bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of the Charlson Comorbidity Index for the prediction of 30-day and 1-year mortality among patients who underwent hip fracture surgery
Authors: de Haan Eveline , van Oosten Benthe , van Rijckevorsel Veronique. A. J. I. M. , Kuijper T. Martijn , de Jong Louis , Roukema Gert R.
Published: July 2024

Introduction

The aim of our study was to validate the original Charlson Comorbidity Index (1987) (CCI) and adjusted CCI (2011) as a prediction model for 30-day and 1-year mortality after hip fracture surgery. The secondary aim of this study was to verify each variable of the CCI as a factor associated with 30-day and 1-year mortality.

Methods

A prospective database of two-level II trauma teaching hospitals in the Netherlands was used. The original CCI from 1987 and the adjusted CCI were calculated based on medical history. To validate the original CCI and the adjusted CCI, the CCI was plotted against the observed 30-day and 1-year mortality, and the area under the curve (AUC) was calculated.

Results

A total of 3523 patients were included in this cohort study. The mean of the original CCI in this cohort was 5.1 (SD ± 2.0) and 4.6 (SD ± 1.9) for the adjusted CCI. The AUCs of the prediction models were 0.674 and 0.696 for 30-day mortality for the original and adjusted CCIs, respectively. The AUCs for 1-year mortality were 0.705 and 0.717 for the original and adjusted CCIs, respectively.

Conclusions

A higher original and adjusted CCI is associated with a higher mortality rate. The AUC was relatively low for 30-day and 1-year mortality for both the original and adjusted CCIs compared to other prediction models for hip fracture patients in our cohort. The CCI is not recommended for the prediction of 30-day and 1-year mortality in hip fracture patients.
Exergetic performance evaluation of louvered finned solar air heater: an experimental investigation
Authors: Chand Subhash , Ghritlahre Harish Kumar , Singh Ajay Partap
Published: July 2024

Solar energy is a promising source of renewable energy, and solar air heaters are an important application for utilizing this energy source. This study investigates the exergetic performance of a louvered fin solar air heater (LFSAH) through experimental analysis conducted during day time from 9 am to 3 pm under identical operating and metrological parameters. Exergy analysis based on the 2nd law of thermodynamics is used to assess the quality of exergy losses and useful energy output and is deemed suitable for LFSAH design. The study experimentally examines the exergetic performance of LFSAH with various fin spacings and compares the results with those of a plane solar air heater (PSAH). The exergy efficiency is optimized by considering the fin spacing (ranging from 2 to 5 cm) and mass flow rate (MFR) (ranging from 0.007 to 0.0158 kg/s) through an exergy analysis of internal and exterior exergy losses. Based on the result analysis, the LFSAH’s maximum exergy efficiency was achieved at 3.31% for a fin spacing of 2 cm and a MFR of 0.007 kg/s. The study found that incorporating louvered fins into the SAH substantially improves its exergetic performance compared to the PSAH.
BY101921: Restoring interferon signaling and anti-tumor immunity through PARP7 inhibition.
Authors: Yu Jinming , Sun Yuping , Wei Yonggang , Ye Fei , Zhu Yuqin , Chen Yang , Liu Rui
Published: July 2024

3123

Background: PARP7( TIPARP), a member of monoPARP family, catalyzes ADP-ribose transfer to specific amino acids within itself and other substrate proteins, utilizing nicotinamide adenine dinucleotide (NAD+) as substrate. It plays a vital role in various biological processes such as gene expression, protein degradation, and cellular stress response. PARP7 amplification has been observed in various cancers, including squamous cell carcinoma, ovarian cancer, breast cancer, and pancreatic ductal adenocarcinoma. Over expression of PARP7 correlates with reduced survival in squamous cell carcinoma. PARP7's MARylation of α-tubulin induces microtubule instability, promoting proliferation and migration of ovarian cancer cells. As a negative regulator of tumor cell nucleic acid sensing, PARP7 inhibits TBK1 through. This, in turn, hampers the cGAS-STING signal pathway and downregulates the type Ⅰ interferon expression. BY101921, developed by Chengdu Baiyu Pharmaceutical, is a highly selective PARP7 inhibitor demonstrating significant anti-tumor effect in vitro and in vivo, both alone and in combination with anti-PD-1. Methods: Enzymatic evaluation was conducted on BY101921 to assess its selectivity among major PARP family members. PK studies were investigated in both mouse and dog species. The anti-tumor activity of BY101921, both as a monotherapy and in combo with anti-PD-1, was investigated in NCI-H1373 and CT26 tumor-bearing mice, respectively. In terms of anti-tumor mechanism, pSTAT1, IFN-β and CXCL10 levels were analyzed in RAW264.7 cells and CT26 tumor-bearing tissues. In addition, the effect of BY101921 on the type Ⅰ interferon signaling pathway was systematically evaluated. Results: BY101921 demonstrated outstanding selectivity as a PARP7 inhibitor, displaying limited off-target effects on PARP1/2, reducing the risk of systemic toxicity, especially hematologic effects. In mice and dogs, BY101921 revealed favorable PK characteristics following oral administration. In vivo, BY101921 exhibited potent inhibition of tumor growth as a monotherapy, and its combination with anti-PD-1 further enhanced its anti-tumor efficacy, with excellent tolerability in animals. Mechanism of action studies showed that BY101921 generated an anti-tumor immune response by upregulating pSTAT1 levels and promoting the secretion of IFN-β and CXCL10, thereby restoring the type Ⅰ interferon signaling pathway. Conclusions: BY101921, a potent and selective PARP7 inhibitor, demonstrates significant anti-tumor efficacy both as a monotherapy and in combo with anti-PD-1, while maintaining excellent tolerability in animal models. With favorable drug-like properties and a promising safety profile, BY101921 holds potential as an enhanced therapeutic option for cancer patients. At present, clinical studies investigating BY101921 as a single agent and in combo with anti-PD-1 are in the recruitment phase.
Avelumab first-line maintenance (1LM) for advanced urothelial carcinoma (aUC): Long-term outcomes from JAVELIN Bladder 100 in patients (pts) with low tumor burden.
Authors: Bellmunt Joaquim , Powles Thomas , Park Se Hoon , Voog Eric , Valderrama Begoña Pérez , Gurney Howard , Ullén Anders , Loriot Yohann , Sridhar Srikala S. , Tsuchiya Norihiko , Sternberg Cora N. , Aragon-Ching Jeanny B. , Petrylak Daniel P. , Climent Duran Miguel A. , Tyroller Karin , Hoffman Jason , Jacob Natalia , Grivas Petros , Gupta Shilpa
Published: July 2024

4566

Background: In the JAVELIN Bladder 100 phase 3 trial, avelumab 1LM + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone in pts with aUC that had not progressed with 1L platinum-based chemotherapy (PBC). Results led to the incorporation of avelumab 1LM into international guidelines. Prior analyses have shown that low tumor burden (eg, nonvisceral metastases or lymph node [LN]-only disease) is associated with better outcomes in pts with aUC receiving immune checkpoint inhibitors. We report post hoc analyses of efficacy and safety in subsets of pts with low tumor burden from JAVELIN Bladder 100. Methods: Eligible pts with unresectable locally advanced (LA) or metastatic UC without progression after 1L PBC were randomized 1:1 to receive avelumab + BSC (n=350) or BSC alone (n=350). The primary endpoint was OS measured from randomization; secondary endpoints included PFS and safety. In this post hoc analysis, pts with nonvisceral metastases included those with LA disease or only nonvisceral disease, including bone metastasis, at randomization. Results: In the avelumab + BSC and BSC alone arms, 159 and 159 pts had nonvisceral metastases and 51 and 51 pts had LN-only disease, of whom 42 and 35 pts had LN-only disease in the pelvic/retroperitoneal area. At the efficacy data cutoff (June 4, 2021), median follow-up was ≥38 mo in both arms (≥2 y in all pts). In all subgroups, OS and PFS were prolonged with avelumab + BSC vs BSC alone (Table). Incidence of treatment-related adverse events (TRAEs) with avelumab were similar across subgroups. In the avelumab + BSC and BSC alone arms, subsequent anticancer drug treatment was received by 90 (56.6%) vs 119 pts (74.8%) with nonvisceral metastases, 27 (52.9%) vs 39 pts (76.5%) with LN-only disease, and 22 (52.4%) vs 27 pts (77.1%) with pelvic/retroperitoneal LN-only disease. Conclusions: Exploratory analyses suggest that avelumab 1LM has pronounced efficacy and manageable toxicity in pts with aUC who have low tumor burden, supporting its use as a standard of care in this setting. Clinical trial information: NCT02603432 . [Table: see text]
A randomised, controlled, multicentre trial of imiquimod versus radiotherapy for lentigo maligna.
Authors: Hong Angela M , Lo Serigne N , Fogarty Gerald B , Stretch Jonathan , Wang Wei , Penas Pablo Fernandez , Martin Richard CW , Foote Matthew C , Soyer Hans Peter , Ruben Jeremy , Mar Victoria , Rocha Lilian , Wratten Christopher , Collgros Helena , Pereira Amanda Regio , Melhoranse Gouveia Bruna , Scolyer Richard A , King Madeleine T , Guitera Pascale
Published: July 2024

9502

Background: Lentigo maligna (LM) is a form of melanoma in situ that occurs mainly on sun exposed skin. For patients with LM who are not suitable for surgery due to location, size, patient preference or co-morbidities, topical imiquimod or radiotherapy are alternative non-surgical treatments. There are no prospective randomized controlled trial data to form the basis of any recommendations for the management of LM. This multi-institutional, international randomized phase 3 trial evaluated the efficacy and safety of imiquimod verus radiotherapy for patients with LM. The primary hypothesis was that treatment of LM with topical imiquimod would result in fewer treatment failures than radiotherapy. Methods: Patients aged > 18 years old with LM not suitable for surgery were randomly assigned (1:1) to imiquimod or radiotherapy. The primary endpoint was treatment failure within 24 months. Secondary endpoints included development of invasive disease within the area, side effects and patient-reported quality of life (QOL) assessed with validated questionnaires (skin-specific Skindex-16 and generic EQ-5D-5L). Results: Between August 2015 and November 2021, 126 patients were randomised from 8 centres (imiquimod 60, radiotherapy 58 in final analysis). The median age was 72 years and 94.9% of lesions were on the head and neck area. Median follow-up was 27 months (range 3-62 months). Six (10.5%) patients in the imiquimod group and 12 (24.0%) patients in the radiotherapy group developed recurrence within 24 months (OR 2.68, 95% CI, 0·92-7.8, p = 0.063). Median time to recurrence was not reached in either group. Treatment failure was significantly different within the subgroup of patients who had reflectance confocal microscopy (RCM) follow up of the LM (imiquimod 4/46, 8.7% radiotherapy 13/52 25.0%; OR 3.50 95% CI 1.05-11.65, p = 0.033). Only one RCM feature was associated with failure at 24 months and significantly different between treatment groups : the presence of atypical round cells at the dermal-epidermal junction (6.9 % of imiquimod failure and 27% of radiotherapy failure: p = 0.035). There were no differences between trial groups in patient-reported skin symptoms (itching, burning/stinging, pain, irritation), skin-specific emotional and functional QOL impacts, or generic QOL at any time points. Conclusions: Both imiquimod and radiotherapy are valid, well-tolerated and efficient non-surgical options for LM. There is no significant difference in the acute or long term QoL for the two treatments. Clinical trial information: NCT02394132 .
A phase 2 clinical trial of regorafenib in patients with advanced pretreated melanoma (RegoMel).
Authors: Dirven Iris , Vounckx Manon , Kessels Jolien Isabel , Vanlaer Nathalie , von Kemp Berlinde , Fasolino Giuseppe , Neyns Bart
Published: July 2024

9518

Background: A majority of advanced melanoma patients (pts) will eventually progress despite treatment with PD-(L)1/CTLA-4/LAG-3 immune checkpoint- and BRAF-/MEK-inhibitors (BRAF-/MEKi; restricted to BRAFV600-mutant pts). Retrospective case observations indicate activity of regorafenib (REGO) in this setting (1). Methods: This single center, prospective, two-stage, phase 2 clinical trial, investigates REGO 80 mg QD (continuous dosing) in pts with advanced melanoma refractory to standard of care treatment. Objective response rate (ORR, by RECIST v1.1) served as the primary endpoint. The sample size (n=16) was determined according to a Simon’s two-stage minimax statistical design; the trial is considered positive if 3 or more responses are observed. Response assessments are performed every 6 weeks (q6w) during the first 24w, and q12w thereafter. Secondary endpoints are safety, progression free survival (PFS) and overall survival (OS). REGO treatment beyond first progression was permitted if considered to be of potential clinical benefit. Database lock was on Jan 9th, 2024. Results: From Oct 2022 to Sep 2023, 16 pts were enrolled (9 male, med age 61y; AJCC stage IIIC: 1; IV-M1a: 1; -M1c: 12, -M1d: 2, ECOG PS 0-1: 100%). Oncogenic driver mutations were identified in BRAFV600: 7-, KIT: 3-, NF1: 3-, NRASQ61K: 2-, RAF fusion: 1 pt. The ORR was 31% (: 5 partial responses (PR) - 4 confirmed in 3 KIT-,and 1 BRAFV600 -mut pt; and 1 unconfirmed in a BRAFV600-mut pt). One KIT-mut pt had previously progressed on imatinib. The median duration of response (DoR) was 29.7w (range 12-44). The disease control rate (DCR) was 56%. The median time on REGO monotherapy was 12.3w [95% CI 2.3-22.3], treatment is ongoing in 3 pts. At first progression, 6 BRAFV600-mut pts continued REGO in association with BRAF-/MEKi, in 5 response evaluable pts there is an ORR of 40% (2 PR with DoR of 24w and 30w) and DCR of 80%. At database lock, 11 pts were alive with a median follow up of 48.4w (range 24-63), 13 pts have progressed on REGO monotherapy (median PFS 11.9w [95% CI 3.5-20.3]; median OS was not reached). There were no grade ≥ 4 treatment related adverse events (TRAE); 56% of pts had at least one grade 3 TRAE, including hypertension (n=3) and maculo-papular rash (n=2). There was one toxicity-related REGO discontinuation. Conclusions: This phase 2 clinical trial on REGO monotherapy in advanced pretreated melanoma patients met its primary endpoint and demonstrated significant anti-tumor activity in KIT-mutant melanoma patients. In BRAFV600-mutant melanoma, continuation of REGO in combination with BRAF-/MEK-inhibitors demonstrated promising activity in patients who previously progressed on BRAF-/MEK-inhibitors for which further prospective investigation is ongoing. 1. Dirven I. et al. ESMO Meeting 2023. Clinical trial information: NCT05370807 .
The 31-GEP to identify patients with localized cutaneous melanoma at the highest risk of metastasis to the central nervous system.
Authors: Hasanov Merve , Martin Brian , Hasanov Elshad , Wu Richard Cheng Han , Goldberg Matthew S. , Cook Robert W. , Kendra Kari Lynn , Jarell Abel
Published: July 2024

9530

Background: Cutaneous melanoma (CM) metastasis to the central nervous system (CNS) has a poor prognosis; however, treatment of CNS metastasis while asymptomatic is associated with better outcomes. CNS imaging is not routinely recommended for patients with early-stage CM (i.e., AJCC stage I–II), yet ˜14% of patients with stage II melanoma will develop CNS metastases. The 31-gene expression profile test (31-GEP) identifies patients at a low (Class 1A), intermediate (Class 1B/2A), or high risk (Class 2B) of tumor recurrence and metastasis. We evaluated the association of CNS metastasis with the 31-GEP test result for the purpose of directing CNS-directed imaging to detect metastasis earlier and, thus, improve outcomes. Methods: A retrospective analysis of patients clinically tested with the 31-GEP from 2013-2017. Patients were included in the study if they had clinical or pathological AJCC stage I-II CM (n=1,662). Kaplan-Meier analysis was used to estimate 5-year recurrence-free survival (RFS), and the log-rank test was used to compare survival between groups. Patients with non-CNS metastasis were censored at the time of recurrence. Univariate analysis to identify predictors of CNS metastasis was performed for tumor location, mitotic rate, Breslow thickness, ulceration status, tumor-infiltrating lymphocytes, age, sex, regression, lymphovascular invasion, tumor subtype, and 31-GEP results. Only significant (p<0.01) factors in univariate analysis were included in Cox multivariable analysis. Results: Median follow-up time was 4.6 years (range: 0.02-14.5 years). Patients with a CNS metastasis tended to have thicker tumors (median 1.1 vs. 0.8, p=0.003), higher mitotic rate/mm2 (median 2.5 vs. 1.0, p<0.001) and a higher proportion of males (73% vs. 55%, p=0.03) than patients that did not develop CNS metastasis. Patients with a Class 2B result were significantly more likely to develop CNS metastasis (7.4% [15/202]) relative to patients with a Class 1B/2A (1.7% [5/291]) or Class 1A (0.9% [10/1,169], p<0.001) 31-GEP result. Patients with a Class 2B result had significantly lower 5-year RFS than patients with a Class 1B/2A or Class 1A result (91.6% vs. 98.2% vs. 99.1%, p<0.001) and had shorter times to CNS metastases (1.5 yrs. vs. 4.2 yrs. vs. 3.4 yrs. p<0.001). In multivariable analysis, only the 31-GEP Class 2B (HR=9.42, p<0.001) result was a significant predictor of CNS metastasis; mitotic rate, Breslow thickness, and ulceration were not significantly predictive. Conclusions: Under multivariable analysis, the 31-GEP was the only significant predictor of CNS metastasis, and CNS metastasis occurred early (1.5 yrs). Patients with early-stage I-II CM and a Class 2B result should be considered for CNS imaging to enable asymptomatic detection of CNS metastasis and, thus, improve survival relative to symptomatic CNS metastasis.
High dose bolus (HDB) interleukin-2 (IL2) and concurrent low dose ipilimumab followed sequentially by nivolumab in patients with advanced melanoma after failure of anti-PD1-based immunotherapy and BRAF-MEK inhibition.
Authors: Tarhini Ahmad A. , Eroglu Zeynep , Galuia Mariem , Eljilany Islam , Kalos Denise , Schell Michael J , Tetteh Leticia , Abraham Edith , Richards Allison , Brohl Andrew Scott , Khushalani Nikhil I. , Markowitz Joseph
Published: July 2024

9543

Background: Options are limited for patients with advanced metastatic melanoma who have disease progression following anti-PD1-based immunotherapy and BRAF-MEK inhibition (if BRAF V600 mutant). Evidence supports synergism between IL2 and CTLA4 blockade in enhancing the immunogenicity of the tumor microenvironment and therapeutic susceptibility to PD1 blockade. Methods: We conducted a phase II study of HDB IL2 in combination with LD ipilimumab followed sequentially by nivolumab in patients with advanced inoperable stage III or stage IV melanoma with progression after anti-PD1-based immunotherapy and BRAF-MEK inhibitors. Treatment consisted of up to 3 courses (One cycle is 21 days and one course is 4 cycles). HDB IL2 and concurrent ipilimumab 1 mg/kg were given during week 1 of the initial 2 cycles of each course. Nivolumab was given during week one of the 3rd cycle of each course. Patients without evidence of disease progression (RECIST v.1.1) or limiting toxicities (CTCAE v.5) were offered additional courses of treatment. A Simon two-stage minimax design (Simon, 1989) was followed. We report the outcomes for Stage I. Results: 12 pts (5 female, 7 male) with metastatic melanoma (2M1a, 1M1b, 6M1c, 3M1d) were treated. Median age 53 years (33 – 69), 11 cutaneous (including 1 acral) and 1 mucosal primary. Tumor mutation status: 4BRAF (V600E), 2NRAS (p.Q61K), 1NF1. The median number of prior regimens for metastatic melanoma was 3 (range 1 - 5). Eight patients previously received ipilimumab as monotherapy or in combination with anti-PD1. On study, the median number of doses of IL2 was 9 during cycle 1 and 7 during cycle 2. A median of 2 doses of ipilimumab and 1 dose of nivolumab were given as part of the combination regimen. Among the 11 evaluable patients (completed 1 course of systemic therapy), the response rate was 2/11 (18.2 %; 95% CI: 2.3% – 51.8%); 1CR, 1 PR, 5 SD, 4 PD and 1 NE as best response. After a median follow up of 39 months, both responses are ongoing (at 10+ and 37+ months), median progression free survival (PFS) was 3 months and median overall survival (OS) was 18.8 months. One-year PFS and OS were 17% (95% CI: 4.7% - 59%) and 83% (95% CI: 65% - 100%), respectively. The adverse event profile was consistent with the expected toxicity profile for each agent with no increase in frequency with the combination. Conclusions: Our combination regimen was relatively safe and well tolerated and demonstrated promising efficacy in a heavily pretreated patient population passing the prespecified efficacy criteria for Simon Stage I. The study has moved into Stage II testing. Clinical trial information: NCT04562129 .
Efficacy and safety of first-line (1L) nivolumab plus relatlimab (NIVO + RELA) versus NIVO plus ipilimumab (NIVO + IPI) in advanced melanoma: An updated indirect treatment comparison (ITC).
Authors: Schadendorf Dirk , Tawbi Hussein A. , Lipson Evan J. , Hodi F. Stephen , Ascierto Paolo Antonio , Larkin James , Lao Christopher D. , Grob Jean-Jacques , Ejzykowicz Flavia , Palaia Jennell , Horton Viviana Garcia , Zhou Zheng-Yi , Christensen Dana , Rosenblatt Lisa , McDonald Laura , Ratto Barbara , Salvatore Anthony , Patel Divya , Sakkal Leon A. , Long Georgina V.
Published: July 2024

9557

Background: An ITC comparing NIVO + RELA and NIVO + IPI, approved dual immunotherapy treatment options for patients with advanced melanoma, was previously conducted using pt-level data from the pivotal RELATIVITY-047 (RELA-047; NIVO + RELA vs NIVO) and CheckMate 067 (CM-067; NIVO + IPI or NIVO vs IPI) trials (Schadendorf 2023). Here we present results using updated, 3-year follow-up data from RELA-047. Methods: Inverse probability of treatment weighting was used to adjust for cross-trial imbalances in baseline characteristics. Database locks were selected to best align follow-up length in RELA-047 (median 34 mo) and CM-067 (median 38 mo). Progression-free survival (PFS) per investigator, confirmed objective response rates (ORRs) per investigator, overall survival (OS), melanoma-specific survival (MSS), treatment-related adverse events (TRAEs), and TRAEs leading to discontinuation (DC) were analyzed. PFS, OS, and ORR were evaluated across key subgroups. PFS, OS, and MSS were compared using Kaplan–Meier curves and hazard ratios (HRs); ORRs were compared using odds ratios (ORs). The weighted NIVO arm from each trial was compared for internal validation. Results: After weighting, key baseline characteristics were balanced for NIVO + RELA (n=339) and NIVO + IPI (n=297). Efficacy outcomes after weighting were similar between NIVO + RELA and NIVO + IPI and between NIVO arms (table). Similar outcomes between the NIVO arms validate the ITC methodology. Across subgroups, efficacy appeared similar between treatments, although trends favoring NIVO + IPI were observed for ORR among pts with BRAF MT disease or lactate dehydrogenase > 2x the upper limit of normal. TRAEs were less common with NIVO + RELA (23%) compared to NIVO + IPI (61%); any-grade TRAEs leading to DC occurred in 17% and 41% of pts, respectively. Conclusions: Consistent with previous results, this updated ITC suggests that 1L treatment with NIVO + RELA may have comparable efficacy to, and lower toxicity than, NIVO + IPI in pts with advanced melanoma. Results should be interpreted with caution given differences in study designs and changes in treatment landscape. Research is ongoing to determine which pts respond best with each combination. [Table: see text]
Metabolic factors affecting response to adjuvant anti-PD1 therapy for melanoma.
Authors: Bruno Sabrina , Knight Andrew David , Wang Hong , Sander Cindy , Karapetyan Lilit , Kirkwood John M.
Published: July 2024

9589

Background: Given the intersection between metabolism and the immune system, and with the increasing use of immune checkpoint inhibitors (ICIs) in the treatment of solid tumors, it is important to determine whether metabolic factors are associated with outcomes for patients treated with ICIs. Obesity is often associated with improved response to immunotherapy for patients with melanoma. However, the impact of other metabolic disorders, such as type 2 diabetes (T2DM), hypertension (HTN), and hyperlipidemia (HLD), on immunotherapy response is not as well understood. The purpose of this study is to determine the impact of these metabolic disorders on immunotherapy treatment. Methods: Patients with stage II or III melanoma who were treated with adjuvant anti-PD-1 therapy and consented to the University of Pittsburgh Melanoma Center repository were included in this study. A retrospective chart review was conducted of the eligible 281 patients. Results: HTN, T2DM, HLD, and body mass index (BMI) > 35 were analyzed together in two multivariate Cox proportional hazard models, one considering overall survival (OS) and the other recurrence free survival (RFS). T2DM (n=49) was significantly associated with both a decreased OS (HR=2.51, 95% CI 1.14-5.52; p=0.0219) and RFS (HR=1.92, 95% CI 1.16-3.164; p=0.011). No significant differences were observed for patients with HTN (n=156) in OS (HR=1.45, 95% CI 0.73-2.87; p=0.29) or RFS (HR=1.22, 95% CI 0.80-1.86; p=0.35), HLD (n=140) in OS (HR=0.62, 95% CI 0.30-1.29; p=0.20) or RFS (HR=0.69, 95% CI 0.44-1.07; p=0.098), or BMI > 35 in OS (HR=1.01, 95% CI 0.48-2.13; p=0.99) or RFS (HR=0.78, 95% CI 0.47-1.29; p=0.34). After adjusting for common pre-treatment comorbidities (coronary artery disease, chronic kidney disease, and smoking), age, and sex, T2DM was no longer significantly associated with reduced OS (HR=1.78, 95% CI 0.83-3.8; p=0.14), but the association with RFS remained significant (HR=1.69, 95% CI 1.04-2.76; p=0.034). In patients with T2DM alone, metformin use (n=24) during immunotherapy treatment was associated with improved OS in univariate (HR=0.28, 95% CI 0.08-0.9; p=0.0385) and multivariate (HR=0.18, 95% CI 0.05-0.7; p=0.0098) analyses controlling for age, sex, and the comorbidities listed above. It was also near significant for increased RFS in a univariate (HR=0.46, 95% CI 0.20-1.06; p=0.067) and multivariate (HR=0.42, 95% CI 0.17-1.06; p=0.065) model. Baseline A1C (n=15) values were not significantly associated with OS (HR=0.18, 95% CI 0.001-24.7; p=0.49) or RFS (HR=0.60, 95% CI 0.21-1.76; p=0.35) in univariate models. Conclusions: T2DM is associated with decreased RFS for patients with melanoma treated with adjuvant anti-PD-1 therapy. Within the T2DM cohort, metformin use was associated with significantly improved RFS and OS. A1C did not correlate with either OS or RFS, suggesting that the effects of both T2DM and metformin may be independent of glycemic control.
Germline pathogenic variants in a large convenience cohort of multiple melanoma subtypes.
Authors: Lochrin Sarah E. , Kemel Yelena , Stuart Jessica , Smithy James William , Mandelker Diana , Momtaz Parisa , Chatila Walid Khaled , Schultz Nikolaus , Postow Michael A. , Stadler Zsofia Kinga , Shoushtari Alexander Noor
Published: July 2024

9595

Background: A heritable component accounts for approximately 10% of melanomas. These estimates derive from populations deemed high risk for a germline pathogenic variant (gPV). The prevalence and clinical features of a broader melanoma patient population are unknown. Methods: Using the MSKCC IMPACT dataset, we identified a convenience cohort of all pts with melanoma who had undergone targeted tumor-normal sequencing (NCT01775072) for gPV in 76-90 genes. gPV were categorized by association with cancer predisposition and penetrance. Results: 701 pts with melanoma and germline sequencing demonstrated 105 pathogenic variants in 29 genes (Table). 14% of pts (n=99) harbored a gPV in a cancer susceptibility gene (gPV+); 49% high/moderately pathogenic, 32% low/recessive, and 19% uncertain. 6% of gPV+ pts had 2 gPVs. 77% of gPVs were involved in DNA damage repair pathways. The genes known to be associated with melanoma risk accounted for 9% of gPVs, inclusive of CDKN2A (2%), CDK 4 (1%), MITF (4%), and BRCA2 (2%). A further 15% were in genes with suggested, as yet undefined, susceptibility for melanoma; BRCA1 (6%), ATM (5%), BAP1 (2%) and PALB2 (2%). gPV+ frequency varied by melanoma subtype: unknown primary (19%, n=18), cutaneous (15%, n=64), mucosal (13%, n=13), acral (7%, n=2) and uveal (4%, n=2) (p=0.039). No significant difference in age, sex, race, stage at diagnosis, personal history of other cancer, or family history (FHx) of melanoma was seen between gPV+ and gPV-, on univariate analysis. 47% of gPV+ pts had either >1 primary melanoma, age<45 years or a FHx of melanoma (n=47), of which 14 pts had >1 risk factor. The presence of >1 melanoma and FHx of melanoma was associated with gPV+ (p=0.016). There was no significant difference in somatic TMB and MAPK pathway alterations between gPV+ and gPV-. In this cohort selected for high-risk melanomas, melanoma was the first presenting cancer for 83% of patients with gPV+. Assessment of biallelic loss to clarify if gPVs may be driving melanoma carcinogenesis is ongoing. Conclusions: This represents the largest cohort of sequenced matched germline and somatic analysis in melanoma. There is a 14% overall gPV prevalence that varies by melanoma subtype. The association of >1 primary melanoma, young age and a family history of melanoma with gPV+ is consistent with prior studies, however, would not capture 53% of gPV+ in this cohort. Melanoma represents the index cancer for the majority of gPVs, informing the need to expand germline testing in patients with melanoma. [Table: see text]
Arthralgia and myalgias associated with aromatase inhibitors: Frequency and characterization in real-life patients.
Authors: Camejo Natalia , Castillo Cecilia , Santana Diego , Argenzio Lucia , Amarillo Dahiana , Herrera Guadalupe , Guerrina Maria , Krygier Gabriel David
Published: July 2024

e12504

Background: Adjuvant treatment with aromatase inhibitors (AI) in estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer (BC) has been shown to increase overall survival (OS). However, arthralgias and myalgias are common adverse effects in patients treated with AI. Objective: To evaluate the frequency and characteristics of arthralgias and myalgias in patients with early BC, treated adjuvantly with AI at the Mastology Unit of the Oncology Service of the Hospital de Clínicas and the Soriano Departmental Hospital. Methods: A prospective, cross-sectional, descriptive study was conducted. A questionnaire was administered to the patients to assess the presence and characteristics of arthralgias and myalgias associated with AI. Statistical analysis: "Age" was described using measures of central tendency and dispersion. Qualitative variables were presented in absolute and relative frequencies. Logistic models were used to assess the association between patient, tumor, and treatment characteristics and the presence of pain. Results: Results were presented using Odds Ratio and p-value, using R software (version 4.1.2) with a significance threshold of 5%. 83 patients were included, with a median age of 69 years. 75.9% presented treatment-related arthralgias and/or myalgias, with an average intensity of 5 to 7. 80.9% received NSAIDs, achieving satisfactory analgesia. The presence of arthralgias and myalgias was significantly associated with age and time since last menstruation, being more frequent in patients over 50 years old and those with more than 5 years since the last menstruation. Conclusions: Approximately 70% of the patients presented arthralgias or myalgias. These findings suggest a possible role of estrogen withdrawal in their development mechanism. It is crucial to carry out multidisciplinary and translational research to evaluate the etiology and therapeutic options for patients with AI-related arthralgia.
Reconstructive plastic surgery in combined treatment of breast cancer: Predictive risk factors of complications and reconstruction failure.
Authors: Ulrikh Daria , Krivorotko Petr , Zhanna Bryantseva , Novikov Sergey , Mortada Viktoriia , Pesotskiy Roman , Bondarchuk Yana , Amirov Nikolay , Emelyanov Alexander , Enaldieva Diana , Levchenko Valerii , Zhiltsova Elena , Tabagua Tengiz , Zernov Konstantin , Semiglazov Vladimir
Published: July 2024

e12594

Background: Breast reconstruction after mastectomy must consider potential complications from surgical techniques as well as additional complications of oncologic treatment such as radiation or systemic therapy. But the consensus is lacking regarding the optimal reconstruction plan for patients requiring adjuvant radiation therapy. Objective: To determine the impact of risk factors on the development complications of breast reconstruction for postmastectomy radiotherapy. Methods: This study included patients diagnosed with breast cancer who received combination treatment from 2016 to 2021 at the FSBI “N.N. Petrov National Medical Research Center of Oncology” of the Russian Ministry of Health. The patients were divided into 3 groups: immediate reconstruction (158 people), immediate-delayed (210 people) and delayed (98 people). Results: Every fourth patient (24.0%, 112/466) may encounter a complication after mastectomy with reconstruction and adjuvant radiation therapy. According to the analyzed data, there was no correlation between potential risk factors depending on the general status of patients (age, obesity, diabetes mellitus, hypertension, history of smoking) and the occurrence of complications after combination treatment. Conclusions: The analysis of complications and reconstructive failures showed that immediate breast reconstruction at the FSBI "N.N. Petrov National Medical Research Center of Oncology" of the Ministry of Health of Russia is the safest method of reconstruction in the combined treatment of breast cancer with the lowest incidence of severe complications (9.5%, 15/158, z>1.96), which plays a key role in the development of reconstructive failures (Pearson Correlation=0.861, p<0.001). However, these surgeries are associated with a significant number of capsular contractures (15.2%, 24/158, z>1.96, Pearson Correlation=0.230, p<0.001), which requires finding ways to minimize these risks to optimize treatment in each individual case in short and long term results.
Impact of breast-conserving surgery incisions on aesthetics, satisfaction, and complications: A prospective study.
Authors: Liu Weijing , Chen Ruixian , Yang Ruoning , Huang Ya , Wu Yunhao , Zhao Xin , Meng Xiangyue , Zhang Zhihao , Ouyang Dengjie , Li Qintong , Luo Ting , Sun Xin , Chen Jie
Published: July 2024

e12603

Background: Breast-conserving (BCS) is favored for its aesthetics benefits and minimal invasiveness. Ensuring tumor safety is essential, but so are post-surgery appearance, satisfaction, and complications. Incision selection for BCS influences both operability of procedures and postoperative results. This study aims to investigate the impact of different incisions on the aesthetic outcome, patient satisfaction, and postoperative complications of BCS. Methods: A prospective single-center cohort study was conducted from July 2020 on breast cancer patients who underwent BCS. The Breast-Q questionnaire and the Aesthetic Items Scale (AIS) were used to assess breast aesthetics and satisfaction outcomes at different times before and after surgery. Complications evaluated include incision dehiscence, subcutaneous hydrops, and nipple-areolar complex (NAC) ischemia, which were recorded once postoperatively and classified according to the Clavien-Dindo classification. Results: A total of 429 patients were enrolled in this study: 247 with a periareolar incision, 30 with a crescentic periareolar incision, 41 with a curvilinear incision, and 111 with a radial incision. Compared to traditional radial incisions, the periareolar and crescent incisions showed significantly better results in psychological well-being, sexual well-being, satisfaction with breasts, and AIS scores at 1-, 3-, and 6-months post-operation. The crescentic incision demonstrated a notable advantage in physical well-being: chest at the 6-month. In contrast, no significant difference was observed between the curvilinear and radial incisions in terms of these outcomes. The overall complication rates for periareolar, crescentic periareolar, curvilinear, and radial incisions were 11.3%, 16.7%, 9.8%, and 7.2%, respectively, indicating no significant differences. Similarly, the rates of NAC ischemia for the periareolar (5.7%) and crescentic (3.3%) incisions did not significantly differ. All complications were graded in categories I to III, and the distribution showed no statistically significant differences among the four groups. Conclusions: Among various incisions, periareolar and crescentic incisions demonstrated superior outcomes in postoperative follow-up, with a comparable incidence of complications to other incisions. These findings may provide valuable surgical decision-making guidance for achieving optimal aesthetic and clinical outcomes in BCS.
Optimization of surgical management of the axilla since MonarchE trial.
Authors: Jankowski Clémentine , Ladoire Sylvain , Coutant Charles
Published: July 2024

e12604

Background: Results of monarchE trial (1) have changed adjuvant therapy recommendations for estrogen-receptor-positive (ER+), HER-2 non amplified early breast cancer. Abemaciclib when combined with endocrine therapy has demonstrated a significant improvement in interval disease free survival for patients at high risk of recurrence defined by 4 or more positive nodes or 1 to 3 nodes and either tumor size ≥ 5cm or histologic grade 3. Given the importance of the extent of nodal disease in this study, surgical management of the axilla has resurfaced as a question asked at multidisciplinary tumor boards. Methods: Using data from a prospective historical cohort (2) in which patients underwent both sentinel node (SN) dissection and axillary node dissection (ALND), we assessed the proportion of patients in whom the absence of ALND indication would have led to a lack of awareness of "high-risk" status, and therefore of the indication for adjuvant Abemaciclib. In addition, we evaluated the contribution of the Katz nomogram (that predict pN2/N3 stage) (3) to guide possible indications for complementary ALND in patients with no indication for ALND according to current guidelines. Results: Among the 536 patients, 88 were excluded (54 were ER- and 34 had isolated cells in SLN). Among the remaining 448, 19.2% (86) already had an indication for abemaciclib (78 grade 3 and 8 with size ≥5cm). Ten patients with 3 SLN+ had an indication for ALND. Overall, among patients with 1 or 2 SLN+, only 8% (28/352) were pN2/N3 (14/279 with 1SLN+ and 14/73 with 2SLN+). When the ratio (number of SLN+/total number of SLN sampled) was less than 1, only 3.9% (9/231) were pN2/N3. The pN2/N3 rate was 16% (19/121) when the ratio was greater than 1. Patients with 1 or 2 SLN + met the ACOSOG Z0011 criteria so none would benefit from an ALND, but 8% (28/352) of patients at high risk will not receive Abemaciclib. When using the Katz nomogram with a threshold ≤5%, this rate decreases to 3.3% (7/352) but 116 patients will have an ALND with no benefit. With a threshold ≤20%, 5% (16/352) patients at high risk will not receive Abemaciclib but 21 patients will have an ALND with no benefit. Conclusions: The indications for adjuvant abemaciclib should not lead to surgical escalation in the surgical management of the axilla. 1.Johnston SRD et al. Lancet Oncology. 2023. 2. Katz A et al. J Clin Oncol. 2008 3. Werkoff G et al. J Clin Oncol. 2009.
A proof-of-concept study of LXP5268 as an add-on neoadjuvant chemotherapy in patients with early-stage triple-negative breast cancer.
Authors: Liu Liang Chih , Way Tzong-Der , Lin Chin-Hua , Chen Ya-Hui , Kuo Pin-Hung , Tseng Chung-Hsin , Chen Chiu-Heng
Published: July 2024

e12607

Background: Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive subtype characterized by a high risk of mortality and a poor prognosis. The 2019 ASCO and St. Gallen International Consensus Guidelines strongly recommend neoadjuvant chemotherapy (NACT) for early-stage TNBC. Previous studies indicated that NACT improved overall and disease-free survival in early-stage TNBC. LXP5268, a drug in the 505(b)(2) category, has demonstrated efficacy in reducing tumor size in animal models. Our study aims to assess whether combining LXP5268 with NACT enhances anti-tumor efficacy and tumor shrinkage rates in early-stage TNBC patients. Methods: Enrolled patients had untreated stage II-III TNBC. NACT consisted of docetaxel every 3 weeks for four cycles, followed by epirubicin plus cyclophosphamide every 3 weeks for an additional four cycles (24 weeks total). In the LXP5268 add-on NACT (LXP5268+NACT) group, patients took LXP5268 orally once daily with NACT. After treatment, we analyzed tumor objective response rate (ORR), shrinkage rate by CT images, and adverse events (AEs) diagnosed by the principal investigator. Whole-exome sequencing (WES) was performed on 6 subjects in the LXP5268+NACT group, identifying potential germline variants and biomarkers, clinically interpreted following ACMG/AMP 2015 guidelines. Results: Both groups had similar baseline characteristics. LXP5268+NACT subjects (54.8 ± 7.2 years) and NACT subjects (59.3 ± 9.8 years) showed significant age differences ( p<0.001). The ORR was 100% in both the LXP5268+NACT group (3 pathological complete response, pCR and 4 pathological partial response, pPR) and NACT group (6 pPR). The tumor shrinkage rate was significantly higher in the LXP5268+NACT group at 77.3% ± 21.8 compared to 43.4% ± 12.8 in the NACT group ( p< 0.001). Moreover, subjects in the LXP5268+NACT group with a tumor reduction exceeding 50% surpassed those in the NACT group. AEs included neutropenia (85.7%), constipation (66.7%), and insomnia (66.7%), all grade 1. Interestingly, mutation in XIRP2 correlated with higher tumor shrinkage rate. Conclusions: LXP5268 combined with NACT was more effective than NACT alone for early-stage TNBC, without increasing AEs. These results highlight LXP5268's potential in TNBC therapy. Previous studies indicated XIRP2 mutations in metastatic breast cancer. LXP5268+NACT achieved pCR in XIRP2-mutated patients. Future clinical trials will expand to enhance result verification accuracy. Clinical trial information: CMUH106-REC3-145.
Real life data of KEYNOTE 522: The Cleveland Clinic experience.
Authors: Lytvynova Olga M. , Jwayyed Jenna , Awada Hussein , Birkholz Tyler , Cheema Asfand Yar , Fargo Kelly , Daw Hamed , Pratt Debra A , Maiti Baidehi
Published: July 2024

e12612

Background: Triple-negative breast cancer (TNBC) constitutes approximately 15% of all breast cancers and predominantly affects younger women with a disproportionate impact on Black and Hispanic ethnicities. Historically, neoadjuvant therapy centered around chemotherapy alone. However, the KEYNOTE 522 trial has demonstrated improved outcomes with the incorporation of the PD-1 inhibitor Pembrolizumab alongside neoadjuvant chemotherapy. Methods: A retrospective cohort analysis of 106 patients treated with the KEYNOTE 522 regimen within Cleveland Clinic from January 2020 to July 2023. The objective is to evaluate the real-life experience, particularly concerning treatment tolerance and pathologic complete response rates (PCR). Results: Among the 106 female patients, 6.6% completed full neoadjuvant therapy without reporting adverse events (AE), achieving a 71.42% PCR rate. Complications were reported in various subgroups: 54.72% associated with paclitaxel and carboplatin, with discontinuation rates of 60.34%, reduction rates of 33.02%, and full continuation rates of 6.9%. The most prevalent AE included cytopenia (46.55%) and febrile neutropenia, along with other infections (27.59%). For patients discontinuing paclitaxel and carboplatin, the PCR was 68.57%, while with dose reductions, it was 68.75%. Complications related to doxorubicin and cyclophosphamide were reported in 16.04% of patients, with 47.06% either discontinuing or reducing dose, and 5.88% continuing full therapy. Febrile neutropenia, along with other infections (64.71%) and cytopenia (23.53%) were the prominent AE. The PCR for patients discontinuing or reduced doxorubicin and cyclophosphamide was 62.50%. Pembrolizumab-related complications were reported in 16.98% of patients, with a 50% discontinuation rate. The most common AE was dermatologic toxicities (27.78%). The PCR for patients discontinuing pembrolizumab was 83.33% versus 62.5% for those continuing full therapy. Conclusions: This retrospective analysis highlights infections and cytopenias as the primary adverse reactions. Notably, the dose reduction or discontinuation of agents did result in a deterioration of PCR rate compared to patients completing full therapy. Remarkably, PCR was improved for the pembrolizumab discontinuation group, perhaps suggesting a correlation between autoimmune toxicities and improved response. Additional prospective study with larger sample size is needed to understand whether all patients benefit from completing the Keynote 522 regimen. [Table: see text]