Significant Improvement In Survival Research Articles

A Meta-Analysis and Review of Radiation Dose Escalation in Definitive Radiation Therapy between Squamous Cell Carcinoma and Adenocarcinoma of Esophageal Cancer

Esophageal cancer, ranked as the eighth most prevalent cancer globally, is characterized by a low survival rate and poor prognosis. Concurrent chemoradiation therapy (CCRT) is the standard therapy in the non-surgical treatment of localized carcinoma of the esophagus. Nevertheless, the radiation doses employed in CCRT remain notably lower compared to the curative definite chemoradiation therapy utilized in the management of other carcinomas. In order to increase the local control rates and enhance the treatment outcomes, several clinical trials have used high-dose radiation to analyze the effect of dose escalation. Despite the integration of technically advanced RT schemes such as intensity-modulated radiation therapy (IMRT), the results of these trials have failed to demonstrate a significant improvement in overall survival or local progression-free survival. In this review, we investigated previous clinical trials to determine the ineffectiveness of radiation dose escalation in the context of CCRT for esophageal cancer. We aim to clarify the factors contributing to the limited efficacy of escalated radiation doses in improving patient outcomes. Furthermore, we delve into recent research endeavors, exploring prospective radiation dose modifications being altered based on the histological characteristics of the carcinoma. The exploration of these recent studies not only sheds light on potential refinements to the existing treatment protocols but also seeks to identify novel approaches that may pave the way for more efficacious and personalized therapeutic strategies for esophageal cancer management.

Prognostic impact of cooccurring mutations in FLT3-ITD pediatric acute myeloid leukemia

AbstractWe sought to define the cooccurring mutational profile of FLT3-ITD–positive (ITDpos) acute myeloid leukemia (AML) in pediatric and young adult patients and to define the prognostic impact of cooperating mutations. We identified 464 patients with FLT3-ITD mutations treated on Children’s Oncology Group trials with available sequencing and outcome data. Overall survival, event-free survival (EFS), and relapse risk were determined according to the presence of cooccurring risk stratifying mutations. Among the cohort, 79% of patients had cooccurring alterations across 239 different genes that were altered through mutations or fusions. Evaluation of the prognostic impact of the cooccurring mutations demonstrated that patients with ITDpos AML experienced significantly different outcomes according to the cooccurring mutational profile. Patients with ITDpos AML harboring a cooccurring favorable-risk mutation of NPM1, CEBPA, t(8;21), or inv(16) experienced a 5-year EFS of 64%, which was significantly superior to of 22.2% for patients with ITDpos AML and poor-risk mutations of WT1, UBTF, or NUP98::NSD1 as well to 40.9% for those who lacked either favorable-risk or poor-risk mutation (ITDpos intermediate; P < .001 for both). Multivariable analysis demonstrated that cooccurring mutations had significant prognostic impact, whereas allelic ratio had no impact. Therapy intensification, specifically consolidation transplant in remission, resulted in significant improvements in survival for ITDpos AML. However, patients with ITDpos/NUP98::NSD1 continued to have poor outcomes with intensified therapy, including sorafenib. Cooccurring mutational profile in ITDpos AML has significant prognostic impacts and is critical to determining risk stratification and therapeutic allocation. These clinical trials were registered at www.clinicaltrials.gov as NCT00002798, NCT00070174, NCT00372593, and NCT01371981.

Patient-reported outcomes (PROs) with talazoparib (TALA) plus enzalutamide (ENZA) vs. placebo (PBO) plus ENZA in men with metastatic castration-resistant prostate cancer (mCRPC): Subgroup analysis of patients with novel hormonal therapy (NHT) pretreatment in the TALAPRO-2 study.

116 Background: In TALAPRO-2 (NCT03395197), TALA +ENZA vs PBO + ENZA demonstrated significant improvement in radiographic progression-free survival, a manageable adverse event (AE) profile, and a delay in time to definitive clinical meaningful deterioration in global health status (GHS)/quality of life (QoL) overall and across all pre-specified subgroups. This post hoc analysis evaluated PROs in patients with prior NHT treatment. Methods: PROs were assessed on day 1 and scheduled visits (every 4 weeks until week 53 then every 8 weeks) until radiographic progression using the EORTC QLQ-C30 and its prostate cancer module, QLQ-PR25. PRO analyses, performed in NHT-pretreated/ patients for GHS/QoL functional and symptom scales, included on treatment comparison of overall change from baseline (per longitudinal repeated measures mixed-effects model). Results: Of the 805 men randomized and treated, 49 patients were included in this subgroup analysis (TALA + ENZA n= 22, PBO + ENZA n= 27). A statistically significant and clinically meaningful estimated overall change from baseline favored TALA + ENZA in physical functioning (20.5 [95% confidence interval {CI}: 8.8, 32.2]; P=0.0007), role functioning (20.4 [95% CI 4.8, 35.9]; P=0.0103), pain (32.9 [95% CI 50.3, 15.5]; P=0.0002), and constipation (12.5 [24.4, 0.6]; P=0.0399). No significant differences disfavoring TALA + ENZA were observed. Conclusions: In these subgroup analyses of NHT pretreated patients, significant differences in PROs favoring TALA + ENZA were observed. Results should be interpreted with caution given the small sample sizes and exploratory nature of this analysis. Clinical trial information: NCT03395197 .

Canine Parvoviral Enteritis Mortality in Shelter Dogs Receiving Conventional Medical Therapy Compared to Integrative Treatment with the Chinese Herbal Medicine, Zhi Li Tang: A Pilot Study

Canine parvoviral (CPV) enteritis is a contagious infection, which particularly affects young dogs, and is associated with high morbidity and mortality rates in the canine population. This study sought to determine whether including the Chinese herbal medicine formula, Zhi Li Tang (ZLT, Red Back Door), in conjunction with conventional therapy can decrease mortality of shelter dogs with CPV enteritis. Nineteen canine subjects from a shelter population diagnosed with CPV enteritis were randomly assigned to a Control Group which received conventional supportive treatment, or an Integrative Treatment Group which received ZLT along with conventional supportive treatment. Study duration was 14 days unless the subject died, or all clinical signs associated with CPV enteritis had resolved. The outcome measurement was a binary response of mortality within the 14-day trial. In the Control Group, there was a 43% (3/7) mortality rate compared to 0% mortality in the Integrative Treatment Group (12/12, all dogs recovered) within the 14-day study period. All subjects that survived in both study groups had resolution of CPV clinical signs by the end of the study. Despite the small sample size in this pilot study, there was a statistically significant (p=0.036) improvement in survival for the dogs receiving Zhi Li Tang in addition to conventional therapy when compared to the dogs receiving conventional therapy only. The results from this study suggest integrating ZLT with conventional treatment of CPV enteritis could reduce mortality from CPV infections in shelter dogs. Further investigation of these findings with larger studies is needed to confirm study results.

First-line PARP inhibitors (PARPi) with androgen receptor pathway inhibitors (ARPi) in metastatic castration-resistant prostate cancer (mCRPC): A systematic review and meta-analysis.

173 Background: The data for combining PARPi and ARPi in mCRPC have shown conflicting results. Here, we report a quantitative summary of benefits by clinically meaningful subgroups (HRR mutation status, BRCA mutation status) to guide the use of PARPi and ARPi combination in mCRPC setting. Methods: MEDLINE, EMBASE, and CENTRAL were systematically searched from each database’s inception through September 7, 2023. Phase III studies comparing PARPi + ARPi with ARPi + placebo in mCRPC were included. Radiographic progression-free survival (rPFS) and overall survival (OS) in patient subgroups based on HRR and BRCA mutation status were assessed. Hazard ratios for rPFS and OS with 95% CI were collected at the level of each trial, and a random-effects meta-analysis was conducted using an inverse variance approach. Subgroup differences were assessed and p-value of interaction &lt;0.1 was considered statistically significant. Results: The literature search identified 4976 studies from which 3 trials (11 references) – TALAPRO2, PROpel and MAGNITUDE met the inclusion criteria. A total of 2254 participants were eligible for analysis. PARPi + ARPi prolonged rPFS in patients with HRR mutations (HR: 0.55, 95%CI: 0.38-0.78) as well as in patients without HRR mutations (HR: 0.74, 95%CI: 0.63-0.88). There is no evidence of treatment interaction by HRR mutation status (p = 0.14). In patients harboring HRR mutations, improved rPFS was observed in those with BRCA mutations (HR: 0.28, 95%CI: 0.13-0.62) as well as those without BRCA mutations (HR: 0.72, 95%CI: 0.59-0.87). However, there is evidence that patients with BRCA mutations derived greater rPFS benefit as compared to patients without BRCA mutations (p =0.02). PARPi + ARPi showed no significant improvement in overall survival either in patients with HRR mutations (HR: 0.79, 95%CI: 0.59-1.05) or in patients without HRR mutations (HR: 0.92, 95%CI: 0.74-1.14). Conclusions: Genomic testing for HRR genes is mandatory to guide clinical decision making in mCRPC patients. Patients harboring BRCA mutations are most likely to derive clinically meaningful benefit from combination PARPi + ARPi treatment. [Table: see text]

Optimal timing of delayed cytoreductive nephrectomy in metastatic renal cell carcinoma during the immunotherapy era.

403 Background: The CARMENA study found no survival benefit from cytoreductive nephrectomy (CN) in poor-risk metastatic renal cell cancer (mRCC) patients treated with first line Sunitinib. Although retrospective studies have reported survival benefits with CN following immunotherapy (IO)-based therapy, the timing remains unclear. We aimed to investigate the ideal timing of CN following IO using the National Cancer Database. Methods: 783 patients with de novo mRCC were diagnosed between 2016 and 2020 who received upfront systemic therapy and underwent CN, 343 patients met our criteria. Patients were categorized into four groups based on the timing of nephrectomy: CN ≤3 months (Group A), 4 to 6 months (Group B), 7 to 9 months (Group C) and ≥ 10 months (Group D) following the initiation of IO-based therapy. Descriptive analysis was performed to examine the demographic and clinical characteristics. Follow up time was measured from the date of surgery to reduce bias. Kaplan-Meier plots were used to analyze survival curves, and a multivariable cox regression analysis was performed to explore associations between timing and survival. Results: 343 patients who received upfront IO -based therapy were divided into four groups: 104 (30%) in A, 114 (33%) in B, 74 (22%) in C and 51 (15%) in D. 71%were male, white (90%), age 40 – 64 (62%), comorbidity index 0 (70%), clear cell histology (69%), sarcomatoid (14%). 54% were treated in academia, 57% had bone metastasis, 50% had lung, 11% had liver, and 7% had brain metastases. 66% received only IO, and 34% received IO + TKI. No significant association between CN timing and survival observed in multivariate cox regression model. (HR 0.87, 95% CI: 0.5- 1.7, p = 0.84). Compared to group A, the HR were 0.96 (95% CI, 0.73 to 1.27; p=0.78), 0.77 (95% CI, 0.53 to 1.13; p=0.19), and 0.66 (95% CI, 0.37 to 1.20; p=0.17) respectively for groups B, C and D. Conclusions: Our study did not find significant survival improvement with an optimal timing of CN following IO-based therapy, while HRs were reduced after 6 months of delay, though insignificant. This could be due to the small sample size or other confounders.

Epidemiology, Characteristics, and Prognostic Factors of Primary Atypical Teratoid/Rhabdoid Tumors in the Spinal Canal: A Systematic Review.

Primary atypical teratoid/rhabdoid tumors (AT/RTs) in the spinal canal are rare central nervous system (CNS) neoplasms that are challenging to diagnose and treat. To date, there has been no standard treatment regimen for these challenging malignant tumors. Thus, we conducted this research to explore potential prognostic factors and feasible treatment modalities for improving the prognosis of these tumors. Articles were retrieved from the PubMed, MEDLINE, and Embase databases, using the keywords "atypical teratoid/rhabdoid tumor," "rhabdoid tumor," "spine," "spinal," "spinal neoplasm", and "spinal cord neoplasm." All eligible cases demonstrated SMARCB1-deficient expression validated by pathological examination. We collected and analyzed data related to clinical presentation, radiological features, pathological characteristics, treatment modalities and prognosis via Kaplan-Meier and Cox regression analyses. Thirty-six articles comprising 58 spinal AT/RT patients were included in the study. The median progression-free survival (PFS) and overall survival (OS) were 18 and 22 months, respectively. Kaplan-Meier analysis demonstrated significant survival improvements for OS in the nonmetastasis, male, radiotherapy and intrathecal chemotherapy groups as well as for PFS in the chemotherapy and radiotherapy groups. Multivariate analysis revealed that chemotherapy and radiotherapy were prognostic factors for improved PFS, and that intrathecal chemotherapy reduced the risk of mortality. Spinal AT/RTs are uncommon malignant entities with a dismal survival rate. Although our review is limited by variability between cases, there is some evidence revealing potential risk factors and the importance of systematic chemotherapy, intrathecal chemotherapy and radiotherapy in spinal AT/RT treatment modalities.

Pronóstico del trasplante cardiaco en pacientes con miocardiopatía hipertrófica y restrictiva. Análisis de un registro nacional

Introduction and objectivesPosttransplant outcomes among recipients with a diagnosis of hypertrophic cardiomyopathy (HCM) or restrictive cardiomyopathy (RCM) remain controversial. MethodsRetrospective analysis of a nationwide registry of first-time recipients undergoing isolated heart transplant between 1984 and 2021. One-year and 5-year mortality in recipients with HCM and RCM were compared with those with dilated cardiomyopathy (DCM). ResultsWe included 3703 patients (3112 DCM; 331 HCM; 260 RCM) with a median follow-up of 5.0 [3.1-5.0] years. Compared with DCM, the adjusted 1-year mortality risk was: HCM: HR, 1.38; 95%CI, 1.07-1.78; P=.01, RCM: HR, 1.48; 95%CI, 1.14-1.93; P=.003. The adjusted 5-year mortality risk was: HCM: HR, 1.17; 95%CI, 0.93-1.47; P=.18; RCM: HR, 1.52; 95%CI, 1.22-1.89; P<.001. Over the last 20 years, the RCM group showed significant improvement in 1-year survival (adjusted R2=0.95) and 5-year survival (R2=0.88); the HCM group showed enhanced the 5-year survival (R2=0.59), but the 1-year survival remained stable (R2=0.16). ConclusionsBoth RCM and HCM were linked to a less favorable early posttransplant prognosis compared with DCM. However, at the 5-year mark, this unfavorable difference was evident only for RCM. Notably, a substantial temporal enhancement in both early and late mortality was observed for RCM, while for HCM, this improvement was mainly evident in late mortality.Full English text available from:www.revespcardiol.org/en

Treatment decision for recurrences in non-small cell lung cancer during or after adjuvant osimertinib: an international Delphi consensus report.

Osimertinib is recommended by major guidelines for use in the adjuvant setting in patients with EGFR mutation-positive NSCLC following the significant improvement in disease-free survival observed in the Phase III ADAURA trials. Due to limited real-world data in the adjuvant setting, little guidance exists on how to approach potential recurrences either during or after the completion of the treatment. This study aimed to reach a broad consensus on key treatment decision criteria in the events of recurrence. To reach a broad consensus, a modified Delphi panel study was conducted consisting of two rounds of surveys, followed by two consensus meetings and a final offline review of key statements. An international panel of experts in the field of NSCLC (n=12) was used to provide clinical insights regarding patient management at various stages of NSCLC disease including patient monitoring, diagnostics, and treatment approach for specific recurrence scenarios. This study tested recurrences occurring 1) within or outside the central nervous system (CNS), 2) during or after the adjuvant-osimertinib regimen in NSCLC disease which is 3) amenable or not amenable to local consolidative therapy. Panellists agreed on various aspects of patient monitoring and diagnostics including the use of standard techniques (e.g., CT, MRI) and tumour biomarker assessment using tissue and liquid biopsies. Consensus was reached on 6 statements describing treatment considerations for the specific NSCLC recurrence scenarios. Panellists agreed on the value of osimertinib as a monotherapy or as part of the overall treatment strategy within the probed recurrence scenarios and acknowledged that more clinical evidence is required before precise recommendations for specific patient populations can be made. This study provides a qualitative expert opinion framework for clinicians to consider within their treatment decision-making when faced with recurrence during or after adjuvant-osimertinib treatment.

Health-related quality of life (HRQoL) in patients with metastatic colorectal cancer (mCRC) treated with sotorasib and panitumumab (pmab) versus trifluridine/tipiracil (T/T) or regorafenib (rego) in CodeBreaK 300.

10 Background: CodeBreaK 300 (NCT05198934) is a phase 3, multicenter, randomized, open-label study, evaluating sotorasib 960 mg (soto960) + pmab, sotorasib 240 mg (soto240) + pmab against investigator’s choice T/T or rego in patients with chemorefractory KRAS G12C-mutated mCRC. The study met its primary endpoint and demonstrated statistically significant improvement in progression-free survival with both doses of sotorasib. This analysis evaluated patient-reported outcomes (PROs) as secondary and exploratory endpoints in CodeBreaK 300. Methods: Change in PRO scores from study baseline through week 8 was compared for soto960+pmab and soto240+pmab vs the control group using a mixed effect model for repeated measures. PRO instruments included the Brief Fatigue Inventory, the Brief Pain Inventory, and the European Organisation for Research and Treatment of Cancer Core 30-item Quality of Life questionnaire. Time to deterioration (TTD) were assessed using Kaplan-Meier plots and Cox proportional hazard models. All analyses were conducted on patients with baseline and at least one post-baseline PRO score. Results: 160 pts were randomized 1:1:1 to soto960+pmab (n=53), soto240+pmab (n=53), or T/T or rego (n=54). Compliance rates for PRO assessments were high (&gt;83%) and similar across the three treatment groups. Least square (LS) mean changes from baseline in fatigue at its worst, pain at its worst, physical functioning (PF), and global health status (GHS)/QoL favored the two sotorasib dose groups (Table). The 95% confidence intervals (CI) suggested improvement in pain at its worst and PF for both sotorasib dose groups, and improvement in GHS/QoL for the soto960+pmab group versus the control group. TTD hazard ratios &lt; 1 indicated a trend in delayed deterioration for patients treated in both sotorasib dose groups. The 95% CIsuggested delays with respect to fatigue at its worst and PF for the soto240+pmab group. Conclusions: In CodeBreaK 300, both doses of sotorasib resulted in better HRQoL and a trend to decreased risk of deterioration vs the control group. In addition to improved clinical outcomes, these findings provide further evidence on the benefit of soto+pmab in patients with chemorefractory mCRC. Clinical trial information: NCT05198934 . [Table: see text]

Real-world analysis of patient characteristics and outcomes among patients with metastatic colorectal cancer receiving trifluridine/tipiracil (FTD/TPI) plus bevacizumab versus FTD/TPI monotherapy.

34 Background: Trifluridine/tipiracil (FTD/TPI) is a standard of care therapy for patients with refractory metastatic colorectal cancer (mCRC). Recently, FTD/TPI in combination with bevacizumab (BEV) was also approved in this setting based on outcomes from the phase 3 SUNLIGHT trial, including statistically significant improvements in overall survival (OS) compared with FTD/TPI. This study examined demographic/clinical characteristics, treatment duration, OS, and healthcare resource use (HCRU), including outpatient/emergency room (ER) visits and hospitalizations, among patients with mCRC receiving FTD/TPI+BEV versus FTD/TPI in a real-world setting. Methods: This was a retrospective study of adults with CRC, who initiated FTD/TPI as monotherapy or in combination with BEV, identified from the Cerner Enviza electronic health records (EHR) database (12/2020–06/2023). A manual chart review of patients’ medical records was conducted where last follow-up was defined as death or last encounter in the EHR. Descriptive statistics were reported for all study variables; Kaplan Meier curves were used to estimate OS. Results: Of 197 patients abstracted, 122 (62%) received FTD/TPI+BEV combination therapy and 75 (38%) FTD/TPI monotherapy. Mean age was similar between the FTD/TPI+BEV and FTD/TPI groups (60.2 y vs 61.8 y) and 66% vs 63%, respectively, were male. Mean Charlson Comorbidity Index was 8.9 for the FTD/TPI+BEV group vs 8.5 for the FTD/TPI group and body mass index was 26.9 kg/m2 vs 27.3 kg/m2, respectively. Most patients received treatment in the third or fourth line (65% FTD/TPI+BEV; 75% FTD/TPI). Median follow-up was 5.3 and 4.6 mo, respectively. Mean duration of treatment was 3.7 vs 2.7 mo for FTD/TPI+BEV vs FTD/TPI monotherapy (Table). Median OS (from FTD/TPI initiation to death) was 11.5 and 9.6 mo for FTD/TPI+BEV and FTD/TPI groups (number of deaths: 38 and 22), respectively. Patients receiving FTD/TPI+BEV had numerically more outpatient visits (20.5 vs 13.9), but similar ER visits (0.5 each) and slightly fewer hospitalizations (1.1 vs 1.2) compared with FTD/TPI, during follow-up. Overall HCRU costs were similar between groups (27,175 vs 27,891). Conclusions: This real-world study supports the value of FTD/TPI+BEV combination therapy vs FTD/TPI monotherapy as seen in the SUNLIGHT trial. Patients with FTDTPI+BEV were treated for longer duration with improved OS and no difference in trends for HCRU and associated costs. [Table: see text]

Treatment outcomes by stratifying the N-acetyl transferase 2 phenotype in pre-treated patients with advanced refractory biliary tract cancer treated with nanvuranlat, an L-type amino acid transporter inhibitor: An ad-hoc analysis of a randomized, double-blind, placebo-controlled phase 2 study.

483 Background: L-type amino acid transporter 1 (LAT1, SLC7A5) is overexpressed in cancer cells, leading to aggressive proliferation and lymphatic metastases. In a placebo-controlled, randomized phase 2 trial involving patients with pre-treated, advanced, refractory biliary tract cancer (BTC), monotherapy with nanvuranlat (JPH203), a selective LAT1 inhibitor, demonstrated a significant improvement in progression free survival (PFS) as the primary endpoint compared to placebo. The safety profile was comparable between nanvuranlat and placebo treated patients, except for a higher rate of cholangitis in the nanvuranlat group. Nanvuranlat is metabolized to its main inactive, off-target metabolite, Nac-JPH203 by N-acetyl transferase 2 ( NAT2). Since the NAT2 unknown patients mislead the benefit and risk ratio of nanvuranlat treatment, an ad-hoc analysis was conducted in enriched NAT2 non-rapid (NR) phenotype patients who slowly produced Nac-JPH203 in plasma. Methods: Among 104 (full analytical set (FAS) - nanvuranlat:69 &amp; placebo:35) enrolled patients, 25 with unknown NAT2 phenotype were enrolled prior to an amendment to only enroll NAT2-NR phenotype. Subsequently, further analysis was conducted to determine the NAT2 phenotypes of these 25 patients. Results: Among the 25 NAT2 unknown patients, 16 and 9 patients were assigned to nanvuranlat or placebo, respectively. NAT2 ad hoc analysis recorded those 9 patients in nanvuranlat and 5 in placebo as NAT2 NR, and 7 patients in nanvuranlat and 4 in placebo were NAT2 rapid (R). As a result, number of NAT2 NR patients was increased from 81 to 94. Efficacy analysis of this enriched population (FAS-NR-nanvuranlat:63 &amp; placebo:31) revealed a significant improvement in PFS. With respect to cholangitis, 8 all-grade (12.7%) and 7 over grade 3 (11.1%) were documented in the FAS-NR population. In the FAS-R population, 2 all grades (28.5%) and 2 over grade 3 (28.5%) were observed (Table). Conclusions: By classifying BTC patients by NAT2 phenotype in this ad hoc analysis, the LAT1 inhibitor nanvuranlat further improved its clinical efficacy and safety in the NAT2 NR population. Therefore, selecting NAT2 NR for nanvuranlat treatment may improve the risk -benefit ratio. Clinical trial information: UMIN000034080 . [Table: see text]

Inhaled nanoparticles for treating idiopathic pulmonary fibrosis by inhibiting honeycomb cyst and alveoli interstitium remodeling

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with high mortality. The Food and Drug Administration-approved drugs, nintedanib and pirfenidone, could delay progressive fibrosis by inhibiting the overactivation of fibroblast, however, there was no significant improvement in patient survival due to low levels of drug accumulation and remodeling of honeycomb cyst and interstitium surrounding the alveoli. Herein, we constructed a dual drug (verteporfin and pirfenidone)-loaded nanoparticle (Lip@VP) with the function of inhibiting airway epithelium fluidization and fibroblast overactivation to prevent honeycomb cyst and interstitium remodeling. Specifically, Lip@VP extensively accumulated in lung tissues via atomized inhalation. Released verteporfin inhibited the fluidization of airway epithelium and the formation of honeycomb cyst, and pirfenidone inhibited fibroblast overactivation and reduced cytokine secretion that promoted the fluidization of airway epithelium. Our results indicated that Lip@VP successfully rescued lung function through inhibiting honeycomb cyst and interstitium remodeling. This study provided a promising strategy to improve the therapeutic efficacy for IPF.

Dental care for cardiac transplant patients in the UK.

Cardiac transplantation replaces a severely damaged non-functioning heart with a healthy heart from a donor. Within the UK, the number of cardiac transplants being performed each year is increasing, with significant improvements in longer-term survival. Dental professionals are therefore more likely to see and manage these patients in the pre- and post-transplant periods. This paper proposes a protocol for the dental management of these patients, reinforced by a case series from Scotland and London.

Clinical characteristics and novel strategies of immune checkpoint inhibitor rechallenge therapy for non-small cell lung cancer: a comprehensive review.

Treatment of non-small-cell lung cancer (NSCLC) has entered the immunotherapy era, marked by significant survival improvements due to the use of immune checkpoint inhibitors (ICIs). However, owing to factors, such as disease progression, long-term use, and side effects, some patients discontinue immunotherapy, resulting in limited subsequent treatment option and a negative impact on their survival and quality of life. We have collected relevant data which reveal that ICI rechallenge may be an effective clinical strategy. However, many factors affect the efficacy of rechallenge, including patient characteristics, initial treatment drugs, treatment duration, efficacy, toxicity, and side effects. Additionally, the side effects of rechallenge and mechanisms of reversing drug resistance play crucial roles. Identifying suitable candidates, optimizing treatment plans and duration, enhancing treatment efficacy, and minimizing toxicity and adverse effects in rechallenges are pressing clinical needs. Addressing these issues can provide guidance for the clinical use of immunotherapy rechallenges to better serve patients. This review focuses on the clinical considerations and strategies for immune therapy rechallenges in NSCLC.

A computational examination of the therapeutic advantages of fourth-generation ALK inhibitors TPX-0131 and repotrectinib over third-generation lorlatinib for NSCLC with ALK F1174C/L/V mutations.

Background: In non-small-cell lung cancer (NSCLC), a pivotal factor in promoting cancer development is the rearrangement in the anaplastic lymphoma kinase ALK gene, resulting in elevated ALK protein expression. F1174C/L/V is the acquired secondary resistant mutation in ALK. Significant survival improvements have been seen while tyrosine kinase inhibitors specifically target ALK. Nevertheless, the emergence of drug resistance hinders the clinical effectiveness of these drugs. Objective: This research sought to find the binding affinity/inhibitory effects of the existing drug lorlatinib (LOR) and upcoming TPX-0131 (zotizalkib/TPX) and repotrectinib (TPX-0005/REP) inhibitors against ALK F1174C/L/V mutations using computational approaches to identify potential strategies over resistance. Methods: We conducted molecular docking, molecular dynamics simulation, and MMPBSA calculations to investigate how compact macrocyclic inhibitors, such as TPX-0131 and repotrectinib, fit within the ATP-binding boundary and differ from LOR. Results: Our results demonstrated that TPX-0131 and repotrectinib contributed to higher binding energy in F1174C and F1174L mutations than LOR. Repotrectinib showed greater binding energy in the F1174V mutation, whereas LOR and TPX-0131 exhibited similar binding energy. However, all three inhibitors showed significant binding energy toward F1174C/L/V mutations found in NSCLC. Conclusion: This comparative study of the potential binding effects of fourth-generation inhibitors TPX-0131 and repotrectinib and third-generation inhibitor LOR for ALK F1174C/L/V mutations revealed the atomistic insights of the binding mechanism. These computational findings enable us to carry out further research for the clinical implementation of fourth-generation ALK inhibitors on ALK-positive NSCLC.

Deciphering the role of adjuvant therapy in melanoma and its actual benefits.

Numerous clinical trials have demonstrated a significant improvement in recurrence-free survival among melanoma patients receiving high-dose interferon-α, immune checkpoint inhibitors (pembrolizumab, nivolumab), and BRAF/MEK inhibitors (dabrafenib-trametinib). This study aimed to investigate whether these findings hold true in real-world conditions for patients with stage III and IV melanoma. In particular, the study explores the efficacy and side effects of adjuvant therapies, focusing on anti-PD-1 antibodies and BRAF/MEK inhibitors. While clinical trials have shown comparable efficacy, differences in side-effect profiles, especially the persistence of immune-related adverse events with anti-PD-1 antibodies, highlight the need for careful consideration in adjuvant settings. In the absence of established biomarkers for guiding adjuvant therapy decisions, it becomes imperative to transparently communicate the advantages and disadvantages of drug administration to patients. The study also delved into the impact of melanoma subtype and BRAF mutation status on the effectiveness of adjuvant therapy, emphasizing the need for further investigation.

Adjuvant Abemaciclib Plus Endocrine Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, High-Risk Early Breast Cancer: Results From a Preplanned monarchE Overall Survival Interim Analysis, Including 5-Year Efficacy Outcomes.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in a significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) that persisted beyond the 2-year treatment period in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer (EBC). Here, we report 5-year efficacy results from a prespecified overall survival (OS) interim analysis. In the intent-to-treat population, with a median follow-up of 54 months, the benefit of abemaciclib was sustained with hazard ratios of 0.680 (95% CI, 0.599 to 0.772) for IDFS and 0.675 (95% CI, 0.588 to 0.774) for DRFS. This persistence of abemaciclib benefit translated to continuous separation of the curves with a deepening in 5-year absolute improvement in IDFS and DRFS rates of 7.6% and 6.7%, respectively, compared with rates of 6% and 5.3% at 4 years and 4.8% and 4.1% at 3 years. With fewer deaths in the abemaciclib plus ET arm compared with the ET-alone arm (208 v 234), statistical significance was not reached for OS. No new safety signals were observed. In conclusion, abemaciclib plus ET continued to reduce the risk of developing invasive and distant disease recurrence beyond the completion of treatment. The increasing absolute improvement at 5 years is consistent with a carryover effect and further supports the use of abemaciclib in patients with high-risk EBC.

Serial cytoreductive surgery and survival outcomes in recurrent adult-type ovarian granulosa cell tumors

BackgroundFew studies have evaluated the role of cytoreductive surgery in patients with recurrent adult granulosa cell tumors of the ovary. Despite a multitude of treatment modalities in the recurrent setting, the optimal management strategy is not known. Cytoreductive surgery offers an attractive option for disease confined to the abdomen/pelvis. However, few studies have evaluated the role of surgery compared to systemic therapy alone following the first recurrence and subsequent disease progressions. ObjectiveTo determine the impact of secondary, tertiary, and quaternary cytoreductive surgery on survival outcomes in recurrent adult granulosa cell tumors of the ovary. Study DesignThis is a multicenter, retrospective cohort study evaluating patients with recurrent adult granulosa cell tumor of the ovary enrolled in the MD Anderson Rare Gynecologic Malignancy Registry from 1970 to 2022. Study inclusion criteria consisted of histology-proven recurrent disease, at least one documented recurrence, and treatment/treatment planning at MD Anderson Cancer Center or Lyndon B. Johnson General Hospital. The primary exposure was cytoreductive surgery and the outcomes of interest were progression-free survival and overall survival. Survival analyses were restricted to eligible patients with resectable disease without medical barriers to surgery at each progression episode. Demographic and Clinicopathologic characteristics were summarized using descriptive statistics. Progression-free survival (after first, second, and third progression) and overall survival were estimated with methods of Kaplan and Meier and were modeled via cox proportional hazards regression. Multivariable analyses were performed for progression-free survival after first progression and overall survival. ResultsAmong the 369 patients with adult granulosa cell tumors of the ovary in the registry, there were 149 patients who met the study inclusion criteria. Secondary cytoreductive surgery was associated with a significant improvement in progression-free survival on univariable (HR 0.37, 95% CI 0.17 – 0.81, p = 0.01) and multivariable analyses (HR 0.42, 95% CI 0.19 – 0.92, p = 0.03). Those who underwent secondary cytoreductive surgery had a significantly improved median overall survival compared to those who did not undergo cytoreductive surgery (181.92 months vs 61.56 months, respectively; p = 0.002). Overall survival benefit remained statistically significant on multivariable analysis (HR 0.28, 95% CI 0.11 – 0.67, p = 0.004). Tertiary cytoreductive surgery was similarly associated with a significant improvement in progression-free survival (HR 0.43, 95% CI 0.26 – 0.70, p = 0.001). Despite a similar trend, quaternary cytoreductive surgery was not associated with a significant improvement in progression-free survival (HR 0.74, 95% CI 0.42 – 1.26, p = 0.27). ConclusionsAmong those with resectable disease and no medical contraindications to surgery, cytoreductive surgery may offer a beneficial impact on progression-free survival and overall survival in patients with recurrent adult granulosa cell tumor of the ovary.

Statin therapy enhances survival in unresectable stage III lung squamous cell carcinoma with concurrent chemoradiotherapy.

To evaluate the impact of statin use on overall survival and lung cancer-specific survival in patients with unresectable stage III lung squamous cell carcinoma (LSCC) undergoing standard concurrent chemoradiotherapy (CCRT). Using data from the Taiwan Cancer Registry Database and National Health Insurance Research Database, this propensity score matching cohort study analyzed the influence of statin use during CCRT on overall survival and lung cancer-specific survival. Statin use during CCRT was independently associated with significant improvements in overall survival and lung cancer-specific survival. The adjusted hazard ratio (95% CI) for all-cause mortality in the statin group versus the non-statin group was 0.60 (0.53-0.68, P < 0.0001). Similarly, the adjusted hazard ratio for lung cancer-specific mortality in the statin group versus the non-statin group was 0.61 (95% CI, 0.54-0.70, P < 0.0001). Pravastatin and fluvastatin exhibited the greatest potential in reducing lung cancer-specific mortality among statins, with rosuvastatin following closely behind. Atorvastatin demonstrated comparable effectiveness, while simvastatin and lovastatin displayed lower efficacy in this regard. Furthermore, a dose-response relationship was observed, with higher cumulative defined daily doses and greater daily intensity of statin use associated with reduced mortality. Our study provides evidence that statin use during CCRT for unresectable stage III LSCC is associated with significant improvements in overall survival and lung cancer-specific survival. Pravastatin showed the highest potential for reducing lung cancer-specific mortality among statins, followed by rosuvastatin. Atorvastatin and fluvastatin exhibited similar effectiveness, while simvastatin and lovastatin demonstrated lower efficacy. The dose-response relationship showed higher statin utilization in reducing lung cancer-specific mortality.