Second-line Treatment Regimens Research Articles

Cost Effectiveness of Treatment Sequences in Advanced Renal Cell Carcinoma

BackgroundThe treatment landscape for metastatic renal cell carcinoma (mRCC) has significantly evolved in recent years. Without direct comparator trials, factors such as cost effectiveness (CE) are important to guide decision-making. ObjectiveTo assess the CE of guideline-recommended approved first- and second-line treatment regimens. Design, setting, and participantsA comprehensive Markov model was developed to analyze the CE of the five current National Comprehensive Cancer Network–recommended first-line therapies with appropriate second-line therapy for patient cohorts with International Metastatic RCC Database Consortium favorable and intermediate/poor risk. Outcome measurements and statistical analysisLife years, quality-adjusted life years (QALYs), and total accumulated costs were estimated using a willingness-to-pay threshold of $150 000 per QALY. One-way and probabilistic sensitivity analyses were performed. Results and limitationsIn patients with favorable risk, pembrolizumab + lenvatinib followed by cabozantinib added $32 935 in costs and yielded 0.28 QALYs, resulting in an incremental CE ratio (ICER) of $117 625 per QALY in comparison to pembrolizumab + axitinib followed by cabozantinib. In patients with intermediate/poor risk, nivolumab + ipilimumab followed by cabozantinib added $2252 in costs and yielded 0.60 QALYs compared to cabozantinib followed by nivolumab, yielding an ICER of $4184. Limitations include differences in median follow-up duration between treatments. ConclusionsPembrolizumab + lenvatinib followed by cabozantinib, and pembrolizumab + axitinib followed by cabozantinib were cost-effective treatment sequences for patients with favorable-risk mRCC. Nivolumab +ipilimumab followed by cabozantinib was the most cost-effective treatment sequence for patients with intermediate-/poor-risk mRCC, dominating all preferred treatments. Patient summaryBecause new treatments for kidney cancer have not been compared head to head, comparison of their cost and efficacy can help in making decisions about the best treatments to use first. Our model showed that patients with a favorable risk profile are most likely to benefit from pembrolizumab and lenvatinib or axitinib followed by cabozantinib, while patients with an intermediate or poor risk profile will probably benefit most from nivolumab and ipilimumab followed by cabozantinib.

An active trend of immunotherapy combination regimen as second-line therapy for advanced biliary tract cancer: A multicenter retrospective study.

520 Background: FOLFOX as second-line therapy remains the standard of care in patients with biliary tract cancer (BTC), but its efficacy is suboptimal. Currently, cytotoxic chemotherapy, targeted therapy, and immunotherapy alone or in combination are being tested in patients with pretreated advanced BTC for in clinical trials. This study aimed to evaluate and compare the anticancer of distinct treatment regimen in patients with advanced BTCs who progress after first-line chemotherapy. Methods: Patients diagnosed BTC who received second-line therapy were retrospectively identified at 3 sites across the Zhejiang province between January 1, 2018, and June 31, 2022. Clinicopathological information and therapeutic outcome, including subtype of BTC, response per RECIST v1.1, treatment duration, adverse events (AE), progression-free survival (PFS), and overall survival (OS), were recorded and estimated. Results: A total of 98 patients with BTCs were reviewed and recruited eventually: the chemotherapy group (cohort A, n=30), the chemotherapy plus ICIs group (cohort B, n=25), the TKIs group (cohort C, n=17), and the TKIs plus ICIs group (cohort D, n=26). The median PFS and OS were 2.4 months (95%CI: 1.6–3.2) and 7.0 months (95% CI: 6.4–7.5) for cohort A, 3.9 months (95%CI: 2.8–5.0) and 10.7 months (95% CI: 6.9–14.5) for cohort B, 1.6 months (95%CI: 0.8–2.4) and 7.1 months (95% CI: 0.7–13.5) for cohort C, and 4.7 months (95%CI: 3.1–6.2) and 10.1 months (95% CI: 4.1–16.1) for cohort D, respectively. In the cohort A, B, C, and D, confirmed ORRs were 10%, 20%, 11.8% and 19.2%, separately, and DCRs were 46.7%, 68%, 43.8% and 76.9%, respectively. The efficacy of ICIs plus TKIs was optimal in terms of tumor response and associated with prolong PFS. Six patients (20%), nine patients (36%), five patients (29.4%), and elven patients (42.3%) were experienced ≥ grade 3 treatment-related AEs in cohort A, B, C, and D, respectively. Conclusions: Immunotherapy combination strategy beyond first-line systemic chemotherapy plays a positive role in advanced BTCs. Both TKIs plus ICIs and chemotherapy plus ICIs could be considered as candidates to second-line trails and turn into a competitive second-line treatment regimen for advanced BTCs in clinical practice.

A single-arm, open-label, phase II study investigating anti-HER2 ADC plus anti-PD-1 antibody in patients with unresectable locally advanced or metastatic BTC with HER2 overexpression.

TPS619 Background: 1. Biliary tract cancer (BTC) accounts for 4% of all digestive tract cancers. In 2016-2020, the incidence of BTC has gradually increased worldwide. In China, gallbladder carcinoma accounted for 1.7% of all tumors and 1.9% of deaths in some regions. 2. The standard second-line treatment regimen is mFOLFOX, with an ORR of 5%, PFS of 2 months and OS of 6.2 months. Methods: This is a single-arm, open-label, phase II study, approximately 31 patients of unresectable locally advanced or metastatic BTC with HER2 overexpression will be enrolled. Each treatment cycle is 14 days. Therapeutic regimen: Disitamab Vedotin 2.5mg/kg IV, D1, Q2W + Zimberelimab 240mg IV, D1, Q2W All patients treated until a loss of clinical benefit or unacceptable toxicity is observed by the investigator. Objective: to evaluate the efficacy and safety of Disitamab Vedotin + Zimberelima in patients with unresectable locally advanced or metastatic BTC with HER2 overexpression Disitamab Vedotin: Vedecitumab is an antibody-drug conjugate (ADC), with a humanized antibody conjugated to four tubulin inhibitor molecules (DAR=4) Zimberelimab: Zimberelimab is a fully human IgG4 monoclonal antibody that specifically binds to PD-1 molecules on the surface of lymphocytes. This drug is approved for r/r cHL and is also effective in the cervical cancer. Clinical trial information: NCT05540483 .

Treatment Patterns and Health Care Costs in Commercially Insured Patients with Follicular Lymphoma.

BackgroundFew studies have estimated the real-world economic burden such as all-cause and follicular lymphoma (FL)-related costs and health care resource utilization (HCRU) in patients with FL.ObjectivesThis study evaluated outcomes in patients who were newly initiated with FL indicated regimens by line of therapy with real-world data.MethodsA retrospective study was conducted among patients with FL from MarketScan® databases between January 1, 2010 and December 31, 2013. Patients were selected if they were ≥18 years old when initiated on a FL indicated therapy, had at least 1 FL-related diagnosis, ≥1 FL commonly prescribed systemic anti-cancer therapy after diagnosis, and did not use any FL indicated regimen in the 24 months prior to the first agent. These patients were followed up at least 48 months and the outcomes, including the distribution of regimens by line of therapy, the treatment duration by line of therapy, all-cause and FL-related costs, and HCRU by line of therapy were evaluated.ResultsThis study identified 598 patients who initiated FL indicated treatment. The average follow-up time was approximately 5.7 years. Of these patients, 50.2% (n=300) were female, with a mean age of 60.7 years (SD=13.1 years) when initiating their treatment with FL indicated regimens. Overall, 598 (100%) patients received first-line therapy, 180 (43.6%) received second-line therapy, 51 received third-line therapy, 21 received fourth-line therapy, and 10 received fifth-line therapy. Duration of treatment by each line of therapy was 370 days, 392 days, 162 days, 148 days, and 88 days, respectively. The most common first-line regimens received by patients were rituximab (n=201, 33.6%), R-CHOP (combination of rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxydaunomycin]; n=143, 24.0%), BR (combination of bendamustine and rituximab; n=143, 24.0%), and R-CVP (combination of rituximab, cyclophosphamide, vincristine, and prednisone; n=71, 11.9%). The most common second-line treatment regimens were (N=180): rituximab (n=78, 43.3%) and BR (n=41, 22.8%). Annualized all-cause health care costs per patient ranged from US$97 141 (SD: US$144 730) for first-line to US$424 758 (SD: US$715 028) for fifth-line therapy.ConclusionsThe primary regimens used across treatment lines conform to those recommended by the National Comprehensive Cancer Network clinical practice guidelines. The economic burden for patients with FL is high and grows with subsequent lines of therapy.

Cost-Effectiveness Analysis of a New Second-Line Treatment Regimenfor Advanced Intrahepatic Cholangiocarcinoma: Biomarker-Driven Targeted Therapy of Pemigatinib Versus 5-FUChemotherapy.

The National Comprehensive Cancer Network recommends a second-line treatment of pemigatinib for patients with intrahepatic cholangiocarcinoma with fibroblast growth factor receptor 2 (FGFR2) fusions/rearrangements and modified FOLFOX (mFOLFOX) for those without FGFR2 alterations. However, these regimens are not yet covered by Taiwa's National Health Insurance. This cost-effectiveness analysis evaluated the cost-effectiveness of the pemigatinib/mFOLFOX regimen as the second-line treatment for advanced intrahepatic cholangiocarcinoma based on FGFR2 status in comparison with the regimen of fluorouracil chemotherapy and provided a cost-effectiveness analysis-based reference price for pemigatinib. A three-state partitioned survival model with a 5-year time horizon was constructed for patients with advanced intrahepatic cholangiocarcinoma who did not respond to first-line therapy. Overall and progression-free survival functionsof pemigatinib, mFOLFOX, and fluorouracil were estimated from the FIGHT-202, ABC-06, and NIFTY trials, respectively. The utility of health states and disutility of adverse events were obtained from the literature. The genetic testing fee and price of pemigatinib were set as the market price. Other costs related to advanced intrahepatic cholangiocarcinoma were calculated using National Health Insurance claims data. The willingness-to-pay threshold was three times the gross domestic product per capita in 2021 (NT$2,889,684). A 3% discount rate was applied to quality-adjusted life-years and costs. Scenario analyses included a gradual price reduction of pemigatinib, alternative survival models, application of a National Health Insurance payment conversion factor to non-medication costs, and consideration of life-years as effectiveness. A deterministic sensitivity analysis, probabilistic sensitivity analysis, and a value of information analysis were performed. The new regimen provided an incremental 0.13 quality-adjusted life-years, with incremental costs of NT$459,697, yielding an incremental cost-effectiveness ratio of NT$3,411,098 per quality-adjusted life-year and an incremental net monetary benefit of -NT$70,268. The new regimen was found to be 53.2% cost effective in the probabilistic sensitivity analysis. The expected value of uncertainty measured by the expected value of perfect information was NT$80,695/person. In scenario analyses, the incremental net monetary benefit was positive when the price of pemigatinib was reduced by 40% or more. When applying a conversion factor to non-medical costs, the probability of the new regimen being cost effective was slightly increased from 53.2 to 56.5% compared with the base-case analysis. The utility and the cost of the new regimen were the main drivers of uncertainty. Although the new second-line genetic-based and biomarker-driven regimen of pemigatinib/mFOLFOX appears not cost effective for patients with advanced intrahepatic cholangiocarcinoma in the base-case analysis, our analysis suggests it is highly likely to be cost effective in the case of a 40% price reduction on pemigatinib.

HDACi Promotes the Occurrence of Ferroptosis in CTCL

Cutaneous T-cell lymphoma (CTCL) is a type of extranodal non-Hodgkin's lymphoma (NHL), a disease caused by clonal proliferation of T-lymphocytes originating in the skin. CHOP is the classic first-line treatment regimen for PTCL, working best for ALK-positive ALCL, while chemotherapy regimens are not very friendly for CTCL and other subtypes of PTCL. Currently, second-line treatment regimens have shown encouraging results with HDAC inhibitors in PTCL, and the anti-tumor mechanisms of HDAC inhibitors are being explored, including induction of apoptosis, cell cycle arrest inhibition of tumor angiogenesis, and so on. Ferroptosis is a new mode of cell death, which was mainly manifested by mitochondrial membrane lipid peroxidation, ferritin phagocytosis, the release of ferrous ions. And ferrous ions further leads to cellular lipid peroxidation, resulting in cell death. Our study shows that HDACi can significantly enhance ferroptosis inducer-mediated ferroptosis. WB and qPCR showed that ferroptosis-related molecules were significantly downregulated. In the case of HDACi combined with ferroptosis inducer, HDACi significantly enhanced the intensity of ferroptosis, and mitochondrial shrinkage and increased membrane density could be observed under electron microscopy. Intracellular iron content was detected by PGSK probe and detected by co Focused microscopy revealed that the fluorescence signal was significantly attenuated in the combination group. Reactive oxygen species assay indicated a significant increase in intracellular reactive oxygen species level, where we found the presence of ferroptosis in PTCL for the first time. In addition, we found that HDACi combined with ferroptosis inducer could enhance the apoptosis level of lymphoma cells, and the combination group significantly downregulated BCL-2, Caspase3,and significantly upregulated p-H2AX expression compared with the single drug.In terms of cycle arrest, CyclinD1 was significantly down-regulated in the combination group, and flow cytometry results were consistent with the above, while CCK8 and Edu showed significant down-regulation of cell viability and proliferation. SD rat transplantation tumor models showed a significant reduction in tumor volume in the combination group compared to the single agent and control groups, suggesting that HDACI combined with ferroptosis inducer is a promising therapeutic strategy.

102P A real-world study comparing apatinib combined with irinotecan versus irinotecan as second-line or above therapy in patients with advanced or metastatic gastric cancer

Irinotecan monotherapy was the standard second-line treatment regimen for metastatic gastric cancer. Previous researches revealed that apatinib combined with chemotherapy is more effective compared with apatinib or chemotherapy alone.The present study was conducted to evaluate the efficacy and safety of apatinib combined with irinotecan versus irinotecan as second-line or above therapy for patients with advanced or metastatic gastric cancer.

Analysis of Membrane Proteins of Streptomycin-Resistant Mycobacterium tuberculosis Isolates

Background: Drug-resistant tuberculosis remains a health security threat and resistance to second-line drugs limits the options for treatment. Consequently, there is an utmost need for identifying and characterizing new biomarkers/drug targets of prime importance. Membrane proteins have an anticipated role in biological processes and could qualify as biomarkers/drug targets. Streptomycin (SM) is recommended as a second-line treatment regimen only when amikacin resistance has been confirmed. As extensively drug-resistant (XDR) isolates are frequently cross-resistant to second-line injectable drugs, an untapped potential for the continued use of SM has been suggested. Objective: The study aimed to analyze the membrane proteins overexpressed in SM resistant isolates of Mycobacterium tuberculosis using proteomics approaches. Methods: Membrane proteins were extracted employing sonication and ultracentrifugation. Twodimensional gel electrophoresis (2DGE) of membrane proteins was performed and identification of proteins was done by liquid chromatography-mass spectrometry (LCMS) and bioinformatics tools. Results: On analyzing the two-dimensional (2D) gels, five protein spots were found overexpressed in the membrane of SM resistant isolates. Docking analysis revealed that SM might bind to the conserved domain of overexpressed proteins and Group-based prediction system-prokaryotic ubiquitinlike protein (GPS-PUP) predicted potential pupylation sites within them. Conclusion: These proteins might be of diagnostic importance for detecting the cases early and for exploring effective control strategies against drug-resistant tuberculosis, particularly SM.

Lenvatinib Plus Programmed Cell Death Protein-1 Inhibitor Beyond First-Line Systemic Therapy in Refractory Advanced Biliary Tract Cancer: A Real-World Retrospective Study in China.

BackgroundCurrently, no second-line systemic treatment regimen has been recommended in advanced biliary tract cancer (BTC). Cumulative clinical evidence showed that systemic treatment with tyrosine kinase inhibitors (TKIs) in combination with immunotherapy may shed light on the dim clinical outcome in advanced BTC.ObjectiveThe aim of this study is to evaluate the anticancer efficacy of lenvatinib plus programmed cell death protein-1 (PD-1) antibody in patients with BTC who progressed after first-line cisplatin/gemcitabine (CisGem) chemotherapy.MethodsPatients with advanced BTCs who progressed after CisGem were recruited. A combination regimen of lenvatinib (8/12 mg daily) plus PD-1 antibody (200/240 mg injection every 3 weeks) was prescribed. Clinicopathological information and therapeutic outcome, including tumor subtypes, biomarkers, treatment duration, adverse events (AE), progression-free survival (PFS), and overall survival (OS), were recorded and estimated.ResultsA total of 351 patients with BTCs were reviewed and 74 were recruited eventually: 35 had intrahepatic cholangiocarcinoma (47.3%), 4 had extrahepatic cholangiocarcinoma (5.4%), and 35 had gallbladder cancer (47.3%). The median administered cycles of PD-1 antibody were 6.43 (95% CI: 5.83–7.04) cycles, and the median duration of lenvatinib medication was 21.0 weeks (95% CI: 18.04–23.93). Twenty-eight patients (37.83%) experienced detectable objective response per RECIST1.1 within a median follow-up duration of 15.0 months. The objective response rate (ORR) was 20.27% (95% CI: 10.89%–29.65%), and the disease control rate (DCR) was 71.62% (95% CI: 61.11%–82.14%). The median PFS and OS were 4.0 months (95% CI: 3.5–5.0) and 9.50 months (95% CI: 9.0–11.0), respectively. Seventy-three patients (98.64%) reported AEs and 39 (52.70%) experienced ≥grade 3 AEs. In subgroup analyses, tumoral PD-L1 expression ≥50% and tumor mutation burden (TMB) ≥2.5 Muts/Mb were associated with prolonged PFS.ConclusionLenvatinib plus PD-1 antibody treatment shows an active trend towards improving survival in patients with advanced BTCs after failure with CisGem chemotherapy. The treatment-related AEs are worthy of attention and are manageable.

Apatinib: A Novel Antiangiogenic Drug in Monotherapy or Combination Immunotherapy for Digestive System Malignancies.

Digestive system malignancies are one of the primary causes of cancer-related death. Meanwhile, angiogenesis has been proved to play an important role in the process of cancer neovascularization. Apatinib, a novel targeted antiangiogenic molecule, could generate highly selective competition in the vascular endothelial growth factor receptor-2, involved in tumor progression and metastasis. It has been implied as a promising cancer treatment agent that can prevent tumor cell proliferation meanwhile inhibit tumor angiogenesis. Furthermore, completed clinical trials demonstrated that apatinib could prolong the progression-free survival and overall survival in advanced gastric cancer and primary liver cancer. Recent studies revealed that apatinib had a synergistic effect with immunotherapy as a second-line and third-line treatment regimen for some other cancers. In this review, we summarize the pharmacological properties of apatinib and the latest clinical application in chemotherapy-refractory patients with advanced digestive system cancer. Based on the comparable survival results, the molecular mechanisms of apatinib are prospective to include the antiangiogenic, apoptosis-inducing, and autophagy-inducing properties in the corresponding signaling pathway. Treatment of apatinib monotherapy or combination immunotherapy remains the optimal option for patients with digestive system malignancies in the future.

Triple Burden of Neurocognitive Impairment and Co-occurring Depression and Anxiety Among People Living With HIV in Bahir Dar, Ethiopia: A Multicenter Study.

BackgroundNeurocognitive impairment is associated with psychological morbidities, such as depression and anxiety, among people living with HIV. The presence of these comorbidities affects viral load suppression, treatment adherence, quality of life, treatment outcomes, and functionality. Despite this fact, there is a dearth of studies that examined the triple burden of neurocognitive impairment and co-occurring depression and anxiety among antiretroviral therapy attendees in Ethiopia. This study aimed to assess the magnitude of HIV-associated neurocognitive impairment and co-occurring depression and anxiety at the same time among people living with HIV/AIDS.MethodWe conducted an institution-based multicenter cross-sectional study in Bahir Dar, Northwest Ethiopia. A total of 410 study participants were selected using a systematic random sampling technique. Neurocognitive impairment was assessed using the International HIV Dementia Scale. Co-occurring depression and anxiety were assessed using the Hospital Anxiety and Depression Scale. A semi-structured questionnaire was applied to collect data on sociodemographic and clinical-related characteristics. Data were analyzed using descriptive statistics and univariate and multivariable logistic regression.ResultsTwo-thirds (66.8%) of the people living with HIV had neurocognitive impairment. The prevalence of co-occurring depression and anxiety was found in 39.8%. Women with HIV, people with comorbid chronic medical illness, and those under a second-line treatment regimen were factors associated with neurocognitive impairment. Furthermore, pill burden, second-line treatment regimen, HIV clinical stages, social support, HIV-perceived stigma, and neurocognitive impairment were associated factors with co-occurring depression and anxiety.ConclusionsWe found a high prevalence of neurocognitive impairment and co-occurring depression and anxiety among people living with HIV/AIDs. Further research is needed to assess the clinical course of neurocognitive impairment and co-occurring depression and anxiety.

Optimal Treatments for NSCLC Patients Harboring Primary or Acquired MET Amplification.

Background: In non-small cell lung cancer (NSCLC) patients harboring MET mutations, MET-tyrosine kinase inhibitors (TKIs) have been proven to achieve a good response. However, the relative efficacy of different therapeutics in primary NSCLC patients with MET amplification and the treatment options for patients harboring acquired MET amplification after the failure of epidermal growth factor receptor (EGFR)-TKIs remain unclear. Methods: In total, 33 patients harboring primary MET amplification and 9 patients harboring acquired MET alterations identified by next-generation sequencing were enrolled. A retrospective analysis was conducted to compare the efficacy of different therapeutics. In addition, studies reporting various treatments for patients harboring MET alterations were included in the meta-analysis. Results: In our cohort of patients harboring primary MET amplification, crizotinib displayed better efficacy than immunotherapy and chemotherapy, as demonstrated both in first-line (P = .0378) and second-line treatment regimens (P = .0181). The disease control rates for crizotinib, immunotherapy, and chemotherapy were 81.8%, 72.7%, and 63.6%, respectively. In particular, the median progression-free survival (PFS) time after immunotherapy in patients harboring MET amplification and high programed death ligand 1 (PD-L1) expression (>50%) was only 77.5 days. The meta-analysis revealed that the median PFS times after crizotinib and immunotherapy were 4.57 and 2.94 months, respectively. In patients harboring acquired MET amplification, chemotherapy plus bevacizumab had superior efficacy (310.0 days vs 73.5 days, P = .0360) compared with MET-TKIs ± EGFR-TKIs. Conclusions: Immunotherapy showed a low response in patients harboring MET alterations, even those with concurrent high PD-L1 expression. MET-TKIs might be an optional treatment with worth-expecting efficacy. However, chemotherapy plus bevacizumab could benefit the subpopulation of patients harboring acquired MET amplification after the failure of EGFR-TKIs.

Advances in pharmacotherapy for cholangiocarcinoma: from conventional therapies to targeted drugs

ABSTRACT Introduction Cholangiocarcinomas (CCA) are rare, highly invasive tumors often diagnosed at an advanced disease stage with an associated poor prognosis. Surgery represents the only chance for curative-intent treatment, but recurrence rates remain high. Neoadjuvant or adjuvant chemotherapy are options for patients with resectable CCA to increase recurrence-free survival and overall survival, while palliative chemotherapy represents the treatment for unresectable disease. Global efforts are currently focused on the development of novel more effective therapies. Areas covered A review was conducted in August 2021 using the PubMed database with the following keywords: ‘cholangiocarcinoma,’ ‘chemotherapy,’ and ‘therapy.’ Manuscripts reporting on first- and second-line chemotherapy, neoadjuvant and adjuvant treatment regimens, and targeted therapies currently being tested or employed in the management of CCA were examined. Expert opinion The prognosis of CCA is negatively affected by several factors including a lack of reliable biomarkers leading to delayed diagnoses, high inter- and intra-tumoral heterogeneity, and few effective chemotherapy regimens. In pursuit of more effective therapies, ongoing trials are testing both conventional and targeted drugs.

Modified FOLFIRINOX versus sequential chemotherapy (FOLFIRI/FOLFOX) as a second-line treatment regimen for unresectable pancreatic cancer: A real-world analysis.

BackgroundAlthough second‐line treatment for pancreatic cancer has been proven to have survival benefit, it is not clear which is the most preferred regimen. This study compared the efficacy and safety of modified FOLFIRINOX (mFOLFIRINOX) and sequential chemotherapy (FOLFIRI/FOLFOX) as a second‐line treatment regimen for unresectable pancreatic cancer.MethodThis was a retrospective single‐center analysis of all patients who initiated treatment with mFOLFIRINOX or sequential chemotherapy from December 2014 to May 2019 as a second‐line treatment for unresectable pancreatic cancer. The sequential chemotherapy group included all patients who initiated sequential chemotherapy. For efficacy analysis, the primary endpoint was overall survival (OS) of all patients, excluding those with locally advanced pancreatic cancer. For safety analysis, we assessed the incidence of grade ≥3 adverse events in all patients.ResultsSeventy‐four patients (mFOLFIRINOX group, n = 44; sequential chemotherapy group, n = 30) were included. OS tended to be slightly prolonged in the mFOLFIRINOX group than in the sequential chemotherapy group (median 10.6 [95% confidence interval {CI} 5.9–13.8] vs. 8.5 [95% CI 5.0–12.2] months; hazard ratio 1.40 [95% CI 0.71–2.71]). The objective response rate and disease control rate were 8.1% and 64.9%, respectively, in the mFOLFIRINOX group and 3.8% and 42.3%, respectively, in the sequential chemotherapy group. In safety analysis, the grade ≥3 rates of neutropenia, febrile neutropenia, and anorexia were 40.9%, 6.8%, and 18.2%, respectively, in the mFOLFIRINOX group and 3.3%, 0%, and 3.3%, respectively, in the sequential chemotherapy group.ConclusionsWhereas efficacy tended to be slightly better in the mFOLFIRINOX group than in the sequential chemotherapy group, given the higher incidence of grade ≥3 adverse events with mFOLFIRINOX than with sequential chemotherapy, sequential chemotherapy is a regimen with better risk–benefit balance than mFOLFIRINOX, and can be considered a second‐line treatment option for patients with unresectable pancreatic cancer.

Predictors of Poor Adherence to CART and Treatment Failure at Second-Line Regimens Among Adults in Public Hospitals of Amhara Region, North-Western Ethiopia: A Retrospective Cohort Study.

BackgroundGlobally, HIV/AIDS has challenged the lives of 36.3 million people and resulted in 17 million orphans. The disease has neither a vaccine nor a cure and the only option currently is highly active antiretroviral therapy. This research was conducted to identify the predictors of poor adherence to CART and treatment failure at second-line regimen among adults living with HIV/AIDS in public hospitals of Amhara region, north-western Ethiopia.MethodsA retrospective cohort study design was conducted on 700 HIV-positive people who were receiving a second-line CART regimen. Participants on second-line regimens who followed their treatment between 2016 and 2019 were considered. Data were extracted from participants’ clinical charts from June 18–July 7, 2020.ResultsA multivariate regression analysis indicates that age of patients (OR = 1.025, 95% CI: 1.001–1.321; p = 0.005), follow-up visits (OR = 0.979, 95% CI: 0.873–0.998; p < 0.001), CD4 cell count change (OR = 0.9860; 95% CI: 0.835–0.998; p < 0.01), marital status (OR = 0.973, 95% CI: 0.789– 0.997; p = 0.006), female HIV-infected patients (OR = 0.990; 95% CI: 0.789–0.999; p <0.001), rural patients (OR = 1.151; 95% CI 1.065–1.398; p = 0.004), non-educated adult patients (OR = 1.026, 95% CI: 1.002–1.198; p = 0.003), existence of social violence (OR = 0.012, 95% CI: 0.008–0.134; p< 0.01), patients with opportunistic diseases (OR = 1.0345, 95% CI 1.002–1.142; p = 0.001), CD4 cell count (OR = 0.901, 95% CI: 0.843–0.995; p = 0.025) and malnutrition (OR = 0.883, 95% CI; 0.762–0.954; p = 0.001) significantly affected the two response variables.ConclusionSeveral variables affected both poor adherence to HAART and treatment failure at second-line regimens in the current investigation. Due attention should be given to aged patients, rural residents, non-educated patients, and patients with other morbidities to be successful with second-line treatment regimens.

Acquired HIV drug resistance and virologic monitoring in a HIV hyper-endemic setting in KwaZulu-Natal Province, South Africa

BackgroundIntroduction of tenofovir (TDF) plus lamivudine (3TC) and dolutegravir (DTG) in first- and second-line HIV treatment regimens in South Africa warrants characterization of acquired HIV-1 drug resistance (ADR) mutations that could impact DTG-based antiretroviral therapy (ART). In this study, we sought to determine prevalence of ADR mutations and their potential impact on susceptibility to drugs used in combination with DTG among HIV-positive adults (≥ 18 years) accessing routine care at a selected ART facility in KwaZulu-Natal, South Africa.MethodsWe enrolled adult participants in a cross-sectional study between May and September 2019. Eligible participants had a most recent documented viral load (VL) ≥ 1000 copies/mL after at least 6 months on ART. We genotyped HIV-1 reverse transcriptase and protease genes by Sanger sequencing and assessed ADR. We characterized the effect of ADR mutations on the predicted susceptibility to drugs used in combination with DTG.ResultsFrom 143 participants enrolled, we obtained sequence data for 115 (80%), and 92.2% (95% CI 85.7–96.4) had ADR. The proportion with ADR was similar for participants on first-line ART (65/70, 92.9%, 95% CI 84.1–97.6) and those on second-line ART (40/44, 90.9%, 95% CI 78.3–97.5), and was present for the single participant on third-line ART. Approximately 89% (62/70) of those on first-line ART had dual class NRTI and NNRTI resistance and only six (13.6%) of those on second-line ART had major PI mutations. Most participants (82%) with first-line viraemia maintained susceptibility to Zidovudine (AZT), and the majority of them had lost susceptibility to TDF (71%) and 3TC (84%). Approximately two in every five TDF-treated individuals had thymidine analogue mutations (TAMs).ConclusionsSusceptibility to AZT among most participants with first-line viraemia suggests that a new second-line regimen of AZT + 3TC + DTG could be effective. However, atypical occurrence of TAMs in TDF-treated individuals suggests a less effective AZT + 3TC + DTG regimen in a subpopulation of patients. As most patients with first-line viraemia had at least low-level resistance to TDF and 3TC, identifying viraemia before switch to TDF + 3TC + DTG is important to avoid DTG functional monotherapy. These findings highlight a need for close monitoring of outcomes on new standardized treatment regimens.

Characteristics, treatment patterns, and economic burden of patients with metastatic cervical cancer receiving systemic anticancer therapy.

51 Background: In 2021, 14,480 patients are estimated to be diagnosed with cervical cancer in the US; 16% of patients are expected to have metastatic disease for whom the 5-year survival rate is 17.6% per SEER estimates. Patients with metastatic cervical cancer (mCC) are treated mainly with systemic therapy. This study aims to describe the clinical characteristics, demographics, treatment patterns, and economic burden of patients with mCC receiving systemic therapy. Methods: Eligible women had been diagnosed with cervical cancer, as evidenced by &gt;2 outpatient or &gt;1 inpatient claim in the Optum Research Database from January 2014 through January 2020. Patients were included if they had metastasis within 6 months before or after cervical cancer diagnosis, with evidence of systemic treatment on or after the latter of a claim date for cervical cancer disease or metastatic disease. The index date was the first-line treatment initiation date. Patients were required to have ≥6 months of pre-index continuous enrollment. The top 3 treatment regimens and median treatment duration by line of therapy were described. All-cause per-patient-per-month (PPPM) costs (2019 US dollars), including plan and patient paid amounts, were reported for full follow-up period from first-line and second-line therapy initiation. Results: The study sample consisted of 778 patients (mean age, 59 years; commercial, 58%; Medicare Advantage, 42%). The mean (median) follow-up period was 14 (9) months. Top baseline comorbidities were diseases of the urinary system (71%) and diseases of the female genital organs (70%), and the median Charlson comorbidity index was 7. In the first line, 80% of patients received platinum-based therapy and 23% received bevacizumab (bev). Of 778 patients, only 294 (38%) received second-line therapy, with 34% receiving bev. Top first-line treatment regimens were carboplatin + paclitaxel (27%), cisplatin (21%), and bev + carboplatin + paclitaxel (10%); the median (95% CI) duration of treatment was 3.4 (3.1-3.7) months. Top second-line treatment regimens were bev + carboplatin + paclitaxel (13%), carboplatin + paclitaxel (11%), and pembrolizumab (6%); the median duration of treatment was 3.8 (3.1-4.2) months. Mean all-cause total PPPM costs were $19,519 from first-line and $22,660 second-line therapy initiation (table). Conclusions: This study indicates that real-world mCC patients have short treatment durations and significant economic burden with first-line and second-line therapy. Novel therapies associated with greater clinical benefits in patients with mCC may provide economic benefit.[Table: see text]

Lenvatinib Rechallenge After Ramucirumab Treatment Failure for Hepatocellular Carcinoma.

While there is increasing evidence supporting the role of several first- and second-line treatment regimens for advanced hepatocellular carcinomas (HCC), the clinical relevance of rechallenge treatment with previously administered drugs, however, remains to be explored. Five consecutive patients with advanced HCC who received lenvatinib rechallenge treatment after ramucirumab were assessed. All patients were clinically diagnosed with failure after ramucirumab treatment, and the frequencies of ramucirumab administration before lenvatinib re-administration ranged from 3 to 11. The alfa-fetoprotein level in four of five patients decreased 1 month after the lenvatinib rechallenge. Radiological findings via the modified Response Evaluation Criteria in Solid Tumors showed stable diseases in four patients and a partial response in one. Rechallenge treatment with lenvatinib after ramucirumab can be effective, and may be a treatment option for HCC in cases wherein the disease progressed after an initial response to lenvatinib treatment.

Phylogenomics and antimicrobial resistance of Salmonella Typhi and Paratyphi A, B and C in England, 2016-2019.

The emergence of antimicrobial resistance (AMR) to first- and second-line treatment regimens of enteric fever is a global public-health problem, and routine genomic surveillance to inform clinical and public-health management guidance is essential. Here, we present the prospective analysis of genomic data to monitor trends in incidence, AMR and travel, and assess hierarchical clustering (HierCC) methodology of 1742 isolates of typhoidal salmonellae. Trend analysis of Salmonella Typhi and S. Paratyphi A cases per year increased 48 and 17.3%, respectively, between 2016 and 2019 in England, mainly associated with travel to South Asia. S. Paratyphi B cases have remained stable and are mainly associated with travel to the Middle East and South America. There has been an increase in the number of S. Typhi exhibiting a multidrug-resistant (MDR) profile and the emergence of extensively drug resistant (XDR) profiles. HierCC was a robust method to categorize clonal groups into clades and clusters associated with travel and AMR profiles. The majority of cases that had XDR S. Typhi reported recent travel to Pakistan (94 %) and belonged to a subpopulation of the 4.3.1 (H58) clone (HC5_1452). The phenotypic and genotypic AMR results showed high concordance for S. Typhi and S. Paratyphi A, B and C, with 99.99 % concordance and only three (0.01 %) discordant results out of a possible 23 178 isolate/antibiotic combinations. Genomic surveillance of enteric fever has shown the recent emergence and increase of MDR and XDR S. Typhi strains, resulting in a review of clinical guidelines to improve management of imported infections.

Novel “High-dose Quad” Salvage Therapy Approach for Helicobacter pylori Infection: A Case Report

Purpose: This case report outlines the successful eradication of chronic Helicobacter pylori (H. pylori) infection using a novel, “high-dose quad” salvage therapy approach. Gastroenterologists may consider using this approach for patients who have previously failed first- and second-line treatment regimens, as recommended by the American College of Gastroenterology (ACG). Summary: H. pylori infection is associated with multiple chronic gastrointestinal diseases, and patients who test positive for H. pylori should undergo treatment until eradication is achieved. Unfortunately, increasing antibiotic resistance to clarithromycin, metronidazole, and levofloxacin makes eradication of H. pylori challenging. This case describes an 84-year-old American woman with chronic H. pylori gastritis who failed two first-line treatment regimens (bismuth quadruple therapy and concomitant therapy), but responded to a novel, “high-dose quad” salvage regimen consisting of high-dose levofloxacin, amoxicillin, metronidazole, and high-dose acid suppression. Conclusion: This is the first time the “high-dose quad” regimen has been reviewed in the literature and is not FDA approved, but may be considered as an alternative salvage therapy in certain patients, based on the efficacy and safety observed in this case.