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Neoadjuvant chemotherapy combined with antiangiogenic therapy and immune checkpoint inhibitors for the treatment of locally advanced gastric cancer: a real - world retrospective cohort study

BackgroundAlthough immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs have demonstrated effectiveness in treating advanced gastric cancer (GC), their role in neoadjuvant or conversion therapy remains uncertain. This study aimed to evaluate the efficacy and safety of combining neoadjuvant chemotherapy with anti-angiogenesis and ICIs in patients with locally advanced GC (LAGC).MethodsIn this cohort study, we reviewed our prospectively maintained GC database and included individuals diagnosed with clinical stage II-III GC who received neoadjuvant therapy followed by surgery between January 2022 and August 2023. The treatment protocol combined ICIs, anti-angiogenic therapy (specifically apatinib), and chemotherapy (S-1 with oxaliplatin). A systematic approach was used to document patients’ clinical and pathological characteristics, pathological findings, and survival outcomes, which were subsequently analyzed in detail.ResultsA total of 38 individuals met the study’s inclusion criteria, with the majority (32 patients, 84.2%) having clinical stage III GC. All participants underwent surgery, resulting in a notable R0 resection rate of 97.4%. The rates of major pathological response (MPR) and pathological complete response (pCR) were 47.4% and 23.7%, respectively. Post-surgery, 36 patients (92.1%) received adjuvant chemotherapy. With a median follow-up of 22 months, ten patients experienced disease recurrence, including three who died from tumor relapse. The 1-year overall survival (OS) rate stood at 100%, and the disease-free survival (DFS) rate was 94.7%, with median OS and DFS yet to be reached. The neoadjuvant therapy regimen was generally well-tolerated, with no grade 5 treatment-related adverse events (TRAEs) reported. Only one patient experienced a grade 4 TRAE (immune-related hepatitis), while the most common grade 3 TRAEs included thrombocytopenia, elevated aminotransferase levels, and neutropenia.ConclusionsThe combination of neoadjuvant chemotherapy, anti-angiogenic therapy, and ICIs has proven effective in treating LAGC patients, achieving high pCR rates and favorable survival outcomes while maintaining an acceptable safety profile.

A modified totally stapled KONO-S anastomosis for ileal and ileo-colic Crohn's disease: technical aspects and case series.

Crohn's disease (CD) is a chronic immune-mediated disorder affecting the gastrointestinal tract. While medical therapies have advanced, approximately 80% of CD patients will require surgery due to disease recurrence. A significant debate exists regarding the primary site of post-operative recurrence. This discrepancy in recurrence patterns underscores the complexity of CD management and the ongoing need for tailored surgical approaches. It has been recently demonstrated that the Kono-S anastomosis is safe and efficient in reducing endoscopic and surgical recurrence. Newer versions of the Kono-S anastomosis using staplers have been reported to further simplify the procedure and decrease operative time. The aim of this paper was to describe a distinct version of a totally stapled Kono-S anastomosis and provide preliminary results from our center. The technical procedure of a totally stapled Kono-S anastomosis is illustrated. A consecutive series of patients undergoing ileal or ileo-colic resection followed by totally stapled Kono-S anastomosis was identified from a prospectively collated database. Data included patient demographics and baseline characteristics, intraoperative details, short- and long-term post-operative outcomes. Between January and November 2023, 41 patients (mean age 36.4years, 61% males) underwent ileal or ileo-colic resection followed by totally stapled Kono-S anastomosis for Crohn's disease. Mean operative time was 150.76 ± 43.22min, and mean time of anastomotic construction was 19.71 ± 4.24. Time to flatus and stool were 2.73 ± 0.70 and 3.51 ± 1.16days, respectively, and the length of post-operative stay was 6.80 ± 2.13days. Only two patients (4.8%) presented complications following surgery, namely anastomotic bleeding. At a mean follow-up of 17.0 ± 2.1months, no patient needed re-do surgery for disease recurrence at anastomotic site. The endoscopic recurrence rate was 14.4% (4/28). Our fully stapled version of the Kono-S anastomosis is safe and feasible, and short construction time and low technical complexity may help its diffusion among colorectal surgeons. Long-term outcomes on disease recurrence are still to be defined.

Tumor tissue modified viral (TTMV)-HPV DNA as a biomarker of treatment efficacy for definitive chemoradiation in anal squamous cell carcinoma: A step towards truly personalized therapy.

10 Background: Cell-free circulating tumor tissue modified viral DNA (ctDNA) has been used as a biomarker to detect recurrence for anal squamous cell carcinoma (ASCC). However, its value in informing treatment modification during definitive chemoradiation (CRT) has yet to be explored. We evaluated ctDNA response during and at completion of definitive CRT to establish patterns of disease response and inform future studies to personalize treatment. Methods: From 11/2022 to 6/2024, 13 consecutive patients with biopsy proven, non-metastatic ASCC received definitive CRT and had ctDNA testing using a commercially available droplet digital quantitative PCR assay. ctDNA testing was done at baseline (pre-CRT), week 4 of CRT, and/or end of CRT, 1-3 months post-CRT, and every 6 months thereafter. CRT included concurrent 5FU/MMC (or capecitabine/MMC) and radiotherapy according to RTOG 0529. Treatment response assessment included: physical exam, anoscopy, and imaging with PET/CT, CT C/A/P +/- MRI abdomen and pelvis. Results: 13 patients had ctDNA testing and 11 patients had HPV-positive ASCC and tested positive for ctDNA. The 11 patients with detectable baseline ctDNA were included in this analysis. The median age at diagnosis was 63 years old. Staging included: 1- Stage IIA, 7- Stage IIB, 1- Stage IIIA, 2- Stage IIIC. 1 patient was cN0, while 11 were cN1. With a median follow-up from completion of CRT of 13 months, 4 patients have persistent or recurrent disease: 2 with distant metastases, 1 with persistent local disease (1 month post-CRT), and 1 with local and distant recurrence. Baseline value of ctDNA did not correlate to stage at diagnosis, rate of clearance during CRT, or likelihood of recurrence. 5 of 11 patients cleared ctDNA by week 4 of CRT. Of 5 patients who cleared ctDNA by week 4 of CRT, 4 remain NED and 1 developed distant metastases. Of 6 patients with persistent ctDNA at week 4 of CRT, 3 have persistent or recurrent disease- 1 local persistence 1 month post-CRT, 1 local and distant recurrence 6 months post-CRT, and 1 with distant recurrence 12 months post- CRT. Among 6 patients who cleared ctDNA by the final week of CRT, 1 patient developed recurrent disease. Among the 4 patients in the series with residual/recurrent disease, 3 of them had not cleared ctDNA by the end of CRT. Of 10 patients with ctDNA testing at 1 month post-CRT, 8 had no detectable ctDNA. 2 patients with persistent (1) or recurrent (1) ctDNA at 1 month post-CRT developed disease recurrence- 1 with distant recurrence and 1 with local and distant recurrence. Conclusions: ctDNA assessment during CRT may provide insight into disease response that can predict patterns of failure and facilitate personalized therapy- treatment intensification, deintensification, or additional testing to detect early metastatic disease. Larger studies and clinical validation are needed.

An analysis of ambulance re-contacts after non-conveyance: a retrospective cohort study in the Netherlands

BackgroundNon-conveyance is an increasing part of ambulance care and has to be safe. One of the indicators to measure safety is an ambulance re-contact within 72 h. However, solely measuring the percentage of re-contacts has limited validity as it lacks insight in actual reasons of an ambulance re-contact. Therefore, the aim of our study was to analyze the incidence, reasons and outcomes of ambulance re-contacts within 72 h after non-conveyance.MethodsWe conducted a one year (2022) retrospective study in one EMS region in the Netherlands. Medical records of all non-conveyance runs with a re-contact were analyzed using a framework to categorize re-contact reasons in illness-related, patient-related, professional-related, and unrelated. Re-contact outcomes were measured in terms of (non-)conveyance and mortality.Results585/13.879 (4.2%) non-conveyance runs had a re-contact within 72 h. 547/585 (93.5%) re-contacts could be categorized with the framework. Re-contacts were related to the illness (n = 267, 48.8%), the patient (n = 130, 23.8%), the professional (n = 106, 19.4%) and unrelated (n = 44, 8.0%). Four subreasons accounted for 68.5% of reasons for re-contacts: progression of disease (19.4%), recurrent disease process/exacerbation (18.6%), reassessment and ambulance request by another medical professional (15.9%), and psychiatric disorder and/or substance abuse (14.6%). 403/547 (73.7%) patients with a re-contact were conveyed to the hospital. Mortality rate for patients with a re-contact was 0.5%.ConclusionsRe-contact incidence after non-conveyance is relatively low, with a very small part of re-contacts related to ambulance care professionals making errors in diagnosis or treatment. Combined with low re-contact mortality, this indicates safe non-conveyance decisions. Re-contacts as quality indicator cover a variety of reasons, with almost half of the re-contacts being related to illness. Four subcategories accounted for the majority of all reasons for re-contacts: progression of disease, recurrent disease process/exacerbation, reassessment and ambulance request by another medical professional, and psychiatric disorder and/or substance abuse. Three-quarters of the patients were conveyed, although more re-contacts due to patient related reasons ended in non-conveyance again.

Anlotinib plus benmelstobart as adjuvant therapy in patients with esophageal squamous cell carcinoma: A phase II clinical trial (ALTER-E005).

459 Background: Surgery represents a primary radical treatment for esophageal cancer, However, the risk of recurrence remains noteworthy after surgical resection, underscoring the need for more effective and tolerable postoperative regimens for esophageal squamous cell carcinoma (ESCC). Benmelstobart, a novel PD-L1 blockade, demonstrated promising antitumor activity when combined with anlotinib, an antiangiogenic agent, in the treatment of various tumors including advanced ESCC (NCT05038813) and biliary tract cancer (NCT03996408). Therefore, ALTER-E005 study aimed to evaluate the efficacy and safety of combining anlotinib with benmelstobart as adjuvant therapy in patients (pts) with ESCC. Methods: This was a single-arm, multi-center phase Ⅱ clinical trial. Thirty pts (≥18 years) with histologically confirmed T1-2N1-3M0 or T3-4NanyM0 ESCC who had undergone radical (R0) resection with no recurrence 6 to 12 weeks after surgery and an ECOG PS ≤ 1 were eligible for enrollment. Enrolled pts received oral anlotinib (12 mg, days 1-14) and intravenous benmelstobart (1200 mg, day 1) every 3 weeks for up to 16 cycles or until disease recurrence. The primary endpoint was disease recurrence free (DFS). while secondary endpoints included safety, 1-year DFS rate, 3-year DFS rate, 1- year overall survival (OS) rate, and 3-year OS rate. Results: As of the data cut-off date (September 20, 2024), a total of 30 patients were enrolled with a median age of 67. Among the 30 surgically resected patients with ESCC, 26 (86.7%) had an ECOG score of 1, and 25 (83.3%) were male. According to the eighth edition of the AJCC Cancer Staging Manual, 9 (30.0%) were classified as stage Ⅱ, and 21 (70.0%) were classified as stage Ⅲ. As of the data cut-off date, the median follow-up time was 8.9 months (95% CI: 7.9-12.3). Four pts experienced disease recurrence, and the median duration of DFS has not yet been reached, with 6-month and 1-year DFS rates of 95.7% (95% CI, 72.9%-99.4%), 84.0% (95% CI, 57.7%-94.6%) respectively. Currently, 13 pts are still undergoing therapy. Out of the total 30 patients, 9 (30%) experienced grade 3 treatment-emergent adverse events (TEAEs). No grade 4 or higher TEAEs were observed. The grade 3 TEAEs included hand-foot syndrome (10.0%), hypertension (3.3%), abnormal liver function (3.3%), immune-related hepatitis (3.3%), pneumonia (3.3%), hyperglycemia (3.3%) Lymphocyte count decreased (3.3%), acute cholecystitis (3.3%) and syncope (3.3%). Conclusions: This study highlighted the promising efficacy and safety preliminarily of combining anlotinib with benmelstobart as adjuvant therapy in patients with ESCC who underwent radical (R0) resection and showed no recurrence 6 to 12 weeks after surgery. Clinical trial information: NCT05252078 .

Q-TWiST analysis of pembrolizumab plus trastuzumab and chemotherapy for patients with metastatic HER2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma in the KEYNOTE-811 trial.

354 Background: In the phase 3 KEYNOTE-811 trial (NCT03615326), first-line pembrolizumab plus trastuzumab and chemotherapy (pembrolizumab group) statistically significantly improved PFS and OS versus placebo plus trastuzumab and chemotherapy (placebo group), with manageable safety, in patients with metastatic HER2-positive G/GEJ adenocarcinoma, while maintaining HRQoL, specifically in patients with PD-L1 combined positive score (CPS) ≥1 tumors. The objective of this analysis was to assess quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) for patients treated in the KEYNOTE-811 trial. Methods: Q-TWiST is a measure of survival weighted by health states utility values. The analysis categorized survival time into 3 health states: time with grade ≥3 adverse events (toxicity [TOX]) and time without symptoms or toxicities (TWiST)—both before disease progression or death—and relapse (REL), defined as time from disease progression to death. Q-TWiST was calculated as the restricted mean survival time spent in each state, with a weighted health state utility for that state. Average utility weights were derived based on pooled EQ-5D-5L scores using the US mapping algorithm and standardized base case utility weights. Relative gains in Q-TWiST of ≥10% and ≥15% were “clinically important” and “clearly clinically important,” respectively, as reported in the literature. Treatment difference 95% CIs were generated using the nonparametric bootstrapping method. Data are reported for patients with PD-L1 CPS ≥1 tumors. The data cutoff date was March 20, 2024. Results: At the maximum follow-up of 63 months, patients in the pembrolizumab group had a 2.36-month (95% CI, −0.24 to 4.56) longer restricted mean time in TOX (6.98 vs 4.63 months), a 3.40-month (95% CI, −0.44 to 7.45) longer restricted mean time in TWiST (12.03 vs 8.62 months), and a 1.45-month (95% CI, −5.84 to 3.09) shorter restricted mean time in REL (8.87 vs 10.32 months) versus the placebo group. For the restricted mean Q-TWIST at month 63, based on the US mapping algorithm, the difference between the pembrolizumab and placebo groups favored the pembrolizumab group by 3.90 months (95% CI, 1.30 to 6.72), representing a 16.57% relative Q-TWiST gain. Based on the standardized base case utility weights, the difference also favored the pembrolizumab group by 3.86 months (95% CI, 1.47 to 6.67), representing a 16.38% relative Q-TWiST gain. Conclusions: Pembrolizumab plus trastuzumab and chemotherapy produced a clearly clinically important improvement in quality-adjusted survival time based on Q-TWiST analyses compared with placebo plus trastuzumab and chemotherapy in patients with previously untreated metastatic HER2-positive G/GEJ adenocarcinoma with PD-L1 CPS ≥1. Clinical trial information: NCT03615326 .

Q-TWiST analysis of pembrolizumab or placebo plus chemotherapy for patients with advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer in KEYNOTE-859.

376 Background: In the phase 3 KEYNOTE-859 study (NCT03675737; N = 1579), patients (pts) with locally advanced or metastatic HER2-negative G/GEJ cancer treated with first-line pembrolizumab (pembro) plus chemotherapy (chemo) had a significant and clinically meaningful improvement in OS with manageable toxicity vs placebo (pbo) plus chemo while maintaining HRQoL in the intention-to-treat and prespecified PD-L1 combined positive score (CPS) populations. We report data from an analysis of quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). Methods: Q-TWiST is a measure of survival weighted by health states utility values. The analysis categorized survival time into 3 health states: time with grade ≥3 AEs (toxicity [TOX]) and time without symptoms or toxicities (TWiST)—both before disease progression or death—and relapse (REL), defined as time from disease progression to death. Q-TWiST was calculated as the restricted mean survival time (RMST) spent in each state, with a weighted health state utility for that state. Average utility weights were derived based on pooled EQ-5D-5L scores using the US mapping algorithm and standardized base case utility weights. Relative gains in Q-TWiST of ≥10% and ≥15% were “clinically important” and “clearly clinically important,” respectively, as reported in the literature. Treatment difference 95% CIs were generated using the nonparametric bootstrapping method. Data are reported for all randomly assigned pts and pts with PD-L1 CPS ≥1 and CPS ≥10 tumors. The data cutoff date was August 22, 2023. Results: At the maximum follow-up of 56 mo for pembro plus chemo vs pbo plus chemo, RMST was 5.16 vs 2.86 mo for TOX, 7.77 vs 5.87 mo for TWiST, and 6.85 vs 7.12 mo for REL. Between-treatment differences are shown in the table. The difference in restricted mean Q-TWiST and relative gain favored pembro plus chemo. Conclusions: A clearly clinically important Q-TWiST gain was observed for pembro plus chemo vs pbo plus chemo in all pts with advanced HER2-negative G/GEJ cancer and pts with PD-L1 CPS ≥1 and CPS ≥10 tumors. Clinical trial information: NCT03675737 . All ptsN = 1579 PD-L1 CPS ≥1n = 1235 PD-L1 CPS ≥10n = 553 RMST in TOX, mo (95% CI) 2.30(1.28 to 3.44) 2.65(1.46 to 3.99) 4.28(2.08 to 6.41) RMST in TWiST, mo (95% CI) 1.90(−0.02 to 3.79) 2.28(0.07 to 4.49) 3.72(0.43 to 7.19) RMST in REL, mo (95% CI) −0.28(−2.43 to 2.01) −0.22(−2.88 to 2.39) −0.45(−4.52 to 3.71) Restricted meanQ-TWiST, mo (95% CI) a 3.31(2.10 to 4.59) 3.98(2.60 to 5.43) 6.45(4.26 to 8.74) Relative Q-TWiST gain, % (95% CI) a 20.90(12.49 to 30.56) 25.34(16.04 to 36.26) 38.05(23.21 to 56.59) Restricted meanQ-TWiST, mo (95% CI) b 2.91(1.58 to 4.14) 3.50(2.02 to 4.88) 5.63(3.31 to 7.99) Relative Q-TWiST gain, % (95% CI) b 18.38(9.78 to 27.46) 22.27(12.65 to 32.52) 33.19(18.76 to 49.97) a Based on US mapping algorithm. b Based on standardized base case utility weights.

Exploring the application of herbal photosensitizers in antimicrobial photodynamic therapy against Mycobacterium Tuberculosis.

Tuberculosis (TB) is one of the leading causes of death in the world, despite being a preventable and curable disease. Irrespective of tremendous advancements in early detection and treatment, this disease still has high mortality rates. This is due to the development of antibiotic resistance, which significantly reduced the efficacy of antibiotics, rendering them useless against this bacterial infection. This, in turn, causes immune system evasion, antibiotic treatment failures, and recurrence of disease in patients. Regarding this, photodynamic inactivation (PDI) may serve as a useful substitute for antibiotic therapy against drug-resistant mycobacteria.This century-old therapy is already being used in cancer treatment, dentistry, and skeletal and cardiovascular diseases, but it is not yet used in tuberculosis treatment. Researchers have previously used PDI to eradicate other members of the genus Mycobacteria in both in vitro and in vivo settings. This suggests PDI can be explored against M. tuberculosis too. The one limitation associated with PDI is the use of chemical photosensitizers, which are fatal to normal tissues and induce side effects. Recent studies suggest herbal photosensitizers are equally potent as chemically synthesized ones. Therefore, herbal photosensitizers could be used to solve the problem because of their less toxicity to healthy tissues and decreased frequency of side effects.This review emphasizes the importance of herbal photosensitizers and their role as anti-tuberculosis drugs in PDI therapy and also presents five potential herbal photosensitizers-curcumin, quercetin, resveratrol, aloe emodin, and phloretin that could be utilized in the clinical development of PDT-mediated tuberculosis therapies.

Genomic analysis of paired primary and metastatic pancreatic ductal adenocarcinoma tumors.

758 Background: The genomics of pancreatic ductal adenocarcinoma (PDAC) have been increasingly understood allowing for improvements in treatment, yet the clinical relevance of PDAC evolution is less well studied. The aim of this study is to evaluate genomic differences and clinical correlations between primary pancreatic tumors and paired metastases using a targeted sequencing panel. Methods: Patients who underwent surgical resection for PDAC with recurrent disease who had targeted genomic sequencing of both the primary tumor and a metastasis were included. Genomic alterations were determined using a panel of cancer-related genes (MSK-IMPACT). OncoKB was used to annotate driver alterations. MATH scores were used to quantify intratumoral heterogeneity. Comparison between paired samples was performed and association with clinical variables was assessed. Results: There were 55 patients included; 20% (n=11) received neoadjuvant therapy, 91% (n=50) had adjuvant therapy and 36% (n=20) had adjuvant radiation. The most common sites of metastasis sequenced were lung (36%, n=20), liver (35%, n=19) and local (13%, n=7). There was concordance between the first site of recurrence and site sequenced in 93% (n=51) of cases with a median time between resection and biopsy of recurrence of 25 months. The most commonly altered genes are KRAS (96%), TP53 (83%), CDKN2A (40%), SMAD4 (25%) and RNF43 (13%). The majority of alterations are shared between the primary tumor and metastasis. Clonal mutations were defined as cancer cell fraction (CCF) >0.8. The majority of shared mutations are clonal; 52% of mutations are clonal in both the primary and metastasis, and clonality is preserved in 76% of shared mutations in metastases. The most commonly shared alterations are in driver genes and the majority are clonal- TP53 (80%), KRAS (78%), CDKN2A (77%) and SMAD4 (64%). The proportion of clonal mutations among drivers is higher than variants of unknown significance (p=0.005). There are 31 mutations private to the metastasis in 19 patients, 12 of which are clonal (39%). Mutations private to the metastasis are more common in patients who received adjuvant systemic therapy (p=0.035); however this was not seen when comparing patients who received adjuvant radiation to those who did not (p=0.38). MATH scores are higher in the metastasis as compared to the primary in all patients (p=0.0096), including those who received adjuvant treatment (p=0.002), indicating increased intratumoral heterogeneity in metastases. Conclusions: A targeted sequencing panel demonstrates that the majority of driver mutations are clonal and preserved between the primary tumor and metastasis. Additional private mutations and increased intratumoral heterogeneity are noted in metastasis, and our data suggests that this may be associated with exposure to systemic therapy.

A multicenter retrospective study of salvage surgery for patients with residual or recurrent esophageal squamous cell carcinoma after definitive chemoradiotherapy: SURGES study.

422 Background: Salvage surgery is defined as an operation for patients with residual or recurrent tumors after definitive chemoradiotherapy (dCRT) with > 50 Gy. Although salvage surgery has been considered to improve prognosis, it is associated with a high incidence of postoperative morbidity and mortality. A previous meta-analysis by Faiz et al. reported anastomotic leakage, pulmonary disorder rates, and 90 day-mortality rates of 18.6%, 30.2%, and 8.8%, respectively. The aim of this study was to assess the efficacy and safety of salvage surgery in patients with residual or recurrent esophageal squamous cell carcinoma (ESCC) after dCRT and to explore the risk factors for postoperative complications and poor prognosis. Methods: This multi-institutional retrospective study enrolled patients treated with salvage surgery after dCRT between January 2017 and December 2021. The preoperative backgrounds of the patients were analyzed to assess their impact on survival or toxicity. Results: In total, 148 patients (59 with recurrent disease and 89 with residual disease) underwent salvage surgery at 10 leading hospitals in Japan. Post-dCRT ycT stages were T0/T1/T2/T3/T4: 12/25/30/78/3, and ycN stages were N0/N1/N2: 87/53/8. Among 136 patients who underwent esophagectomy, 108 underwent minimally invasive surgery and 28 underwent open surgery. Twelve patients had metastatic lymph nodes without primary disease. Severe postoperative complications (≧Clavien-Dindo Grade III) occurred in 39 (26.3%) patients and overall postoperative complications (≧Grade II) rate was 46.6%, including 19 (12.8%) anastomotic leakage and 25 (16.9%) pneumonia. Thirty- and 90-day mortality rates were observed in 0 and 5 (3.3%) patients, respectively. Multivariate logistic regression analysis showed that a total radiation dose ≥60 Gy (odds ratio [OR] 2.65, 95% confidence interval [CI] 1.07-6.55) and residual disease (OR 3.04, 95%CI 1.32-7.00) were associated with severe postoperative complications. The 3-year overall survival (OS) and progression-free survival (PFS) rates were 48.9% and 40.0%, respectively (median follow-up time: 42.1 months). Multivariate analysis revealed that patients with a long interval between dCRT and salvage surgery (≥180 days) had significantly longer OS (hazard ratio [HR] 0.60, 95%CI 0.38-0.95, p=0.032), and ycN0 was associated with longer PFS (HR 0.56, 95%CI 0.36-0.87, p = 0.011). The total radiation dose was not an independent prognostic factor for either OS or PFS. Conclusions: Salvage surgery is safe and provides substantial long-term outcomes. In cases with a total radiation dose of ≥60 Gy and residual disease, special caution is required because of the higher incidence of postoperative morbidity. A longer interval between dCRT and salvage surgery and ycN0 were prognostic factors.

Gender-specific outcomes in pilonidal sinus disease: Female outcomes after cleft lift surgery in a large prospective Danish cohort.

Pilonidal sinus disease (PSD) is a common condition particularly affecting young men. Females affected by the condition account for about 20% of patients and are rarely mentioned, much less studied specifically. In this study we evaluate the surgical outcomes in a female population following Bascom's cleft lift (BCL) surgery in primary extensive disease, non-healing wounds after previous surgery and recurrent disease in a large Danish cohort from a high-volume centre. The study is based on a prospective database established at Randers Regional Hospital in 2016. All patients undergoing BCL surgery from June 2016 until October 2022 were included in this study. In all, 560 patients underwent BCL surgery at our centre during this period. Eighty-eight (15.7%) were women. Only 10 (11.3%) were operated due to primary extensive manifestations. The rest presented with either non-healing wounds after previous surgery (47.7%) or recurrent PSD (41%). Risk of recurrence in female patients was 30% higher than in male patients (risk ratio 1.30, 95% CI 0.79-2.09) and the risk of prolonged healing after BCL surgery was 46% higher in women compared to men (risk ratio 1.46, 95% CI 1.02-2.14). Female PSD patients may represent a subcategory of patients at higher risk of treatment failure and should be dealt with as such. Initially, few present with the need for extensive surgery. However, given the common occurrence of prolonged healing and recurrence, we recommend a minimal invasive approach when possible.

Safety and efficacy of conversion therapy for metastatic esophageal cancer: Exploratory analysis of JCOG1314.

401 Background: Patients with esophageal cancer (EC) with distant metastasis were treated with systemic chemotherapy. Recent advances in multimodal treatments have made conversion therapy (CT) a viable option for patients with metastatic EC. JCOG1314 was a randomized phase III trial to confirm the survival benefit of docetaxel plus cisplatin plus 5-fluorouracil (DCF) versus cisplatin plus 5-fluorouracil (CF) as initial treatment for unresectable or recurrent esophageal cancer. The purpose of this study was to evaluate the safety and survival impact of CT in patients enrolled in JCOG1314. Methods: CT was defined as surgery or chemoradiotherapy (CRT) aiming at cure after initial treatment for tumors that were initially unresectable due to distant metastasis. Clinicopathologic factors, surgical outcomes, toxicities during CRT, and survival were compared between CT and non-CT groups. CTCAE v4.0-JCOG was used to evaluate postoperative complications and adverse events during CRT. Results: Between September 2014 and April 2021, 240 patients were randomized to CF or DCF. Excluding patients with recurrent disease, 154 patients with initially unresectable esophageal cancer due to distant metastasis were selected for this study. Among them, 21 patients received CT which included conversion surgery (n=5) and conversion CRT (n=16). There was no significant difference in the number of metastatic organs, depth of invasion of the primary tumor, lymph node metastasis, and chemotherapy regiment between CT and non-CT groups. The most common M1 factor in CT group was the thoracic lymph node, followed by abdominal lymph node and cervical node. In conversion surgery group, there was no incidence of Grade 3 or higher pneumonia/leakage. Regarding the Grade 3 or higher non-hematological toxicities during conversion CRT, the incidence of appetite loss/ oral mucositis/pneumonia was 2 (13%)/2 (13%)/1 (6%), respectively. The 3-year overall survival (OS) of CT and non-CT groups was 52.4% and 14.3%, respectively. On multivariable analysis, patients with CT showed significantly better OS compared with the non-CT group (HR 0.36, 95% CI 0.19-0.67, p<0.01). In patients who underwent CT, there was no significant difference in OS between conversion surgery and CRT groups. Conclusions: This study demonstrated that CT was safely performed with favorable prognosis. A prospective study is warranted to investigate whether CT would improve survival in metastatic esophageal cancer.

EVEREST-2: A seamless phase 1/2 study of A2B694, a logic-gated Tmod chimeric antigen receptor T-cell (CAR T) therapy, in patients with pancreatic cancer (PANC) or other mesothelin (MSLN)-expressing solid tumors and human leukocyte antigen (HLA)–A*02 loss of heterozygosity (LOH).

TPS788 Background: MSLN is a desirable candidate for targeted therapy given its limited expression in normal tissues and its overexpression in several malignancies, including PANC, mesothelioma, non-small cell lung, and ovarian cancers (TCGA 2022). MSLN-targeted CAR T and T-cell receptor therapies have shown promising clinical activity; however, on-target, off-tumor toxicity, including fatal events, have occurred (1-3). Autologous logic-gated Tmod CAR T therapies address the challenges of on-target, off-tumor toxicity by combining 2 CARs: activating and blocking receptors. The activator recognizes a tumor-associated antigen present on the surface of both tumor and normal cells; the blocker prevents CAR T activity when it binds HLA-A*02, which is present in normal cells and often lost in tumor cells. Thus, in patients with tumor-associated HLA-A*02 LOH, the blocker prevents on-target, off-tumor toxicity on normal cells due to retained HLA-A*02 expression (4). HLA-A*02 LOH is observed in various solid tumors, including ~20% of PANC (5). Two autologous CAR T therapies are currently under investigation: A2B530, targeting carcinoembryonic antigen, in the EVEREST-1 trial, and A2B694, targeting MSLN, in the EVEREST-2 trial, described herein. A2B694 may provide a therapeutic window to treat patients with PANC and other MSLN-expressing solid tumors exhibiting HLA-A*02 LOH due to its unique discriminatory mechanism. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 for recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including PANC. Eligible patients must have exhausted options of potentially curative therapy and have recurrent disease. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), in which patients with tumor-associated HLA-A*02 LOH are identified via next-generation sequencing (Tempus AI, Inc) and leukapheresis product is collected. A2B694 is manufactured from cryopreserved T cells when clinically appropriate for patients. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B694 and identify the recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Phase 2 will assess the primary endpoint overall response rate per RECIST v1.1 and secondary endpoints progression-free survival and overall survival. The first patient was dosed on April 24, 2024 and dose escalation is ongoing. 1. Beatty, et al. Gastroenterology . 2018. 2. Haas, et al. Mol Ther . 2023. 3. Hong, et al. ESMO 2021. Abstr 9590. 4. Hamburger, et al. Mol Immunol . 2020. 5. Hecht, et al. J Clin Oncol . 2022. Clinical trial information: NCT06051695 .

MIR218 polygenic risk score is associated with cognitive function and neurochemical metabolites among patients with depressed bipolar disorders.

Evidence from animal and population studies has consistently revealed that microRNA 218 (MIR218) is involved in susceptibility to depression and cognitive functions. Nevertheless, few studies have evaluated the association between MIR218 and clinical features in patients with depressed bipolar disorder (BD). A total of 66 patients with depressed BD and 49 healthy controls (HCs) were recruited for this study. MIR218 polygenic risk score (PRS) was used to assess the addictive effects of the MIR218 regulated genes. We compared the MIR218 PRS between patients with depressed BD and HCs to investigate whether it can be used to predict the risk of BD, and further explored the association between MIR218 PRS and cognitive performance as well as neurochemical metabolites among depressed BD. We found that there was a significant difference in MIR218 PRS between patients with depressed BD and HCs. The correlation analysis indicated that MIR218 PRS was negative associated with the number of disease onset (r=-0.311, P=0.033) and choline (Cho)/creatine (Cr) in right thalamus (r=-0.285, P=0.021). Additionally, as supported by previous findings, patients with lower MIR218 PRS presented more domains of impaired cognitive function than those with higher scores. These findings suggested MIR218 PRS might be useful in differentiating patients with depressed BD from HCs. Moreover, depressed BD with lower MIR218 PRS showed more pronounced cognitive impairment than those with higher scores, which may be associated with disease recurrence and Cho metabolism in right thalamus.

Frequency of surveillance CT scan ordering in patients with stage II/III colorectal cancer.

106 Background: Patients with stage II/III colorectal cancer (CRC) undergo surveillance CT scans to detect early asymptomatic oligometastatic spread, which can be treated with curative intent. However, randomized clinical trials show no difference in 5-year mortality in those that undergo low intensity surveillance (annual) compared a higher intensity strategy (every 6 months). In Ontario, the Program in Evidence-Based Care (PEBC), Ontario Health (Cancer Care Ontario) guidelines recommend surveillance CT scan for patients with stage II/III CRC every 12 months. We aimed to determine the frequency at which clinicians in our Ontario-based hospital system ordered surveillance CT scans for patients with stage II/III CRC. Methods: This single centre retrospective cohort study included all patients that underwent surgical resection for CRC from April 1, 2018 – March 31, 2019 at our academic tertiary care centre in Ontario, Canada. We excluded patients that were followed at an outside hospital, had stage IV disease, had disease recurrence, had a concurrent neoplasm, or did not have CRC. The primary outcome was the proportion of surveillance CT scans completed 10+ months after the previous scan. We also described sociodemographic and medical characteristics of included patients. Follow-up was until August 2023. Results: We included 200 patients. The median age was 62 years (IQR: 52-70), 48% (N=96) were female, the rectum was the most commonly involved disease site (43%, N=86), 38% (N=76) had stage III disease, and 54% (N=107) received adjuvant chemotherapy. A total of 1286 scans were ordered during the study period. Of these, 67% (N=860) were ordered as surveillance. Of these, 18% (n=155) were completed 10 months or longer from the previous scan. The median time interval between surveillance scans was 6.6 months (IQR: 5.9-7.9). Approximately 20% (n=137 of 630) of surveillance scans ordered by general surgeons were completed 10 months or longer from the previous scan, whereas only 9% (n=18 of 205) of scans ordered by medical oncologists were completed 10 months or longer from the previous scan. Less than 1% of surveillance scans (n=3) identified new metastatic disease. Conclusions: The minority of surveillance CT scans ordered in patients with stage II/III CRC in our hospital were timed in concordance with Ontario-based guidelines. Future studies should seek to standardize ordering habits such that they align with best practices.

Updated results from ALTER-H004 study: Anlotinib combined with TACE as adjuvant therapy in patients with hepatocellular carcinoma (HCC) at high risk of recurrence after surgery—A single arm, multi-center, phase II clinical trial.

588 Background: High recurrence rate after curative resection significantly compromised the long-term survival of patients with HCC patients (pts). TACE as adjuvant therapy was proved to improve clinical outcomes for pts with high recurrence risk factors after hepatectomy. However, the prognosis of TACE reminded unsatisfactory and controversial. Therefore, this study aimed to identify the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. The preliminary results had been reported in 2024 ASCO GI (Poster 513) and the update results were reported here with longer follow-up duration. Methods: HCC pts with one of the following high risk factors after hepatectomy: ≥5 cm and <10 cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng's classification I/II) were recruited. Eligible pts received cTACE treatment within 1-2 months after hepatectomy, on the 3-5th day after cTACE, oral anlotinib (12mg, qd, d1-d14, q3w) was given until disease recurrence or unacceptable toxicity. The predefined sample size was 30. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety. Results: The data cut-off date was April 2024, 29 pts were enrolled and 27 pts received at least once tumor assessment. The median follow-up was 34.1 (IQR, 32.0-40.9) months. Of 27 with assessable efficacy, mDFS was 40.9 (95% CI, 11.4-70.3) months, with 1-, 2-, and 3-year DFS rates of 72.1% (95% CI, 50.2%-85.6%), 63.0% (95% CI, 40.7%-78.9%), and 56.7% (95% CI, 33.6%-74.5%), respectively. 21 of 27 pts (77.8%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 5 pts (18.5%) included hypertension (7.4%), leukocytopenia (7.4%) and ascites (3.7%), and blood bilirubin increased (3.7%). No grade 4 or 5 TRAEs occurred. Conclusions: Anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited encouraging efficacy and tolerable safety profile. And the conclusions needed to be confirmed in large scale clinical trials subsequently. Clinical trial information: NCT04213118 .

The role and molecular mechanism of GDF5 in regulating cell migration and angiogenesis via the Hippo-YAP signaling pathway in colorectal cancer.

292 Background: Distant metastasis is a leading cause of poor prognosis and mortality in colorectal cancer (CRC) patients, with angiogenesis playing a crucial role in tumor progression. The TGF-β superfamily has been shown to significantly influence tumor angiogenesis, yet the biological function and molecular mechanism of Growth Differentiation Factor 5 (GDF5), a member of this superfamily, remain unexplored in CRC. Given that the efficacy of current anti-angiogenic therapies is limited to a subset of patients, identifying new therapeutic targets involved in tumor angiogenesis is of great clinical importance. GDF5, with its potential role in angiogenesis regulation, presents a promising candidate to bridge this therapeutic gap. Methods: In this study, we analyzed GDF5 expression in CRC tissue samples using both the TCGA dataset and samples from our center, revealing significantly lower GDF5 expression in tumors compared to adjacent normal tissues. Moreover, GDF5 downregulation correlated with lymph node metastasis and disease recurrence. Functional assays in vitro demonstrated that GDF5 overexpression reduced tumor cell migration and invasion, while its knockdown produced the opposite effect. Co-culture assays showed that GDF5 knockdown significantly enhanced endothelial cell migration and angiogenesis, whereas overexpression diminished these effects. Additionally, F-actin cytoskeletal staining indicated that GDF5 overexpression led to cytoskeletal remodeling in endothelial cells. Mechanistically, we found that GDF5 overexpression in tumor cells downregulated the epithelial-mesenchymal transition (EMT) marker Slug and upregulated E-cadherin, while downregulating N-cadherin. In endothelial cells, GDF5 inhibited the Hippo-YAP signaling pathway, increasing YAP phosphorylation and reducing nuclear YAP levels. Conversely, GDF5 knockdown suppressed YAP phosphorylation and promoted its nuclear translocation. Results: Our findings demonstrate that GDF5 functions as a tumor suppressor in CRC by regulating cell migration and angiogenesis. This study reveals that GDF5 exerts its anti-cancer effects by modulating both EMT in tumor cells and cytoskeletal changes in endothelial cells, leading to the inhibition of the Hippo-YAP signaling pathway and reduced angiogenic potential. These results identify GDF5 as a promising new target for anti-angiogenic therapy in CRC, offering potential avenues for improving treatment strategies in patients resistant to current therapies. Conclusions: GDF5 acts as a tumor suppressor in colorectal cancer by inhibiting cell migration and angiogenesis through modulation of the Hippo-YAP signaling pathway, making it a promising therapeutic target for anti-angiogenic treatment in patients resistant to current therapies.

Updated results of ALTER-H006: A phase II study of benmelstobart (PD-L1 inhibitor) plus anlotinib as adjuvant therapy in hepatocellular carcinoma (HCC) with high risk of recurrence after radical resection.

601 Background: Although radical resection offers one of the most favorable prognosis for hepatocellular carcinoma (HCC), the rate of postoperative recurrence remains high, which is the primary cause of mortality in HCC patients. The optimal adjuvant treatment strategy for patients is still under active investigation. Herein we evaluated the efficacy and safety of the anti-angiogenic tyrosine kinase inhibitor, anlotinib, plus benmelstobart, a novel programmed death-ligand 1 (PD-L1) inhibitor as an adjuvant treatment for HCC with high risk of recurrence after radical resection. Methods: This study enrolled patients diagnosed with HCC confirmed through histological or cytological examination, whose age was 18-75, with ECOG 0-1, Child-Pugh class A, 4~8 weeks after R0 resection with any of the following high-risk factors for recurrence: a) tumor nodules ≥4; b) portal vein tumor thrombus (PVTT): vp1 or vp2; c) hepatic vein tumor thrombus (HVTT): vv1 or vv2. Enrolled patients received anlotinib (12 mg, p.o., qd, d1-14, q3w) plus benmelstobart (1200 mg, i.v., d1, q3w) until disease recurrence or unacceptable toxicity or up to 18 cycles (~1 year), whichever occurred first. Tumor assessment was performed at the end of the second cycle and every four cycles thereafter, according to RECIST v1.1. The predefined sample size was 37. The primary endpoint was 1-year recurrence-free survival (RFS) rate. Secondary endpoints included RFS, 1-year overall survival (OS) rate, and safety. Results: As the cutoff date of September 13,2024, a total of 38 patients (pts) were enrolled and 35 pts included in per-protocol set analysis. The majority of the 38 pts were male (94.7%, n = 36), and the median age was 56.5 years (range: 33-75). 18 pts (47.3%) had CNLC Stage IIb and 20 (52.6%) had CNLC Stage IIIa HCC. Among them, 35 pts received at least once tumor assessment. According to RECIST 1.1, of the 35 pts, 18 had no recurrence, 15 experienced relapse, 1 dropped out and 1 discontinued due to serious adverse events. The 1-year RFS rate was 59.97% (95%CI: 39.12-79.68) and the primary median RFS was 16.89m(95%CI: 6.82-26.96). The 1-year OS rate was 91.47% (95%CI: 69.23-97.86). 34 of 38 pts (89.5%) experienced treatment-related adverse events (TRAEs). The most common grade 3 TRAEs occurred in 17 pts (44.7%) including hypertension (32%) and neutropenia(5.3%). No grade 4 or 5 TRAEs were observed. Conclusions: The present study indicated that anlotinib plus benmelstobart as adjuvant treatment for HCC with high risk of recurrence after radical resection exhibited promising efficacy and tolerable safety profile. The conclusion should be validated in more participants included subsequently. Clinical trial information: NCT05111366 .

Neoadjuvant PD-1 blockade in mismatch repair-deficient or microsatellite instability-high, locally advanced and resectable colorectal cancer: A retrospective real-world analysis.

185 Background: Neoadjuvant PD-1 blockade therapy has shown encouraging efficacy in patients with mismatch repair- deficient (dMMR)/microsatellite instability-high (MSI-H) locally advanced colorectal cancer. However, data from the real-world setting are scarce. Methods: We retrospectively collected clinical data of patients with dMMR/MSI-H locally advanced colorectal cancer diagnosed between 2022-2024 that received neoadjuvant anti-PD-1 monotherapy at the First Affiliated Hospital of Zhengzhou University. Pathological complete response, clinical complete response, R0 resection rate, and safety were analyzed. All statistical analyses were conducted using SPSS Statistics, version 22.0. Results: A total of 45 patients were enrolled. As of the data cutoff (Sep 15, 2024), the median follow-up was 14.0 months (range: 4.0-31.4). The median age was 53 years (range: 29.0–78.0) and 25 (55.6%) of 45 patients were male. 32 (71.1%) patients had clinical stage III disease and 39 (86.7%) patients had colon cancer. A higher proportion of patients (53.3%) had clinical T4 stage. 37 patients underwent the surgery of whom 29(78.9%) had a pathological complete response. The R0 resection was 100%. The median treatment duration was 4 cycles (range: 2-10). Among the 18 patients who received equal to or less than 4 cycles, the pCR rate was 77.8%, while for the remaining 17 patients who had more than 4 cycles of treatment, the pCR rate was 84.2%. Eight other patients had a clinical complete response and chose the watch and wait strategy. Treatment-related adverse events ≥3-4grade were observed in 3 patients. All patients survived without any disease recurrence. Conclusions: In this retrospective analysis, anti-PD-1 monotherapy is effective and tolerable for patients with dMMR/MSI-H locally advanced colorectal cancer. This study shows that pCR rate increases is associated with a longer treatment cycles probably. Further analysis of larger real-world datasets with longer follow-up will be essential to validate these results.

24-week, all-oral regimens for pulmonary rifampicin-resistant tuberculosis in TB-PRACTECAL trial sites: an economic evaluation.

New 6-month rifampicin-resistant tuberculosis treatment regimens containing bedaquiline, pretomanid, and linezolid (BPaL) with or without moxifloxacin or clofazimine, could improve treatment efficacy, safety, and tolerability, and free up resources within the health system. Following a change to WHO rifampicin-resistant tuberculosis treatment guidelines, countries are facing difficult decisions about when and how to incorporate new drug regimens into national guidelines. We aimed to assess the probability of BPaL-based regimens being cost-saving using data collected in the TB-PRACTECAL trial. This economic evaluation using a cost-utility analysis was embedded in five TB-PRACTECAL trial sites in Belarus, Uzbekistan, and South Africa. Between Nov 19, 2020, and Sept 27, 2022, we collected detailed primary unit cost data in six hospitals and four ambulatory health facilities and collected data on patient-incurred costs from 73 trial participants. The primary efficacy endpoint of the main trial, a composite of unfavourable outcomes (death, disease recurrence, treatment failure, early discontinuation of therapy, withdrawal, or loss to follow-up) and clinically important safety outcomes by 72 weeks of follow-up were incorporated into the analysis. Societal perspective cost data and effect outcome data were input into a Markov model to estimate the cost per disability-adjusted life-year (DALY) averted by BPaL-based regimens compared with the standard of care over a 20-year time horizon. We conducted a range of univariate and probabilistic sensitivity analyses to test our findings. BPaL-based regimens averted a mean of 1·28 DALYs and saved a mean of US$14 868 (SD 291) per person from the provider perspective compared with standard-of-care regimens over 20 years. Patient-incurred costs were reduced by a mean of $172 (SD 0·84) in BPaL-based regimen groups compared with standard of care. The main cost drivers for both providers and patients were inpatient bed-days; the duration of the inpatient period varied across countries. Varying a range of model parameters affected the degree of cost savings but did not change the finding that BPaL-based regimens are cost-saving compared with standard of care. This trial-based evidence adds to consistent indications from modelling studies that BPaL-based regimens are cost-saving for both the patient and health system. Urgent implementation of BPaL-based regimens in countries with a high burden of tuberculosis could improve treatment of rifampicin-resistant tuberculosis, reduce pill burden, and free up desperately needed resources within the health system. Médecins Sans Frontières.