progressed after first-line chemotherapy, the association of pembrolizumab with an oral antiangiogenic kinase inhibitor (lenvatinib) has demonstrated its superiority over second-line chemotherapy regimens, regardless molecular subgroups, and has become the new standard of care in this indication.

Clinical Efficacy and Safety of an Immune Checkpoint Inhibitor in Combination with Regorafenib Therapy as Second-Line Regimen for Patients with Unresectable Hepatocellular Carcinoma.

This study aimed to evaluate the safety and efficacy of a combination of programmed death-1 (PD-1) inhibitor and regorafenib as second-line treatment for advanced hepatocellular carcinoma (HCC). We retrospectively analyzed the data of 38 patients with unresectable HCC who were treated with PD-1 inhibitor in combination with regorafenib as a second⁃line therapy as well as the data of 32 patients treated with regorafenib only therapy as a control. The clinical data, previous treatment strategies, follow-up imaging results, and adverse events during follow-ups were recorded. The mRECIST Criteria were used to evaluate the treatment outcome of intrahepatic lesions, and the Kaplan-Meier method was used to evaluate survival time. Up to the last follow-up, the rego-PD-1 group had higher objective response rate (39.5% vs 15.6%, P = 0.028), longer progression-free survival (median 5.9 vs 4.6 months; P = 0.044), and better overall survival (OS) (median 14.5 vs 9.5 months; P = 0.041) than the regorafenib only group. Among the 38 patients in rego-PD-1 group, 1 patient (2.7%) achieved complete response, 14 patients (36.8%) achieved partial response, 14 patients (36.8%) achieved stable disease, and 9 patients (23.7%) achieved progressive disease. Among the 32 patients in regorafenib alone, 5 (15.6%) achieved partial response, 12 (37.5%) achieved stable disease, and 15 (46.9%) achieved progressive disease. Regorafenib alone, Child-Pugh B, and tumors >3 were independent prognostic factors for poor OS. The difference in the incidence of grade 3/4 adverse events between the two groups was not statistically significant (36.8% vs 28.1%; P = 0.439). Grade ≥3 treatment-related adverse events included hypertension and diarrhea. PD-1 inhibitor combined with regorafenib is a promising regimen in treating patients with unresectable HCC owing to its safety and effectiveness as well as low incidence of serious adverse events with its use.

Early warning indicators of HIV drug resistance in the southern highlands region of Tanzania: Lessons from a cross-sectional surveillance study.

The World Health Organization early warning indicators (EWIs) permit surveillance of factors associated with the emergence of HIV drug resistance (HIVDR). We examined cross- and within-region performance on HIVDR EWIs for selected HIV care and treatment clinics (CTCs) in five regions of southern Tanzania. We retrospectively abstracted EWI data from 50 CTCs for the January to December 2013 period. EWIs included the following: on time ART pick-up, retention on ART, ARV stockouts, and pharmacy prescribing and dispensing practices. Data for pediatric and adult people living with HIV were abstracted from source files, and frequencies and proportions were calculated for each EWI overall, as well as stratified by region, facility, and age group. Across and within all regions, on average, on-time pick-up of pills (63.0%), retention on ART (76.0%), and pharmacy stockouts (69.0%) were consistently poor for the pediatric population. Similarly, on-time pill pick up (66.0%), retention on ART (72.0%) and pharmacy stockouts (53.0%) for adults were also poor. By contrast, performance on pharmacy prescribing and dispensing practices were as desired for both pediatric and adult populations with few facility-level exceptions. In this study, regions and facilities in the southern highlands of Tanzania reported widespread presence of HIVDR risk factors, including sub-optimal timeliness of pill pickup, retention on ART, and drug stockouts. There is an urgent need to implement the WHO EWIs monitoring to minimize the emergence of preventable HIV drug resistance and to maintain the effectiveness of first and second-line ART regimens. This is particularly critical in the context of new ART drug roll-out such as dolutegravir during the COVID-19 pandemic when resultant HIV service disruptions require careful monitoring, and for virologic suppression as countries move closer to epidemic control.

Precise prediction of the sensitivity of platinum chemotherapy in SCLC: Establishing and verifying the feasibility of a CT-based radiomics nomogram.

To develop and validate a CT-based radiomics nomogram that can provide individualized pretreatment prediction of the response to platinum treatment in small cell lung cancer (SCLC). A total of 134 SCLC patients who were treated with platinum as a first-line therapy were eligible for this study, including 51 patients with platinum resistance (PR) and 83 patients with platinum sensitivity (PS). The variance threshold, SelectKBest, and least absolute shrinkage and selection operator (LASSO) were applied for feature selection and model construction. The selected texture features were calculated to obtain the radiomics score (Rad-score), and the predictive nomogram model was composed of the Rad-score and the clinical features selected by multivariate analysis. Receiver operating characteristic (ROC) curves, calibration curves, and decision curves were used to assess the performance of the nomogram. The Rad-score was calculated using 10 radiomic features, and the resulting radiomics signature demonstrated good discrimination in both the training set (area under the curve [AUC], 0.727; 95% confidence interval [CI], 0.627-0.809) and the validation set (AUC, 0.723; 95% CI, 0.562-0.799). To improve diagnostic effectiveness, the Rad-score created a novel prediction nomogram by combining CA125 and CA72-4. The radiomics nomogram showed good calibration and discrimination in the training set (AUC, 0.900; 95% CI, 0.844-0.947) and the validation set (AUC, 0.838; 95% CI, 0.534-0.735). The radiomics nomogram proved to be clinically beneficial based on decision curve analysis. We developed and validated a radiomicsnomogram model for predicting the response to platinum in SCLC patients. The outcomes of this model can provide useful suggestions for the development of tailored and customized second-line chemotherapy regimens.

Optimal treatment strategy after first-line induction therapy in advanced HER2-positive oeso-gastric adenocarcinoma-a retrospective, international, multicentric AGEO study.

The optimal treatment strategy after first-line induction therapy in advanced HER2-positive oeso-gastric adenocarcinoma (OGA) remains challenging. Patients treated with trastuzumab (T) plus platinum salts and fluoropyrimidine (F) as first-line chemotherapy between 2010 and 2020 for HER2-positive advanced OGA at 17 academic care centers in France, Italy, and Austria were included. The primary objective was the comparison of F + T vs T alone as maintenance regimen in terms of progression-free survival (PFS) and overall survival (OS) after a platinum-based chemotherapy induction + T. As secondary objective, PFS and OS between patients treated with reintroduction of initial chemotherapy or standard second-line chemotherapy at progression were assessed. Among the 157 patients included, 86 (55%) received F + T and 71 (45%) T alone as a maintenance regimen after a median of 4months of induction chemotherapy. Median PFS from start of maintenance therapy was 5.1months in both groups (95% CI 4.2-7.7 for F + T and 95% CI 3.7-7.5 for T alone; p = 0.60) and median OS was 15.2 (95% CI 10.9-19.1) and 17.0months (95% CI 15.5-21.6) for F + T and T alone, respectively (p = 0.40). Of 112/157 patients (71%) receiving systemic therapy after progression under maintenance, 26/112 (23%) were treated with a reintroduction of initial chemotherapy + T and 86/112 (77%) with a standard second-line regimen. Here, median OS was significantly longer with the reintroduction (13.8 (95% CI 12.1-19.9) vs 9.0months (95% CI 7.1-11.9); p = 0.007) as confirmed by multivariate analysis (HR 0.49; 95% CI 0.28-0.85; p = 0.01). No additional benefit of adding F to T monotherapy as a maintenance treatment could be observed. Reintroduction of initial therapy at first progression may be a feasible approach to preserve later treatment lines.

32P Clinical efficacy and safety of an immune checkpoint inhibitor in combination with regorafenib therapy as second-line regimen for patients with unresectable hepatocellular carcinoma

32P Clinical efficacy and safety of an immune checkpoint inhibitor in combination with regorafenib therapy as second-line regimen for patients with unresectable hepatocellular carcinoma

A Multicenter Retrospective Chart Review of Clinical Outcomes Among Patients With KRAS G12C Mutant Non–Small Cell Lung Cancer

BackgroundOn May 28, 2021, the United States Food and Drug Administration (FDA) granted accelerated approval to sotorasib for second-line or later treatment of patients with locally advanced or metastatic KRAS G12C mutant non–small cell lung cancer (NSCLC). This was the first FDA-approved targeted therapy for this patient population. Due to a paucity of real world data describing clinical outcomes in patients with locally advanced or metastatic KRAS G12C mutated NSCLC in the second-line or later, we sought to compile a large, academic medical center-based historical dataset to clarify clinical outcomes in this patient population. Materials and MethodsThe clinical outcomes of 396 patients with stage IV (n = 268, 68%) or recurrent, metastatic (n = 128, 32%) KRAS G12C mutant NSCLC were evaluated in this multicenter retrospective chart review conducted through the Academic Thoracic Oncology Medical Investigator's Consortium (ATOMIC). Patients treated at 13 sites in the United States and Canada and diagnosed between 2006 and 2020 (30% 2006-2015, 70% 2016-2020) were included. Primary outcomes included real-world PFS (rwPFS) and overall survival (OS) from time of stage IV or metastatic diagnosis, with particular interest in patients treated with second-line docetaxel-containing regimens, as well as clinical outcomes in the known presence or absence of STK11 or KEAP1 comutations. ResultsAmong all patients with stage IV or recurrent, metastatic KRAS G12C mutant NSCLC (n = 201 with KRAS G12C confirmed prior to first line systemic therapy), the median first-line rwPFS was 9.3 months (95% CI, 7.3-11.8 months) and median OS was 16.8 months (95% CI, 12.7-22.3 months). In this historical dataset, first line systemic therapy among these 201 patients included platinum doublet alone (44%), PD-(L)1 inhibitor monotherapy (30%), platinum doublet chemotherapy plus PD-(L)1 inhibitor (18%), and other regimens (8%). Among patients with documented second-line systemic therapy (n = 123), the second-line median rwPFS was 8.3 months (95% CI, 6.1-11.9 months), with median rwPFS 4.6 months (95% CI, 1.4-NA) among 10 docetaxel-treated patients (9 received docetaxel and 1 received docetaxel plus ramucirumab). Within the total study population, 49 patients (12%) had a co-occurring STK11 mutation and 3 (1%) had a co-occurring KEAP1 mutation. Among the 49 patients with a co-occurring KRAS G12C and STK11 mutation, median rwPFS on first-line systemic therapy (n = 23) was 6.0 months (95% CI, 4.7-NA), and median OS was 14.0 months (95% CI, 10.8-35.3 months). ConclusionIn this large, multicenter retrospective chart review of patients with KRAS G12C mutant NSCLC we observed a relatively short median rwPFS of 4.6 months among 10 patients with KRAS G12C mutant NSCLC treated with docetaxel with or without ramucirumab in the second-line setting, which aligns with the recently reported CodeBreak 200 dataset.

Dinutuximab beta combined with chemotherapy in patients with relapsed or refractory neuroblastoma.

Prognosis in children with refractory and relapsed high-risk neuroblastoma is poor. Only a minority of patients obtain remission when treated with second-line chemotherapy regimens. Chemotherapy combined with anti-GD2 antibodies has previously been shown to increase response and survival rates. We retrospectively analyzed a cohort of 25 patients with relapsed or refractory high-risk neuroblastoma who were treated with irinotecan/temozolomide chemotherapy in combination with the anti-GD2 antibody dinutuximab beta. The therapy resulted in an objective response rate of 64%, with 32% of patients achieving a complete response. Response to treatment was observed in patients with refractory disease (n=5) and those with first (n=12) or consecutive (n=8) relapses, including patients with progressing disease. In four patients, best response was achieved after more than 5 cycles, suggesting that some patients may benefit from prolonged chemotherapy and dinutuximab beta treatment. Fourteen of our 25 patients had previously received dinutuximab beta, four of whom achieved complete response and six partial response (objective response rate 71%). The therapy was well tolerated, even in heavily pre-treated patients and those who had previously received dinutuximab beta treatment. Toxicities were comparable to those previously reported for the individual therapies, and no discontinuations due to toxicities occurred. Combination of chemotherapy with dinutuximab beta is a promising treatment option for patients with relapsed or refractory high-risk neuroblastoma and should be further explored in clinical studies.

Efficacy of the third-line chemotherapy in patients with advanced pancreatic cancer.

711 Background: First-line FOLFIRINOX or gemcitabine plus nab-paclitaxel (GNP) have improved the survival outcomes of patients with advanced pancreatic cancer (APC) and nano-liposomal irinotecan (nal-IRI) plus 5-FU/leucovorin is proven as the second-line agents. The current study aims to assess the efficacy of the third-line palliative chemotherapy in APC. Methods: Medical records were retrospectively reviewed in a single tertiary hospital between 2012 and 2020. The enrolled patients have APC who received the first and second-line chemotherapy. To fine the efficacy of the third-line chemotherapy, Kaplan Meier curve with cox-regression analysis was performed. Results: Of total 1,152 patients with pancreatic cancer, 362 patients were enrolled. Of these, 125 received the third-line chemotherapy and 238 received only supportive care after progression of the second-line chemotherapy. Median age at diagnosis was 60.3 years (range 36.0 – 86.0) and males were 52.0%. The first-line chemotherapy regimen was FOLFIRINOX (85, 68.0%), GNP (33, 26.4%), and others (7, 5.6%). The second-line chemotherapy regimen was GNP (55, 44.0%), FOLFIRINOX (34, 27.2%). As the third-line regimen, TS-1 and nal-IRI plus 5-FU/leucovorin were 73 (58.4%) and 20 (16.0%). The median overall survival (OS) from diagnosis was 18.0 months in all patients (95% CI, 14.6 – 21.4). The median OS after progression of the second-line therapy were 15.1 (95% CI, 12.8 – 17.5) and 8.5 weeks (95% CI, 7.7 – 9.4, p=0.007) between the patients with the third-line chemotherapy and supportive care only. Of the patients with the third-line chemotherapy, female showed the significant longer OS than male (12.4 (95% CI 10.2-14.6) vs. 6.6 weeks (95% CI 13.4-19.7), p=0.042). Conclusions: The current study suggested that proceeding with the third-line chemotherapy could be recommended in some patients. Females showed significantly more benefit than males. Further research on the selection for patient who will get the benefit from the third-line therapy is necessary.

Clinical Outcome and Treatment Sequences of Patients with Advanced Pancreatic Cancer Treated with Contemporary Chemotherapy Protocols

Introduction: Systemic therapy is firmly established in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Clinical efficacy is still modest and options are limited. Combination therapy protocols such as FOLFIRINOX and gemcitabine/nab-paclitaxel (Gem/NP) define standard-of-care. Patients may receive a sequence of both regimens as first- and second-line palliative treatment. However, there is no guidance regarding a preferred order. Methods: This is a retrospective analysis of clinical characteristics, treatment trajectories, and outcomes of patients with advanced PDAC treated at the West German Cancer Center Essen from 2014 to 2020 to inform treatment decisions with respect to predictive factors, impact of chemotherapy regimen sequence, and maintenance treatment. Results: We identified 170 patients with available follow-up. Of those, 160 (94.1%) patients received palliative CTX for primary metastatic, locally advanced, or recurrent PDAC. Median progression-free survival (PFS) upon first palliative chemotherapy was 4.1 (3.1–5.9) months. First-line FOLFIRINOX was associated with superior PFS (median 6.3 months) and OS (9.7 months, HR 0.7, p = 0.03) as compared to Gem/NP or other regimens (PFS 3.0, OS 6.9 months). However, OS benefit of first-line FOLFIRINOX was lost in patients who received at least two treatment lines (median OS 12.1 vs. 13.1 months, p = 0.43). A landmark analysis of patients with clinical benefit (defined as CR/PR/SD for at least 20 weeks) upon first-line therapy revealed improved OS (HR 0.53, p = 0.02) for patients receiving continued deescalated maintenance therapy. Second-line regimens resulted in similar PFS (overall log-rank p = 0.92, median PFS upon second-line therapy 2.3 [1.8–2.9], per-regimen median between 1.8 and 3.9 months). A previously established systemic inflammation score proved to be strongly prognostic and allowed identification of a patient subgroup with dismal prognosis (OS 2.9 vs. 11.4 months, HR 5.23, p < 0.001), independent of other prognostic factors and with no relevant interaction with the choice of first-line regimen. Conclusion: In this real-world population of PDAC patients treated with contemporary combination chemotherapies, a positive impact of first-line FOLFIRINOX was only observed when no second or further line treatment was administered. Intensity-reduced maintenance therapy may lead to superior survival.

Treatment of Advanced Non-Small Cell Lung Cancer with RET Fusions: Reality and Hopes.

RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib have revolutionized the landscape of RET-positive (RET+) advanced non-small cell lung cancer (NSCLC) treatment, thanks to their efficacy and safety profiles. This class of medications currently represents the standard of care for both naïve and patients that have not received selective RET-TKIs in the first-line setting. However, we presently lack a satisfactory understanding of resistance mechanism developing after selective RET-TKIs usage, as well as a specific treatment for patients progressing on selpercatinib or pralsetinib. Chemotherapy ± immunotherapy is considered as a recommended subsequent second-line regimen in these patients. Therefore, it is of paramount importance to better define and understand the resistance mechanisms triggered by RET-TKIs. With this in mind, the present review article has been conceived to provide a comprehensive overview about RET+ advanced NSCLC, both from a therapeutic and molecular point of view. Besides comparing the clinical outcome achieved in RET+ advanced NSCLC patients after multikinase inhibitors (MKIs) and/or RET-selective TKIs' administration, we focused on the molecular mechanisms accountable for their long-term resistance. Finally, a critical perspective on many of today's most debated issues and concerns is provided, with the purpose of shaping the possible pharmacological approaches for tomorrow's therapies.

Impact of sub-optimal HIV viral control on activated T-cells: an earnest sub study.

HIV viral load (VL) monitoring is generally conducted 6-12 monthly in low- and middle-income countries, risking relatively prolonged periods of poor viral control. We explored the effects of different levels of loss of viral control on immune reconstitution and activation. : 208 participants starting Protease Inhibitor (PI)-based second-line therapy in the EARNEST trial (ISRCTN37737787) in Uganda and Zimbabwe were enrolled and CD38+/HLA-DR+ immunophenotyping performed (CD8-FITC/CD38-PE/CD3-PerCP/HLA-DR-APC; centrally gated) in real-time at 0, 12, 48, 96 and 144 weeks from randomisation. Viral Load (Viral load (VL) was assayed retrospectively on samples collected every 12-16 weeks and classified as (1) continuous suppression (<40 copies/ml throughout); (2) suppression with transient blips; (3) low-level rebound (two or more consecutive VL >40, <5000 copies/ml); (4) high-level rebound/non-response (two or more consecutive VL >5000 copies/ml). Immunophenotype reconstitution varied between that defined by numbers of cells and that defined by cell percentages. Furthermore, VL dynamics were associated with substantial differences in expression of CD4+ and CD8+ cell activation markers, with only individuals with high-level rebound/non-response (>5000 copies/ml) experiencing significantly greater activation and impaired reconstitution. There was little difference between participants who suppressed consistently and who exhibited transient blips or even low-level rebound by 144 weeks (p > 0.2 vs suppressed consistently). Detectable viral load below the threshold at which WHO guidelines recommend that treatment can be maintained without switching (1000 copies/ml) appear to have at most, small effects on reconstitution and activation, for patients taking a PI-based second-line regimen.

Second-Line Chemotherapy in Gastric Cancer: a Retrospective Study.

Second-line chemotherapy is recommended for patients who have disease progression after first-line chemotherapy and have a good performance status. The aim of our study is thus to determine which chemotherapy regimen is more appropriate for second-line gastric cancer treatment. Patients were included if they met the following inclusion criteria: metastatic gastric adenocarcinoma pathology; no previous treatment for local gastric cancer (surgery, chemotherapy, or radiotherapy); received first-line chemotherapy for metastatic gastric cancer and had the disease progress afterward; had adequate organ functions for second-line chemotherapy; had an Eastern Cooperative Oncology Group (ECOG) score 0-2; and were HER-2 negative. The patients were examined in three groups according to the second-line chemotherapy regimen they received. These three groups were compared in terms of overall and progression-free survival. The three groups were statistically similar in overall survival, which was the primary endpoint of the study; the median overall survival was 5months in the FOLFIRI group (n = 79), 6.5months in the platinum-based group (n = 55), and 5.6months in the taxane-based group (n = 40) (p = 0.554). There was no statistical difference between the groups' progression-free survival either; the median progression-free survival time was 3.43months in the FOLFIRI group, 4months in the platinum-based group, and 2.77months in the taxane-based group (p = 0.546). There was no statistically significant difference between the three irinotecan-based, platinum-based, and taxane-based treatments. According to our study's results, the chemotherapy given in second-line treatment should be decided on an individual basis according to toxicity and cost.

Treatment Outcomes After Switching to Second-Line Anti-Retroviral Therapy: Results From the Thai National Treatment Program.

This study aimed to assess second-line antiretroviral therapy (ART) outcomes in a National HIV Treatment program. People living with HIV aged ≥18 years initiating first-line ART who switched to second-line protease inhibitor-based regimens from January 2008 to May 2019, with a minimum of 1-year follow-up were studied. The primary outcome was second-line treatment failure (two consecutive virological failure episodes (viral load ≥1000 copies/mL)). Of 318,506 PLH initiating ART, 29,015 (9.1%) switched to second-line regimens after a median (IQR) ART duration of 1.63 (0.60-3.59) years. Lost to follow-up (LTFU) occurred in 5316 (18.3%) of whom 1376 (5%) remained LTFU and alive; 4606 (15.9%) died. Cumulative second-line failure incidence was 9.8% at 6 years, more common in females, younger PLH those with lower switch CD4 cell counts. Multidisciplinary, innovative support systems are needed to improve second-line treatment outcomes, particularly those relating to modifiable risk factors.

Pharmacological effects of Niraparib and its combination with angiogenic inhibitor in ovarian cancer.

Background: Ovarian cancer (OC) represents the seventh most lethal female tumors worldwide. The combination of PARP inhibitor (PARPi) and angiogenic inhibitor has been shown to be effective as a first-line or second-line maintenance regimen to synergistically exert antitumor effects, which prompts us to further evaluate the therapeutic effect of the combination of PARP inhibitor Niraparib and anti-angiogenic Brivanib on OC. Method:3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay were applied to evaluate the anti-proliferative effect of Niraparib, Brivanib, or the combination treatment on OC cells. The Annexin V-FITC/PI apoptotic assay was adopted to detect cell apoptosis. Tumor xenograft experiment and immunohistochemical (IHC) analysis were performed to evaluate the effect of single or combination treatment on the tumorigenicity of OC in vivo. Results: Our current findings revealed that OC cells harboring BRAC1/2 mutations were more sensitive to Niraparib treatment compared to those with BRAC wild-type, and the addition of Brivanib enhanced programmed cell death (PCD) to sensitize OC cells with BRAC mutations to Niraparib treatment in vitro and in vivo. Conclusion: Our work illustrates that the combination regimen of PARPi and angiogenic inhibitor treatment should be beneficial for the OC patients with BRAC mutations, at least partially owing to the induction of multiple forms of programmed cell death (PCD).

Effectiveness of first and second-line empirical treatment in Italy: Results of the European registry on Helicobacter pylori management.

The optimal management of naïve and not naïve Helicobacter pylori patients remains unclear. Therefore, it is essential to evaluate whether the actual clinical practice mirrors the indications suggested by the guidelines. This study aimed to assess the effectiveness and the safety of the empirical first- and second-line treatments prescribed to patients enroled at Italian centres participating in the European Registry on H. pylori Management (Hp-EuReg). The Hp-EuReg is an international multicentre prospective non-interventional registry starting in 2013 aiming to evaluate the management of H. pylori infection by European gastroenterologists. Patients were registered in an e-CRF by AEG-REDCap. Variables assessed included demographics, previous eradication attempts, treatment regimen, effectiveness, and tolerance. Overall, 3723 patients from 2013 to February 2021 were included: 2996 and 727 received an empirical first- and second-line treatment, respectively. According to the modified ITT analysis, among the first-line regimens, only the bismuth quadruple therapy with three-in-one-single capsule (BQT-TSC), the concomitant, and the sequential treatment - all lasting 10 days - achieved an eradication rate >90%. Among the second-line regimens, only the 10-day BQT-TSC reported an effectiveness >90%. High-dose PPI twice daily also significantly increased the effectiveness of some therapies. The BQT-TSC was the regimen with the highest incidence of adverse events. Only quadruple therapies lasting at least 10days achieved over 90% eradication rates among the empirical first- and second-line regimens. It remains unclear whether high-dose PPI twice daily can improve the efficacy of quadruple treatment.