Localized Disease Research Articles

Penile Carcinoma Cuniculatum: A Case Report of an Extremely Rare Subtype of Squamous Cell Carcinoma.

Carcinoma cuniculatum is a very rare subtype of well-differentiated squamous cell carcinoma affecting several anatomical locations, including the penis. In this paper, we describe a case report of penile carcinoma cuniculatum highlighting some unusual clinical features. The patient was 61-year-old with a cauliflower-like tumor of the glans penis of less than 1-year duration. Microscopic examination revealed a p16-negative well-differentiated squamous proliferation characterized by narrow and cystic spaces extending through the lesion. Carcinoma cuniculatum is characterized by a strong tendency to deep penetration, typically presenting in patients in their seventh to eighth decades and with a long duration of the disease. In contrast, the tumor presented herein occurred in a younger patient with a shorter disease duration and showed only shallow growth into the underlying structures. Since penile carcinoma cuniculatum is a local disease without metastatic potential (regardless of tumor size and disease duration), awareness of this entity is important, especially for distinguishing it from other more aggressive subtypes of squamous cell carcinoma, which require different therapeutic approaches.

Local tick populations and human disease risk along popular hiking trails in northern California after multiple weather extremes

Local tick populations and human disease risk along popular hiking trails in northern California after multiple weather extremes

Most oncological pancreas resections must consider the mesopancreas.

In preoperative staging for patients with a ductal adenocarcinoma of the pancreatic head (PDAC), resectability is anatomically characterized by the possible clearance of the medial vascular grove. Borderline resectable PDAC patients who retain an increased risk of infiltration to the portomesenteric system and/or arterial vasculate are candidates for neoadjuvant therapy. However, redefined pathological analysis revealed the dorsal resection margin to be similar at risk for R1 resection. Mesopancreatic excision (MPE) aims to secure the integrity of the dorsal and ventral resection margins. The existence of the mesopancreas (MP) is inevitable, since the pancreas is of a secondary retroperitoneal nature and the dorsal as well as ventral fascial coverings define the peripancreatic compartment anatomy. It remains unknown if the MP area is only infiltrated in high-risk PDAC patients or if MPE during pancreatoduodenectomy should be employed for localized PDAC patients as well. Patients who underwent upfront pancreatoduodenectomy were included. CRM evaluation and analysis of the MP was standardized in all patients. Patients were sub-grouped by the infiltration status of the vascular groove (localized disease: LOC). In LOC patients there was evidently no cancerous infiltration into the medial vascular groove (true + primary resectable). Two hundred eighty-four consecutive patients who underwent pancreatoduodenectomy were included (169 LOC patients). In LOC patients the MP infiltration rate remained high but was significantly lower when compared to advanced PDAC patients (MP + 69.2% vs. 83.5%, p = 0.005). In LOC patients, CRM resection status of the dorsal resection status remained significantly affected by the MP infiltration status (R0CRM- 80.5% vs. 62.8%, p = 0.019). These important findings clearly show underestimated tumor extensions into the mesopancreas even in localized, primary resectable PDAC patients who are currently amenable for upfront resection. Synergistically to total mesorectal or mesocolic excision, which is applied to all stages of colorectal disease, MPE is justified in primary resectable patients as well. Therefore, MPE should be employed in all PDAC patients. Since the infiltration status of the mesopancreas was a significant factor for incomplete resection in primary resectable PDAC patients, neoadjuvant treatment options for must be discussed.

Radiotherapy-Associated Cellular Senescence and EMT Alterations Contribute to Distinct Disease Relapse Patterns in Locally Advanced Cervical Cancer.

A notable number of locally advanced cervical carcinoma (LACC) patients experience local or distant disease relapse following radiotherapy. The contribution of tumor microenvironment (TME) to tumor recurrence at different sites remains unclear. Here, single-nucleus RNA sequencing data from 28 pre- and on-treatment LACC samples from patients with different disease relapse patterns is analyzed. The findings revealed opposing alterations in the expression levels of the cellular senescence pathway after radiotherapy in patients with local and distant relapses. In contrast, an increase in the expression of the epithelial-mesenchymal transition module after radiotherapy in both relapse groups is observed. Cell-cell interactions, drug-target expression analyses in malignant cells after radiation, and multiplex immunofluorescence of tumor tissue identified interleukin-1 receptor type I (IL1R1) as a potential therapeutic target. It is demonstrated that combining the IL1R1 inhibitor anakinra with radiation can mitigate the effects of radiation on tumor cells. This study highlights the distinct roles of cellular senescence and EMT in tumor recurrence.

The relationship between involutional ectropion and inflammatory disorders of the eyelids and ocular surface: insights from a large-scale national study

This study investigated potential associations between ectropion and various chronic and systemic inflammatory diseases affecting the eyelids and ocular surface. This retrospective case-control study, spanning 2001–2022, used electronic medical records from Clalit Health Services (CHS) in Israel. Patients diagnosed with involutional ectropion served as the case group, while two control groups were used for comparison: one comprising patients diagnosed with senile cataract and the other with various ophthalmic diseases. Matching for the control groups was performed at a 1:3 ratio based on year of birth, sex, and ethnicity. A total of 17,292 patients with involutional ectropion and 51,876 matched controls in each group were included. The average age of the patients with involutional ectropion was 78 ± 10 years and 58% were men. Significant associations were found between involutional ectropion and several local inflammatory eyelid diseases: blepharitis (OR 4.66), chalazion (OR 2.94), hordeolum (OR 2.26), and dermatitis of the eyelid (OR 2.46). Ocular surface diseases associated with ectropion included chronic conjunctivitis (OR2.89 ) and pterygium (OR 2.48). Systemic diseases such as hypertension (OR 1.46), dyslipidemia (OR 1.45), and autoimmune rheumatic diseases (OR 1.43) were also associated with involutional ectropion. This study found that localized chronic inflammatory conditions affecting the periocular tissues and ocular surface are significantly associated with the development of involutional ectropion.

Gravity-based microfiltration reveals unexpected prevalence of circulating tumor cell clusters in ovarian and colorectal cancer

BackgroundCirculating tumor cells (CTCs) are rare (a few cells per milliliter of blood) and mostly isolated as single-cell CTCs (scCTCs). CTC clusters (cCTCs), even rarer, are of growing interest, notably because of their higher metastatic potential, but very difficult to isolate.MethodWe introduce gravity-based microfiltration (GµF) for facile isolation of cCTCs using in-house fabricated microfilters and 3D printed cartridges. Optimal flow rate and pore size for cCTC isolation are determined by GµF of cultured ovarian single cells and cell clusters spiked in healthy blood. We perform GµF of blood from orthotopic ovarian cancer mouse models and characterize the morphological features of scCTCs and cCTCs, and the expression of molecular markers for aggressiveness. Finally, we analyze blood from 17 epithelial ovarian cancer patients with either localized or metastatic disease, and from 13 colorectal cancer liver metastasis patients.ResultsHere, we show that GµF optimized for cell cluster isolation captures cCTCs from blood while minimizing unwanted cluster disaggregation, with ~85% capture efficiency. We detect cCTCs in every patient, with between 2–100+ cells. We find cCTCs represent between 5–30% of all CTC capture events, and 10-80% of the CTCs are clustered; remarkably, in 10 patients, most CTCs are circulating not as scCTCs, but as cCTCs.ConclusionsGµF uncovers the unexpected prevalence and frequency of cCTCs including sometimes very large ones in epithelial ovarian cancer patients, and motivates additional studies to uncover their properties and role in disease progression.

A familial early-onset Crohn's disease-based testing of a small bowel versus colonic location-associated discovery gene network.

What is Known IBD has a complex, polygenic genetic origin with multiple susceptibility genes. We recently reported candidate gene networks may direct disease location between small bowel‐predominant Crohn's disease (SB‐CD, L4b) or colon‐predominant CD (C‐CD, L2 and/or colon‐predominant L3).What is New? Exome sequencing in a unique family refined CD location‐specific networks: SB‐CD: SVEP1, DSG1 SNPs were most discriminatory. C‐CD: ACACB, PDCD6IP SNPs were most discriminatory.

Chondrosarcoma in Japan: an analytic study using population-based National Cancer Registry.

Chondrosarcoma (CS) is a rare malignant bone tumor exhibiting diverse histological features and clinical behaviors. This study aimed to investigate the epidemiological characteristics, clinical features, prognostic factors, and subtype-specific differences of CS in Japan using National Cancer Registry data. We analyzed data from CS cases diagnosed between 2016 and 2019, calculating age-adjusted incidence, estimating overall survival, and identifying prognostic factors through multivariate analysis. The study identified 1015 CS cases with an age-adjusted incidence of 0.159 per 100 000 population and a mean overall survival of 1205.2days. Multivariate analysis revealed that female sex, younger age (15-39years), histological subtypes other than dedifferentiated CS, localized disease, and surgical treatment were associated with better prognoses. Conversely, male sex, older age (≥75years), dedifferentiated subtype, advanced stage, and non-surgical treatment were linked to a higher risk of death. Significant differences in sex distribution, age at diagnosis, tumor location, disease stage, and tumor differentiation were observed among CS subtypes. This comprehensive analysis provides valuable insights into CS epidemiology, prognostic factors, and subtype-specific characteristics in Japan. The identification of high-risk groups emphasizes the need for improved therapeutic strategies and supportive care. The observed heterogeneity among CS subtypes underscores the importance of individualized management approaches in treating this complex malignancy.

A cross-sectional analysis from a real-world cohort of patients with microsatellite instability colorectal cancer (MSI-CRC) with localized disease from the Spanish RETUD registry.

173 Background: Microsatellite instability (MSI) localized colorectal cancer (CRC) constitutes a subgroup of patients (pts) with different clinical and molecular characteristics and prognosis compared to microsatellite stable (MSS) disease. Here, we present our real world data regarding the management and clinical outcomes of a cohort of MSI-h localized CRC patients included in the Spanish Group of Treatment of Digestive Tumors (TTD) Registry (RETUD). Methods: RETUD is a national, multicenter registry for gastrointestinal tumors from the Spanish TTD Group. In this cross-sectional analysis we evaluated a real-world cohort of MSI-h localized CRC pts diagnosed from 1 st January 2017 to 29 th April 2024. Baseline characteristics and neo/adjuvant treatments are descriptively presented. Disease-free survival (DFS) and overall survival (OS) analyzed by Kaplan-Meier method are presented along with 95% confidence intervals (CI). Results: Five hundred and sixty-one (561) evaluable pts out of 679 MSI-CRC included in RETUD had a localized disease as initial diagnosis. Pts had a median age of 73.1 years and were predominantly Caucasian (97.7%) and female (52.6%). Fifty (12.4%) pts had Lynch Syndrome. Main tumor baseline characteristics are described (Table). Local-locoregional therapeutic procedures were: primary tumor resection in 531 (99.1%) pts and radiotherapy in 18 (3.2%) pts. A total of 198 (35.3%) pts received systemic therapy, mostly chemotherapy (n=165 83.3%) but 18 (9.1%) were treated with pembrolizumab due to unresectable disease. At database cut-off, 123 (21.9%) patients died, mostly due to not related intercurrent illness, and 96 (17.1%) pts developed metastasis. After a median follow up period of 28.5 months, the median (95% CI) OS was not reached and DFS was 78.2 (55.4-NA) months. The impact of adjuvant systemic therapy (chemotherapy vs. non-chemotherapy) for both stage II and stage III pts is under evaluation. Conclusions: Our work provides valuable real-world data from a cohort of MSI-h localized CRC pts treated under clinical practice conditions in Spain, reiterating the good disease prognosis exhibited by this subset of pts in contrast to MSS pts. Main tumor characteristics. Stage at initial diagnosis, n (%) I/II n (%) 55 (9.8) / 258 (46.0) III, n (%) 248 (44.2) Location of primary tumor a , n (%) right colon /left colon /rectum 447 (78.4) / 82 (14.4) / 41 (7.2) Type histological b , n (%) Intestinal 271 (48.9) Mucinous (colloid) adenocarcinoma (>50% mucinous) 115 (20.8) Signet ring cell carcinoma (>50% signet ring) 14 (2.5) Medullary carcinoma 18 (3.2) a Pts with more than 1 primary tumor; the percentage may be over 100%. b Unknown histology in 132 (23.8%) pts and missing data in 7 pts.

Prevalence and Clinical Outcomes of Human Epidermal Growth Factor Receptor 2 Expression in Patients With Advanced Urothelial Carcinoma.

The prognosis for urothelial carcinoma remains poor, with limited therapeutic options, emphasizing the need for further research into targeted therapies. The prognostic and predictive significance of human epidermal growth factor receptor 2 (HER2) expression in urothelial carcinoma remains unclear, with previous studies reporting conflicting results. We conducted a retrospective analysis of advanced urothelial carcinoma cases diagnosed between January 2017 and December 2022. HER2 status was prospectively determined using the Leica CB11 antibody on available biopsy specimens. Patient data, tumor characteristics, and survival outcomes were retrieved from hospital records for analysis. Of the 84 patients initially identified with muscle-invasive disease, HER2 immunohistochemistry (IHC) was performed on 50 samples. Among these, 54% exhibited HER2 scores ≥ 1+, with 22% classified as HER2-positive (3+ score by IHC), 10% as equivocal (2+ score by IHC), and 22% as HER2-low (1+ score by IHC). The distribution of HER2 score ≥ 1+ tumors included 25.7% in the bladder, 20.0% in the renal pelvis, and none in the ureter. HER2-positive (3+ score by IHC) tumors were all histological grade 3. Among these patients, 13.4% presented with localized disease, 20% with locally advanced disease, and 50% with metastatic disease at the time of diagnosis. Notably, 42.8% of recurrent tumors originating from the renal pelvis and 62.5% of those from the bladder exhibited HER2 scores ≥ 1+. Among patients diagnosed with non-metastatic disease, 100% with renal pelvis tumors and 75% with bladder tumors experienced metastatic recurrence if they were HER2-positive (3+ score by IHC). The overall survival for HER2-negative patients was 31.0 months (95% confidence interval (CI): 15.29 - 66.70) compared to 13.0 months (95% CI: 7.32 - 18.68) in the HER2 score ≥ 1+ population (P = 0.0029). In this cohort of Mexican patients with urothelial carcinoma, HER2 expression was observed in 54.4% of cases. HER2-positive (+3 by IHC) tumors were associated with higher histological grade and worse prognostic outcomes, including increased recurrence, progression, and mortality.

Clinical outcomes and molecular characteristics of patients with locoregional ampullary carcinoma.

732 Background: Ampullary carcinoma (AC) is a rare malignancy arising from the ampulla of Vater which has a more favorable prognosis compared to other pancreatic malignancies. Current guidelines favor surgical resection followed by adjuvant therapy for average risk patients (pts), however the type of regimen as well as other perioperative treatment modalities are still being explored. The objective of this retrospective study aims to provide insight into the management of locoregional disease. Methods: Pathology records from Mayo Clinic (AZ, FL, MN) denoting AC between 2010 to 2024 were searched using Mayo Data Explorer and selected for retrospective review. Pt demographics, treatment courses, and next generation sequencing (NGS) data were collected. Statistical analysis was conducted using SAS version 9.04. Results: A total of 137 pts (62% male, n = 85) were identified with median age 66 years old. Histologic subtypes were 54% pancreatobiliary (44/81), 40% intestinal (32/81), 6% mixed (5/81), with 56 pts unknown. Stages at diagnosis were 81% resectable (111/137), 11% locally advanced (15/137), and 8% metastatic (11/137). Nearly all (93%, n = 103/111) pts with localized disease had resection with a 97% R0 resection rate (100/103). Majority (68%, n = 75/111) of resectable pts had perioperative chemotherapy with 5-FU or gemcitabine-based regimens (24%, n = 18/75 neoadjuvant vs. 76%, n = 57/75 adjuvant). Perioperative chemoradiation was given in 17% (19/111) of pts. At median follow up of 30.5 months, recurrence rates were 40% (41/103), primarily to the liver (18/41). Median recurrence free survival (RFS) was 29.3 months (95% CI 24.7 – NE). Median overall survival (OS) has not been reached. The 5-year RFS and OS rates were 0.37 (95% CI 0.25 - 0.55) and 0.69 (95% CI 0.58 - 0.82), respectively. Univariate analysis showed no difference in OS with the addition of neoadjuvant or adjuvant chemotherapy or chemoradiation. Somatic NGS testing showed pathogenic mutations in 90% of pts (63/70): 57% KRAS (36/63; 44% G12D, 19% G12V, 8% G12C, 8% G12D, 19% others); 13% homologous recombination (HR) (8/63); 6% ERRB2 /Her2 amplification (4/63), and 5% mismatch repair (MMR) (3/63). Conclusions: AC has a favorable prognosis in resectable pts. However, high recurrence rates indicate the need for better systemic therapies and improved selection of pts who would benefit from these treatments. Future research should focus on refining perioperative strategies to enhance outcomes and reduce recurrence.

Characteristics and outcomes of patients with early-onset versus average-onset small bowel neuroendocrine tumors.

670 Background: The global incidence of early-onset gastrointestinal cancers (GI) is increasing. Although patients with more common early-onset GI cancers, e.g. colorectal cancer, often present with more advanced disease and experience relatively worse outcomes; the characteristics and treatment outcomes for less common early-onset small bowel neuroendocrine tumors (SBNETs) have yet to be explored. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with SBNETs (2004-2021), using ICD-0-3 SEER histology codes (8240/3, 8241/3, 8243/3, 8244/3, 8249/3, 8246/3). Patients with poorly differentiated histology were excluded. We used the chi-square test to compare categorical variables between early-onset SBNETs (EO-SBNETs, aged 30-49 years) and average-onset SBNETs (AO-SBNETs, aged ≥ 50 years) patients. Overall survival was estimated using the Kaplan-Meier method followed by application of the log-rank test to assess for differences in survival. A multivariable Cox regression analysis included early onset of disease, sex, race/ethnicity, marital status, urban/rural residence, prior treatments, and disease extent as covariates. All tests were conducted with a significance threshold of p < 0.05 using RStudio. Results: A total of 3,713 patients were included, of which, 925 (25%) were EO-SBNETs. Compared to AO-SBNETs, EO-SBNETs patients were more likely to be females (51.1% vs 46.7%, p=0.02), non-Hispanic Black (20.8% vs 17.6%, p=0.04), Hispanic (13.6% vs 8.8%, p<0.0001) and less likely to be non-Hispanic White 60.8% vs 69.9%, p<0.0001). There were no differences in stage at diagnosis between the EO-SBNETs and AO-SBNETs, i.e,, localized disease (33.5% vs 31.0%, p=0.15), regional spread (41.9% vs 42.8%, p=0.64) and distant metastatic disease (20.9% vs 21.9%, p=0.50). There were no differences in receipt of surgical resection (90.5% vs 89.1%, p=0.25) or chemotherapy (5% vs 6.3%, p=0.15) comparing EO-SBNETs and AO-SBNETs respectively. In a multivariate cox regression analysis, early onset was associated with a significantly better overall survival (HR=0.49, 95% CI 0.41-0.59, p<0.0001). Conclusions: With this first of its kind analysis, significantly superior overall outcomes among EO-SBNETs despite no differences in stage and receipt of surgery establishes age at diagnosis as a significant prognostic factor for SBNETs. Further studies investigating the role of factors such as differences in tumor biology and patient preferences in receipt of other therapies besides surgery are needed.

Impact of long-term chemotherapy (CTx) on outcomes in pancreatic ductal adenocarcinoma (PDAC): A real-world UK multi-centre study.

687 Background: PDAC is associated with poor outcomes with limited treatment options. Here, we present a multi-institutional review evaluating outcomes following short and long-term CTx with or without treatment breaks in PDAC patients (pts). Methods: All consecutive PDAC pts receiving > 3 CTx cycles between 2019 – 2023 at University College London Hospitals and Oxford University Hospitals were included. Treatment response, survival outcomes and predictors of clinical benefit were evaluated. Wilcoxon test, Kaplan-Meier and multivariate Cox regression models were performed. Results: Of the 213 screened pts, 127 eligible subjects met the study criteria. 1 st , 2 nd and 3 rd line CTx were received by 127, 40 and 2 pts, respectively. 21 pts had resectable disease (9 remained relapse-free after adjuvant CTx and 8 pts alive at post 2 years follow-up surveillance). 106 pts had unresectable or metastatic disease and were selected for final analyses (12% borderline resectable (BR), 19% locally advanced (LA), 9% localised disease who developed metastases and 60% de novo metastatic pts). 7 pts (7%) pts underwent genetic profiling on pt request or previous clinical trial screening; KRAS aberrations (N = 4), actionable PLAB2 / BRCA2 mutations (N = 2). BR and LA pts (N = 33) achieved a median PFS1 (Progression Free Survival while on 1 st line CTx) of 8.28 (95% Confidence Interval (CI), 5.49 – 15.11) and Overall Survival (OS) of 15.15 (95% CI, 9.46 – 26.41) months (mos). De novo metastatic pts (N = 64) attained a PFS1 of 6.64 (95% CI, 5.98 – 8.18) and OS of 9.30 (95% CI, 8.05 – 12.81) mos. Patient-specific factors in both cohorts comprising of age, gender, performance status, smoking history, co-morbidities were not associated with PFS1 and OS. Improved PFS was associated with ≥ 6 cycles of 1 st line CTx (P = < 0.001), median duration of 1 st CTx of ≥ 3.58 mos (P = < 0.001) and best response to 1 st CTx (P = 0.007). A favourable OS was associated with > 1 line of CTx (P = < 0.001), ≥ 6 cycles of 1 st line CTx (P = 0.009), median duration of 1 st CTx of ≥ 3.58 mos (P = < 0.001) and best response to 1 st CTx (P = 0.002). Subjects receiving ≥ 6 cycles of 1 st CTx were younger than pts tolerating fewer cycles (median age 62.41 vs 72.25 years) (P = 0.04). In the localised disease group, improved PFS was associated with ≥ 6 cycles of 1 st line CTx (P = 0.003), median duration of 1 st CTx of ≥ 2.99 mos (P = 0.008) and local treatment after commencing 1 st line CTx (P = < 0.001). These three factors were also associated with OS; P = 0.02, P = 0.02 and P = < 0.001, respectively. Median number and duration of 1 st line CTx interruptions were not associated with PFS1 or OS in both cohorts. Conclusions: Despite challenges associated with long-term CTx, survival outcomes may be better in pts receiving CTx for longer periods and multiple treatment lines. Genetic profiling currently offers limited value but in carefully selected pts, localised treatment options may be associated with improved survival outcomes.

A comprehensive molecular and clinical study of patients with young-onset CRC.

235 Background: Young-onset colorectal cancer (YO-CRC), defined as colorectal cancer diagnosed in individuals under 50 years of age, has emerged as a distinct clinical entity, often presenting at advanced stages. Despite the increasing incidence, molecular and clinical underpinnings of YO-CRC remain underexplored. This study aims to characterize the clinical and molecular features of YO-CRC and to evaluate their impact on OS. Methods: We retrospectively reviewed 110 patients diagnosed with YO-CRCfrom our institution’s molecular database. All patients underwent next-generation sequencing. Demographic, clinical, and molecular data, including age, gender, race, tumor location, cancer stage, and mutation status (KRAS, NRAS, BRAF, POLE, ERBB-2/HER2, microsatellite status), were collected by reviewing electronic medical records. For OS analysis, we focused on patients diagnosed with de novo Stage 4. Cox proportional hazards regression and Kaplan-Meier survival analysis were utilized to assess the association of these factors with OS, with statistical significance determined by a p-value threshold of <0.05. Results: Among 110 patients, N=44 (40%) presented with local disease (stage 1-3), while N=66 (60%) patients presented with de novo metastatic disease at the time of diagnosis. The median age at diagnosis was 44.5 years. The cohort consisted of 64% males and 36% females, with 84% of patients identified as White. Most tumors were left-sided (77%), including the distal colon/sigmoid (44%) and rectum (33%). KRAS and BRAF mutations were present 36% and 5.5%, respectively. ERBB-2/HER2 amplification and microsatellite instability were observed in 4.5% and 6.4% respectively. Tumor mutation burden (TMB) was <10 in 57% of patients, with 14% having TMB >20. CNV analysis revealed that 14% of patients had copy gains, 12% had concurrent gains/losses, and 31% had copy losses. Among the 66 Stage 4 patients, 44% had died by the time of analysis, with a median overall survival (OS) of 43.6 months (95% CI, 28.7 - not reached). KRAS mutation was found to be significantly associated with worse survival outcomes. Cox regression analysis reveals the prognostic significance of KRAS status, with a hazard ratio (HR) of 3.52 (95% CI: 1.59-7.76, P = 0.002 < 0.05), indicating a significantly higher risk of death for KRAS-mutant YO-CRC patients. Conclusions: KRAS mutations are a key prognostic factor in YO-CRC, highlighting the need for therapeutic need to improve outcomes in this high-risk group.

A phase I, single-center, open label, dose de-escalation and expansion study of Ivosidenib + mFOLFIRINOX in patients with resectable pancreatic adenocarcinoma.

TPS794 Background: Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis, with a 34% 5-year survival rate for patients with localized disease. Guidelines recommend consideration of neoadjuvant approaches in localized PDA with the goals of controlling microscopic metastatic disease and increasing rates of microscopically margin-negative resections. One of the hallmark characteristics of PDA is a micronutrient poor, highly stromal microenvironment. Surviving in this environment requires enhanced mitochondrial function, which utilizes isocitrate dehydrogenase 1 (IDH1). In pre-clinical studies, ivosidenib, an FDA approved medication for IDH1 mutant AML, induced high levels of reactive oxygen species in PDA cells with wild-type IDH1, and caused tumor regressions and extended survival in implanted KPC mouse models. Here, we investigate the addition of ivosidenib to standard of care neoadjuvant mFOLFIRINOX in patients with resectable PDA to determine safety, pharmacodynamics, and early efficacy signals. Methods: This is a phase I, single-center, open label, dose de-escalation and expansion study in patients with resectable PDA. Eligible patients must have histologically confirmed and resectable right-sided PDA based on CT or MRI imaging. Patients receive approximately 10 weeks of neoadjuvant treatment composed of 2 weeks of ivosidenib monotherapy, followed by 6 weeks (3 cycles) of mFOLFIRINOX with ivosidenib, followed by up to 4 weeks of ivosidenib monotherapy until the day of surgery. Ivosidenib is administered once daily at 500mg; it is to be de-escalated to 250mg based on Bayesian Optimal Interval Design with Informative Prior and a target dose limiting toxicity (DLT) rate of 30%. The primary endpoint is to determine the safety and tolerability of ivosidenib in combination with mFOLFIRINOX. Secondary endpoints include RECIST version 1.1 response rates, major pathologic response rates, and biochemical (CA19-9, CEA) response rates. Correlative studies will be performed on surgical samples to evaluate metabolomic profiles. At the time of submission, 10 out of 16 planned patients have been enrolled. There have been no DLT at 500mg of ivosidenib. Clinical trial information: NCT05209074 .

Dose-escalated radiation for locally advanced unresectable pancreatic cancer.

750 Background: Patients with unresectable locally advanced pancreatic cancer have limited therapeutic options. Historical treatments have included systemic chemotherapy or palliative radiation. New advanced radiotherapy treatment techniques have allowed dose escalated ablative radiotherapy to be delivered for patients with cancer limited to the pancreas. This study retrospectively reviews the long term outcomes of patients receiving dose escalated radiation for unresectable localized pancreatic cancer. Methods: Patients with locally advanced unresectable pancreatic underwent neoadjuvant chemotherapy with either gemcitabine or FOLFIRINOX based regimens. When maximum response was achieved with chemotherapy or this was no longer tolerated, patients were reassessed with imaging. Patients with localized unresectable disease then proceeded to definitive dose escalated radiation with either SBRT radiosurgery (40Gy in 5 fractions) or IMRT radiation (65-70Gy in 30-35 fractions) with concurrent 5FU. Surveillance of disease was performed with CT imaging and Ca19-9 biomarker assessment. Results: A total of 38 patients (21 male, 17 female) underwent definitive radiation. Radiation technique was determined by treating physician based on patient anatomy, with 7 patients having SBRT and 31 IMRT/5FU. Average patient age at diagnosis was 71. All patients underwent at least 6 months of follow up and mean follow up was 14 months. At time of latest follow up, 30 patients had no evidence of local progression and 12 patients had no evidence of progression at any site. The most common side effect at last follow up was grade 2/3 duodenal ulcer experienced by 7 patients. Conclusions: Advances in systemic chemotherapy have increased the population of patients with locally advanced unresectable pancreatic cancer who have persistent pancreatic disease after induction chemotherapy. Definitive dose escalated radiation is a new and effective technique to provide local control in this setting. This approach is well tolerated with manageable toxicity and effective durable local control. Patients continue to experience distant disease failure despite improving local control rates, though at a lower rate than historical controls. Control of primary pancreatic malignancy with dose escalated radiation can potentially improve quality of life and function for these patients for whom additional chemotherapy or surgery is not indicated.

A biokinetic approach in primary knee osteoarthritis prevention and management-exploring movement profiles and kinetic chain interactions: Current concepts.

Knee osteoarthritis (OA) is a chronic disease characterized by increasing prevalence and significant physical, psychological, and economic burdens. Despite extensive research, the definition, risk factors, and effective cost-efficient treatments for knee OA remain unclear. This article aims to revisit primary knee OA, understanding its etiology, and focusing on prevention and individualized nonoperative treatment modalities. This study reviews various aspects of knee OA, including its global prevalence, economic impact, and current treatment strategies. It explores the role of mechanical loading pathways in the disease's onset, highlighting the importance of considering not only the knee but the entire kinetic chain in diagnosis and treatment. Also, it discusses knee anatomy and biomechanics during functional activities, emphasizing the role of neuromuscular control and the influence of proximal and distal joints on knee health. Current treatments focus mainly on symptom management, with limited success in disease prevention and curative interventions. This review underlines the importance of understanding the biomechanical risk factors contributing to knee OA and the necessity of individualized interventions based on biokinetic profile analysis. Knee OA management and prevention necessitate a paradigm shift from viewing it as a localized knee disease to recognizing related mechanical overloads of the human complex motion system. Identifying individual inductive elements is paramount for effective knee OA prevention, management, and rehabilitation. Future research should endeavor to identify movement profile subgroups to establish an early-stage prognosis and the impact of interventions for each group. LEVEL OF EVIDENCE V: Expert opinion based on nonsystematic review.

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.

Advances in the Pathogenesis, Diagnosis, Treatment, and Prognosis of Marginal Zone Lymphoma.

The management of marginal zone lymphoma (MZL), an indolent B-cell non-Hodgkin lymphoma, requires a personalized and adaptive approach due to its clinical and prognostic heterogeneity. We believe treatment should emphasize a balanced strategy considering the subtype, disease burden, symptoms, and actionable genetic or environmental factors, such as infections or autoimmune diseases. For asymptomatic patients with low tumor burden or disseminated disease, a watch-and-wait approach remains appropriate, given MZL's indolent nature and the risks of overtreatment. Conversely, for symptomatic or high-burden cases, early intervention with chemoimmunotherapy is recommended for effective disease control. Surgery remains essential for both diagnosis and the treatment of localized disease. Incorporating molecular profiling and prognostic models, such as MZL-IPI and POD24, is crucial for decision-making and risk stratification. Testing for infectious agents like Helicobacter pylori or Hepatitis C virus should be standard practice, as eradication therapy offers a targeted, less toxic, and effective option in select patients. With ongoing advancements in understanding dysregulated signaling pathways and the tumor microenvironment, we anticipate novel targeted therapies and combination regimens will further improve outcomes. We advocate for molecular testing at diagnosis to identify actionable biomarkers, particularly for patients with refractory or relapsed disease. Finally, MZL management requires vigilant follow-up with adjustments based on evolving disease features. Treatment decisions should integrate patient preferences, clinical context, and the latest evidence to maximize survival while preserving quality of life.

Comparative outcomes of neuroendocrine tumors in the historically underserved population of Bronx, NY: Montefiore Einstein Comprehensive Cancer Center.

671 Background: Neuroendocrine tumors (NETs) pose different clinical implications based upon age at diagnosis, with regards to early-onset (EO<50yrs) versus late-onset (LO>=50yrs) disease. While primary-tumor resection is crucial for localized NETs, its benefit in metastatic cases without metastasectomy remains uncertain. This study examines variables associated with survival in EO versus LO cases, including primary tumor resection. Methods: A retrospective cohort of 91 patients with gastrointestinal(GI)-NETs were identified as part of an IRB-approved project. Disease-stage (local vs. metastatic), tumor grade (G1-3), 5-year-survival, primary-tumor removal, and race/ethnicity were included in this analysis. Results: Among all patients, 31.9% identified as Hispanic, 33% as non-Hispanic Black, 22% as non-Hispanic White, and 13.1% as other. Among all patients, 79 were classified as G1/G2. Among LO patients, 87.5% (n=63) were G1/G2, among which 46% (n=29) were metastatic. Among EO patients, 84% (n=16) were G1/G2, among which 68.8% (n=11) were metastatic. In the LO group with G1/G2 tumors, 5-year survival rate was 48.3% for metastatic disease and 58.8% for localized disease. For EO with G1/G2 tumors, the 5-year survival rate was 72.7% for metastatic disease and 80% for localized disease. In the EO G1/G2 group, 5 of the 11 patients with metastatic disease had primary tumor removal without metastasectomy with 100% 5-year survival rate. In the LO G1/G2 group, 7 of 29 metastatic patients had primary tumor removal without metastasectomy, with 86% 5-year survival rate. Resection of primary tumor (without metastasectomy) in patients with metastatic G1/G2 NETs was associated with improved 5-year survival, independent of age at diagnosis ( p-value =0.008), as shown in the table. Conclusions: This study helps to emphasize the importance of primary tumor removal in improving survival outcomes for patients with metastatic low-grade GI-NETs, regardless of age. Further investigation is warranted to study the role of certain imperative variables such as site of metastases, number of metastases, and patient co-morbidities. Survival outcomes based on primary tumor removal in metastatic low-grade GI-NETs. No 5-year survival 5-year survival Primary tumor removal without metastasectomy 1 11 No surgery 12 8