Clinical Tumor Research Articles

IGH Complementarity Determining Region-3-Cytomegalovirus Protein Chemical Complementarity Linked to Better Overall Survival Probabilities for Glioblastoma.

Cytomegalovirus (CMV) has long been thought to have an association with glioblastoma multiforme (GBM), although the exact role of CMV and any subsequent implications for treatment have yet to be fully understood. This study addressed whether IGH complementarity determining region-3 (CDR3)-CMV protein chemical complementarity, with IGH CDR3s representing both tumor resident and blood-sourced IGH recombinations, was associated with overall survival (OS) distinctions. IGH recombination sequencing reads were obtained from (a) the Clinical Proteomic Tumor Analysis Consortium, tumor RNAseq files; and (b) the cancer genome atlas, blood exome-derived files. The Adaptive Match web tool was used to calculate chemical complementarity scores (CSs) based on hydrophobic interactions, and those scores were used to group GBM cases and assess survival probabilities. We found a higher OS probability for cases whose hydrophobic IGH CDR3-CMV protein chemical complementarity scores (Hydro CSs) were in the upper 50th percentile for several CMV proteins, including UL99 and UL123, as well as for CSs based on known B cell epitopes representing these proteins. We also identified multiple immune signature genes, including CD79A and TNFRSF17, for which higher RNA expression was associated with higher Hydro CSs. Results were consistent with the idea that stronger immunoglobulin responses to CMV are associated with better OS probabilities for GBM.

Analysis of clinical characteristics and prognosis of lung cancer patients with CPFE or COPD: a retrospective study

BackgroundLung cancer (LC) commonly occurs in patients with combined pulmonary fibrosis and emphysema (CPFE) and chronic obstructive pulmonary disease (COPD), but comparative research is limited. This study examines clinical characteristics, treatments, and prognosis in LC patients with CPFE or COPD.MethodsThe retrospective study involved 75 lung cancer patients with CPFE and 182 with COPD. It analyzed clinical features, tumor pathology, pulmonary function, laboratory parameters, and treatment responses.ResultsNotable differences were found between the CPFE + LC and COPD + LC groups. Both groups were mostly elderly, male smokers. The CPFE + LC group had higher BMI and more adenocarcinoma and squamous cell carcinoma, while COPD + LC had predominantly squamous cell carcinoma. CPFE + LC tumors were mostly in the lower lobes; COPD + LC’s were in the upper lobes. The CPFE + LC group showed higher tumor metastasis rates, more paraseptal emphysema, and elevated levels of TG, CEA, NSE, and Killer T Cells. In advanced stages (IIIB-IV), the CPFE + LC group receiving first-line treatment had shorter median progression-free survival (PFS) and a higher risk of progression or death than the COPD + LC group, regardless of whether it was non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). No significant PFS difference was found within CPFE + LC between chemotherapy and immunotherapy, nor in immune-related adverse events between groups, with interstitial pneumonia being common.ConclusionThis study emphasizes distinct lung cancer characteristics in CPFE or COPD patients, highlighting the need for tailored diagnostic and treatment approaches. It advocates for further research to improve care for this high-risk group.

Comparison of MRI features among squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma, usual-type endocervical adenocarcinoma and gastric adenocarcinoma of cervix

ObjectiveTo compare and explore the characteristics of squamous cell carcinoma (SCC), adenocarcinoma (AC) and adenosquamous carcinoma (ASC), usual-type endocervical adenocarcinoma (UEA) and gastric adenocarcinoma (GAC) of cervix. Materials and methodsA total of 728 cervical cancers (254 cases of AC, 252 cases of ASC, and 222 cases of SCC) confirmed by histopathology were retrospectively reviewed. Among AC, 119 UEA and 47 GAC were included. Clinical baseline data and tumor morphological features on MRI (including tumor location, shape, diameter and volume, margin, growth pattern, presence of fluid component or cyst, heterogenous and peritumoral enhancement) of all cases were collected and analyzed. The signal intensity (SI) of tumor and gluteus maximus muscle were measured and their ratios (SIR) were calculated based on T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) and contrast-enhanced T1WI at arterial and delay phases (A/DCE-T1WI). These clinical and MRI features were compared between SCC, AC and ASC, UEA and GAC, and the specific ones of each subtype were identified. ResultsThere was a significant difference in SCC-Ag, CA-199, CEA, ADC value, SIR-DWI, presence of intratumor cyst and peritumoral enhancement between AC and ASC; in patient age, menopausal status, International Federation of Gynecology and Obstetrics (FIGO) stage, SCC-Ag, CA-125, CA-199, CEA, tumor shape, growth pattern, margin, presence of intratumor fluid component and cyst, tumor diameter and volume, ADC value, SIR-T1WI, SIR-T2WI, and SIR-DWI between SCC and AC, as well as SCC and ASC. Also, there was a significant difference in deep stromal invasion (DSI), peritumoral and heterogenous enhancement between SCC and AC, and in SIR-ACE-T1WI between SCC and ASC. There was a significant difference in reproductive history, menopausal status, FIGO stage, CA-199, DSI, lymph node metastasis (LNM), parametrial invasion (PMI), tumor location, shape, margin, growth pattern, presence of fluid component and cyst, tumor diameter and volume, SIR-T1WI, SIR-DWI, and heterogenous enhancement between GAC and UEA. ConclusionThe clinical and MRI features with significant differences among SCC, AC and ASC, and between UEA and GAC, can help to identify each subtype of cervical cancer.

Socioeconomic Status, Length of Stay, and Postoperative Complications in Oral Cavity Squamous Cell Carcinoma.

Background: Despite universal healthcare in Canada, low socioeconomic status (SES) has been associated with worse survival in oral cavity squamous cell carcinoma (OCSCC) patients. However, the relationship between SES and outcomes during the acute postoperative period is poorly defined. Hamilton, Ontario, presents a unique population with widely varying SES within the same geography. The objective of this study was to examine the relationship between SES, length of hospital stay (LOHS), and postoperative complications in OCSCC. Methods: Newly diagnosed OCSCC patients receiving primary surgical treatment from 2010 to 2014 were identified within a prospectively collected database. Inclusion criteria included age >18 years old, pathological diagnosis of oral cavity cancer, and primary surgical treatment with curative intent. Patients were excluded if they were undergoing palliative treatment or had previous head and neck surgery/radiotherapy. Postal codes were used to identify neighborhood-level socioeconomic variables via 2011 Canada Census data. Income quartiles were defined from groups of neighboring municipalities based on Canada Census definitions. Demographic, social, pathological, staging, and treatment data were collected through chart review. Results: One hundred and seventy-four patients were included in the final analysis. OCSCC patients with lower SES were more likely to be younger (P = .041), male (P = .040), have significant tobacco and alcohol use (P = .001), higher Charlson Comorbidity Index (CCI; P = .014), lower levels of education (P = .001), and have lower employment levels (P = .001). Lower SES patients had higher clinical tumor (P = .006) and clinical nodal (P = .004) staging and were more likely to receive adjuvant therapy (P = .001) and G-tubes (P = .001). Multivariable regression analysis showed that low SES was a statistically significant predictor of postoperative complications [β 2.50 (95% confidence interval (CI) 0.200, 3.17); P = .014] and LOHS [β 2.03 (95% CI 1.06, 2.99); P = .0001]. Tobacco and alcohol use, clinical tumor, and nodal stage, CCI, and planned adjuvant therapy were also statistically significant predictors of postoperative complications and LOHS (P < .05). Conclusion: Patients with lower SES have more advanced OCSCC disease with increased comorbidities that owes itself to more acute postoperative complications and LOHS within this study population. Patients with low SES should be identified as patients that require more support during their cancer treatment.

PPIH acts as a potential predictive biomarker for patients with common solid tumors

BackgroundOur previous studies have indicated that mRNA and protein levels of PPIH are significantly upregulated in Hepatocellular Carcinoma (LIHC) and could act as predictive biomarkers for patients with LIHC. Nonetheless, the expression and implications of PPIH in the etiology and progression of common solid tumors have yet to be explored, including its potential as a serum tumor marker.MethodsWe employed bioinformatics analyses, augmented with clinical sample evaluations, to investigate the mRNA and protein expression and gene regulation networks of PPIH in various solid tumors. We also assessed the association between PPIH expression and overall survival (OS) in cancer patients using Kaplan-Meier analysis with TCGA database information. Furthermore, we evaluated the feasibility and diagnostic efficacy of PPIH as a serum marker by integrating serological studies with established clinical tumor markers.ResultsThrough pan-cancer analysis, we found that the expression levels of PPIH mRNA in multiple tumors were significantly different from those in normal tissues. This study is the first to report that PPIH mRNA and protein levels are markedly elevated in LIHC, Colon adenocarcinoma (COAD), and Breast cancer (BC), and are associated with a worse prognosis in these cancer patients. Conversely, serum PPIH levels are decreased in patients with these tumors (LIHC, COAD, BC, gastric cancer), and when combined with traditional tumor markers, offer enhanced sensitivity and specificity for diagnosis.ConclusionOur findings propose that PPIH may serve as a valuable predictive biomarker in tumor patients, and its secreted protein could be a potential serum marker, providing insights into the role of PPIH in cancer development and progression.

Partial nephrectomy after a period of active surveillance: Are perioperative and pathology outcomes worsened compared to immediate surgery?

IntroductionActive surveillance (AS) is a viable strategy for managing small renal masses (SRMs) in lieu of immediate surgery, but concerns persist regarding its impact on delayed partial nephrectomy (PN) outcomes. We aimed to compare perioperative and pathological outcomes of patients initially on AS for SRMs, later undergoing PN, against those undergoing immediate PN. Materials and methodsData were extracted from a prospective institutional database (January 2018–September 2023) for patients with cT1a renal masses. Only malignancies confirmed at final pathology were included. Baseline patient and tumor characteristics and the time from AS enrollment to PN were recorded. Surgical, renal functional, and final pathology outcomes were analyzed, including histology, tumor size, pT stage, upstaging rate, and positive surgical margins. Predictors of upstaging were identified using logistic regression models. ResultsAnalysis included 356 patients: 307 immediate PN and 49 deferred PN after a median of 18 months in AS. Groups had comparable baseline characteristics; no significant differences emerged in surgical and postoperative outcomes. Final pathology revealed no significant disparities in tumor size, histology, positive margins, or upstaging, though pT stage distribution differed (2.4 % versus 4.3 % for pT3a, immediate versus deferred, p = 0.04). Univariable analysis identified RENAL Score (OR 1.29, 95 % C.I. 1.09–1.53, p = 0.003) and clinical tumor size (OR 1.16, 95 % C.I. 1.10–1.22, p < 0.01) as upstaging predictors, confirmed by multivariable analysis (p < 0.01). ConclusionOur comparative analysis found no worsened perioperative or adverse pathological outcomes in patients with deferred PN, supporting the safety of this approach in managing SRMs, at least as an initial option.

A Concordance Between Clinical and Pathological Tumor Staging of Oral Squamous Cell Carcinoma: An Institutional Study.

Among oral diseases, oral cancer is the primary cause of death and poses a serious health risk. Primary tumor (T) - regional lymph node (N) - distant metastasis (M) comprising (TNM) staging is crucial for planning treatment strategies for patients with oral squamous cell carcinoma (OSCC). This study evaluated the predictive accuracy of clinical TNM staging of OSCC to histopathological staging (pTNM) in an institutional setting. Fifty-four consecutive histologically confirmed, surgically treated OSCC cases were evaluated for TNM staging. The study compared the clinical staging at the time of surgery with the pathological staging obtained from excisional biopsy reports. Microsoft Excel (Microsoft® Corp., Redmond, WA, USA) was used for the data compilation and descriptive analysis. The chi-square test, analysis of variance (ANOVA), and Tukey's Honest Significant Difference (HSD) posthoc test were used to compare the data for statistical significance with p value <0.05 using Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, IBM Corp., Version 23.0, Armonk, NY). The alveolar mucosa (n=22, 40.74%) was the most frequently occurring site, followed by the tongue (n=17, 31.48%). Out of the 54 included cases, based on clinical tumor size, there were T1 (n=6), T2 (n=13), T3 (n=13), T4a (n=16) and T4b (n=6). T2 tumors were usually upstaged (n=7) while T4a (n=8) tumors were most often downstaged. T4a (n=8) had the best concordance between clinical and histopathological staging, followed by T2, T3, and T1. In nodal status, N1 showed the most variation. The chi-squared test showed statistical significance for tumor size comparison (p <0.001) and nodal status comparison (p=0.002). ANOVA test did not show any statistical significance. Tukey's HSD posthoc test showed statistical significance (p=0.034) for N0 and N1 status. The highest concordance was shown by N0 and N1 followed by N2b. Preoperative radiological and clinical assessments are essential for deciding on a patient's course of treatment. However, not all patients may require radiographs to determine tumor size or nodal status assessment. Accurate diagnosis is vital for the treatment planning of OSCC.

Repurposing hemostatic drug desmopressin in AVPR2-expressing triple-negative breast cancer: Target expression analysis and preclinical antineoplastic effects on tumor growth and metastatic progression.

e15087 Background: Desmopressin (dDAVP) is a hemostatic drug that acts as an agonist of the arginine vasopressin receptor 2 (AVPR2) that is present in vascular and malignant cells. Preclinical data show that dDAVP triggers cytostatic mechanisms, blocking angiogenesis and reducing metastases by limiting the survival of circulating tumor cells. Triple-negative breast cancer (TNBC) is associated with poor prognosis due to limited response to therapy and frequent early metastatic recurrence. Considering the unsatisfied clinical need for novel therapeutic options in TNBC, we evaluated the antitumoral activity of dDAVP on experimental models of TNBC, alone or in addition to chemotherapy. We also assessed the expression and clinical impact of AVPR2 in breast cancer samples. Methods: Human and murine TNBC cell lines were used for in vitro experiments. Target expression was assessed by qPCR and immunohistochemistry (IHC), in experimental or clinical tumors (NCT01606072). Effects of dDAVP were evaluated by proliferation, clonogenic, 3D growth and chemotaxis assays, qPCR arrays, and confocal microscopy. Local and distant tumor progression were assessed in vivo in nude or BALB/c mice. TIMER2.0 and UCSC Xena platforms (BRCA TCGA /n = 1260) were used for bioinformatic studies. Results: dDAVP significantly reduced growth and chemotaxis of AVPR2-expressing TNBC cells. Cytostatic effects of dDAVP were associated with altered actin cytoskeleton dynamics and differential expression of angiogenesis and metastasis-related genes. Cooperative effects were observed in vitro and in vivo after combining dDAVP with taxane or alkylating therapy. Tumor-bearing mice were treated with intravenous injections of dDAVP (0.3 µg/kg, thrice weekly) in combination with weekly cycles of paclitaxel (10 mg/kg i.p.) or carmustine (25 mg/kg i.p.). Combination regimens resulted in greater survival and tumor growth and metastasis inhibition. Bioinformatic analysis of the TCGA database showed that AVPR2 had a positive prognostic impact on overall survival in breast cancer patients, especially in the basal-like molecular subtype. AVPR2 also correlated with different immune cell infiltrates such as NK and dendritic cells, and CD4+ and CD8+ T cells. Moreover, AVPR2 expression was detected by IHC in 6/18 breast cancer clinical samples using a small cohort of surgical specimens. Conclusions: AVPR2 expression is associated with improved outcomes in patients with TNBC. Agonist activation of AVPR2 using dDAVP leads to cancer cell growth inhibition in TNBC cell lines and mouse models. We propose dDAVP as a potential novel therapeutic option for treating TNBC either as monotherapy or in combination with chemotherapy. The therapeutic impact of its addition to immune checkpoint inhibitors remains to be explored.

Perimarginal lymph node metastasis in gingivo-buccal complex carcinoma: Is it time to push the limits of neck dissection?.

6069 Background: Perimarginal nodes (PMN) are a group of perifacial lymph nodes that lie in close relationship with marginal mandibular nerve (MMN). They lie in the lymphatic drainage pathway of gingivo-buccal cancers (GBC), above the lower border of mandible which forms the superior limit of conventional neck dissection and thus remain unaddressed. With reported incidence of metastasis as high as 20.5%, we aimed to explore incidence of PMN metastasis in GBC, its correlation with histopathological tumor and nodal characteristics. Methods: A prospective study was conducted on 112 consecutive treatment naïve patients of GB squamous cell carcinoma. Patients with unresectable nodal disease, distant metastasis and prior radiotherapy or surgery to neck were excluded. PMN dissection was performed in the quadrangle bounded superiorly by the mandibular alveolar ridge, inferiorly by lower border of mandible, anteriorly by mental foramen and posteriorly by anterior border of masseter. On histopathological analysis, serial step sectioning and cytokeratin immunohistochemistry were performed. Prospective clinical characteristics analyzed were subsite, clinical tumor, nodal stage, location of primary and clinical skin involvement. PMN positivity was correlated with demographic, clinical, nodal status. Histopathological characteristics analyzed included tumor grade, pathological tumor, nodal stage, tumor size, skin and/or bone involvement, depth of invasion, Brandwein Gensler histological risk score and lympho-vascular emboli. MMN functional outcome was graded according to House-Brackman (HB) grading recorded at 3 and 6 months post-operatively. Results: Baseline characteristics are summarized in the table. The PMN were identified histologically in 75.89% (85/112) patients. Metastasis in these nodes were identified in 15.2% (17/112) patients. Our study revealed an occult PMN metastasis of 16.67% (13/78). None of the pre-operative clinical factors was found to be significant in predicting incidence of metastasis. Higher nodal burden (p=0.01) and pathological skin involvement (p=0.03) had statistically significant odds of having PMN metastasis on multivariable analysis. At 6 months follow-up, none of the patients had any MMN functional deformity at rest. Conclusions: There is a high incidence of occult PMN metastasis from gingivo-buccal complex cancer. High nodal stage and pathological skin involvement are independent adverse prognostic factors for PMN metastasis. The limits of conventional neck dissection should be expanded to include clearance of PMN in all cases of gingivo-buccal cancers. [Table: see text]

Preoperative (neoadjuvant) therapy with tislelizumab for locally advanced colorectal cancer with high microsatellite instability or deficient mismatch repair: An open-label, single-arm, multicenter phase II study.

3599 Background: Tislelizumab (TIS), an anti-programmed cell death protein 1 (PD-1) antibody, demonstrated improved anti-tumor response and tolerable safety in patients (pts) with previously treated, locally advanced unresectable or metastatic microsatellite instability high/deficient mismatch repair (MSI-H/dMMR) solid tumors, including colorectal cancer (CRC; NCT03736889). Recent studies of other anti-PD-1 antibodies indicate potential clinical benefit of neoadjuvant anti-PD-1 therapy in pts with resectable MSI-H/dMMR CRC. Here, we report efficacy and safety outcomes of neoadjuvant TIS from a multicenter phase II trial (NCT05116085) in this population. Methods: Pts aged ≥18 years with stage II/III MSI-H/dMMR CRC, ECOG PS 0-1, evaluable disease per RECIST v1.1, and eligible for R0 (complete) resection were enrolled. Pts received TIS 200 mg IV every 3 weeks for 3 cycles followed by surgical resection within 10 weeks of first TIS dose. The primary endpoint was major pathological response (MPR) rate (proportion of pts with ≤10% residual viable tumor in the surgically resected primary tumor). Secondary endpoints included pathological complete response (pCR) rate (proportion of pts with absence of residual tumor in the surgically resected specimen), and safety. The R0 resection rate was an exploratory endpoint. Results: Overall, 33 pts were enrolled across eight sites in China. The median age of enrolled pts was 52.0 years (range: 23-84), 14 (42.4%) pts were male. Ten (30.3%) pts had rectal cancer and 23 (69.7%) colon cancer. At study entry, clinical tumor (T) stage was reported as T2, T3, and T4 in 1 (3.0%), 7 (21.2%), and 25 (75.8%) pts, respectively, and node (N) stage as N0, N1, and N2 in 6 (18.2%), 14 (42.4%), and 13 (39.4%) pts, respectively. All pts had a metastasis (M) stage of M0. A total of 29 (87.9%) pts underwent surgery and were evaluable for efficacy endpoints. Surgery was not performed in 4 pts, 3 of whom were managed non-operatively (1 pt had progressive disease). MPR and pCR rates were 89.7% and 62.1%, respectively (Table). Any-grade and grade ≥3 TIS-related adverse events (TRAEs) were reported in 20 (60.6%) and 1 (3.0%) pts, respectively. Two (6.1%) pts experienced serious TRAEs; no TRAEs led to death or surgery cancellation. One pt (3.0%) experienced a TRAE (grade 2 hypothyroidism) leading to surgery delay. No grade ≥3 or serious TIS-related surgery-relevant adverse events were reported. Immune-mediated adverse events were reported in 10 (30.3%) pts (all grade 1-2). Conclusions: Neoadjuvant TIS was associated with high MPR and pCR rates and an acceptable safety profile, and did not compromise surgery in pts with resectable MSI-H/dMMR CRC. Clinical trial information: NCT05116085 . [Table: see text]

Determinants of pathological complete response and tumor regression in high-risk breast cancer treated with neoadjuvant radiotherapy and chemotherapy.

e12652 Background: Pathological complete response (pCR) is a recognized prognostic indicator in breast cancer patients undergoing neoadjuvant systemic therapy (naST). Known determinants of pCR include intrinsic subtype, proliferation index, grading, clinical tumor and nodal stage, as well as the type of systemic therapy. Incorporating neoadjuvant radiotherapy (naRT) may enhance response rates, disease-free survival, toxicity profiles, and cosmetic outcomes compared to adjuvant radiotherapy. However, the factors influencing pCR and primary tumor regression with the addition of neoadjuvant radiotherapy to chemotherapy are not well-documented. Methods: A retrospective analysis was conducted on 341 patients (cT1-cT4/cN0-N+) who received naRT and neoadjuvant chemotherapy between 1990 and 2003. Treatment included naRT to the breast and, in most cases, to the supra-/infraclavicular lymph nodes, complemented by an electron or brachytherapy boost. NaST was administered either sequentially or concurrently with RT, utilizing various regimens. Univariate and multivariate regression analyses were employed to evaluate the impact of different subgroups and treatment modalities on pCR (ypT0/Tis and ypN0) and complete primary tumor response (ypT0/Tis). Receiver operating characteristic (ROC) analysis assessed the interval between radiotherapy (RT) and surgical resection (Rx), as well as the radiotherapy dose. Results: Out of 341 analyzed patients, 31.1% achieved pCR. Multivariate analysis revealed that pCR rates were affected by the planned type of resection, breast cancer subtype, primary tumor stage, and the interval between radiation and surgery. The biologically effective dose to the tumor did not significantly impact pCR. Univariate analysis identified age, resection type, breast cancer subtype, clinical tumor stage, and grading as significant factors for primary tumor regression. In the multivariate analysis, resection type, subtype, and clinical tumor stage remained significant. Radiation dose to the tumor and the interval from radiation to surgery were not significant for pCR. However, a longer interval from radiotherapy to resection significantly predicted pCR when treatment factors were included in the model. Conclusions: The factors associated with pCR following combined neoadjuvant chemotherapy and radiotherapy are akin to those identified with neoadjuvant chemotherapy alone. A prolonged interval to surgery may be linked to higher pCR rates. Escalating the dose beyond 60 Gy did not lead to increased response rates.

Short-course radiotherapy (SCRT) followed by fruquintinib plus adebrelimab and CAPOX in the total neoadjuvant therapy of locally advanced rectal cancer (LARC): A multicenter, single-arm, open-label, phase II study.

TPS3643 Background: For LARC patients (pts), long-course concurrent chemoradiotherapy or SCRT followed by chemotherapy is recommended by the NCCN guidelines (Version 1.2024) as neoadjuvant therapy. Compared with chemoradiotherapy, the addition of immune checkpoint inhibitors (ICIs) or anti-angiogenic drugs could further improve complete response (CR) rate in the neoadjuvant treatment of LARC. Fruquintinib, a highly selective small-molecule inhibitor of VEGFR-1, -2, and -3, has gained FDA approval for pts with metastatic colorectal cancer previously treated. For pts with LARC at high risk of recurrence, the CR rate of SCRT followed by chemotherapy was 29%. There is an urgent need for new therapeutical options to improve the CR rate in these pts. This study introduces an innovative approach, combining SCRT, chemotherapy, Fruquintinib, and ICIs as a total neoadjuvant therapy for high-risk LARC pts. Methods: This is a multicenter, single-arm, open-label, phase II study (NCT06234007) investigating the efficacy and safety of SCRT sequential fruquintinib, combined with adebrelimab (an anti-PD-L1 monoclonal antibody) and CAPOX in pts with LARC. Eligible participants were 18 years or older, with an ECOG PS of 0–1, and a biopsy-proven, newly diagnosed, primary, LARC, classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for surgery. Total neoadjuvant therapy included SCRT (5 × 5 Gy over 5 days, 1-week rest) followed by six cycles of fruquintinib (4mg, qd, po, q3w. For the initial 6 pts in the safety run-in period, dosage was adjusted based on dose-limited toxicities in the 1st cycle) combined with adebrelimab (1200mg, iv, d1, q3w) and CAPOX (q3w). Subsequently, pts who did not reach clinical CR underwent total mesorectal excision, others received the “Watch and Wait” policy or surgery. Primary endpoint was CR rate (including clinical CR &amp; pathologic CR). Secondary endpoints included 3-year event free survival rate, overall survival, R0 resection rate and adverse events (AEs). Exploratory endpoints aimed to evaluate the correlation between potential biomarkers and efficacy. Using PASS 15 software (version 15.0.5.0), in the Tests for One Proportion analysis, with a two-sided α of 5% and to guarantee the power over 80%. The null hypothesis of CR rate was 29%, and the alternative hypothesis was 51%, accounting for a 10% drop-out rate, resulting in a sample size of 39 pts. With the 6 pts in the safety run-in period, a total of 45 pts would be enrolled in the study. Until Feb 1, 2024, 7 of planned 45 pts have been enrolled. Clinical trial information: NCT06234007 .

Overexpression of COX7A1 Promotes the Resistance of Gastric Cancer to Oxaliplatin and Weakens the Efficacy of Immunotherapy

Gastric cancer (GC) is one of the most common clinical malignant tumors worldwide, with high morbidity and mortality. Presently, the overall response rate to immunotherapy is low, and current methods for predicting the prognosis of GC are not optimal. Therefore, novel biomarkers with accuracy, efficiency, stability, performance ratio and wide clinical application are needed. Based on public data sets, the Chemotherapy Cohort and the Immunotherapy Cohort from Sun Yat-sen University Cancer Center, a series of bioinformatics analyses, such as differential expression analysis, survival analysis, drug sensitivity prediction, enrichment analysis, tumor immune dysfunction and exclusion (TIDE) analysis, single-sample gene set enrichment analysis (ssGSEA), stemness index calculation, immune cell infiltration analysis, were performed for screening and preliminary exploration. Immunohistochemical staining and in vitro experiments were performed for further verification. Overexpression of COX7A1 promoted the resistance of GC cells to Oxaliplatin. COX7A1 may induce immune escape by regulating the number of fibroblasts and their cellular communication with immune cells. In summary, measuring the expression levels of COX7A1 in the clinic may be useful to predict the prognosis of GC patients, the degree of chemotherapy resistance and the efficacy of immunotherapy.

Cervical cancer-specific long non-coding RNA landscape reveals the favorable prognosis predictive performance of an ion-channel-related signature model.

Ion channels play an important role in tumorigenesis and progression of cervical cancer. Multiple long non-coding RNA genes are widely involved in ion channel-related signaling regulation. However, the association and potential clinical application of lncRNAs in the prognosis of cervical cancer are still poorly explored. Thirteen patients with cervical cancer were enrolled in current study. Whole transcriptome (involving both mRNAs and lncRNAs) sequencing was performed on fresh tumor and adjacent normal tissues that were surgically resected from patients. A comprehensive cervical cancer-specific lncRNA landscape was obtained by our custom pipeline. Then, a prognostic scoring model of ion-channel-related lncRNAs was established by regression algorithms. The performance of the predictive model as well as its association with the clinical characteristics and tumor microenvironment (TME) status were further evaluated. To comprehensively identify cervical cancer-specific lncRNAs, we sequenced 26 samples of cervical cancer patients and integrated the transcriptomic results. We built a custom analysis pipeline to improve the accuracy of lncRNA identification and functional annotation and obtained 18,482 novel lncRNAs in cervical cancer. Then, 159 ion channel- and tumorigenesis-related (ICTR-) lncRNAs were identified. Based on nine ICTR-lncRNAs, we also established a prognostic scoring model and validated its accuracy and robustness in assessing the prognosis of patients with cervical cancer. Besides, the TME was characterized, and we found that B cells, activated CD8+ T, and tertiary lymphoid structures were significantly associated with ICTR-lncRNAs signature scores. We provided a thorough landscape of cervical cancer-specific lncRNAs. Through integrative analyses, we identified ion-channel-related lncRNAs and established a predictive model for assessing the prognosis of patients with cervical cancer. Meanwhile, we characterized its association with TME status. This study improved our knowledge of the prominent roles of lncRNAs in regulating ion channel in cervical cancer.

Real world incidence, prevention, and management of tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with venetoclax in the inpatient and outpatient settings.

7045 Background: Venetoclax (ven) is a BCL2 inhibitor used for the treatment (tx) of chronic lymphocytic leukemia (CLL) which can cause clinical or laboratory (lab) tumor lysis syndrome (TLS). A dose ramp-up schedule and prophylaxis strategies are incorporated into NCCN guidelines and prescribing information. Prior reports have of TLS focused mostly on patients (pts) with relapsed/refractory CLL receiving ven as monotherapy. Methods: We included pts &gt;18y who were diagnosed with CLL or small lymphocytic lymphoma (SLL) and received tx with commercial ven in any line of therapy at our institution from 1/1/2016 to 12/31/2020. TLS was defined using the modified Cairo Bishop Criteria. TLS risk was based on the size of the largest lymph node (LN) on imaging or examination and the absolute lymphocyte count (ALC) as defined by ven prescribing information. Results: We included 616 ven escalations among 136 pts with CLL. Median age was 70 years and 86% were white. Ven was part of first line of tx for 48 pts (35%). 11% had high TLS risk at baseline; 37% among those escalated exclusively inpatient (IP) and 2% among those escalated exclusively outpatient (OP). Among those treated with ven, 47 pts (35%) received ven monotherapy. 74 (54%) of pts were escalated exclusively OP, 35 (26%) had at least one prophylactic hospitalization and 27 (20%) were escalated exclusively IP. During ven initiation, 86% of pts received allopurinol, 71% intravenous hydration, 18% phosphate binders, and 10% prophylactic rasburicase. Among the entire cohort, 8 pts (5.9%) developed lab TLS and zero developed clinical TLS. There were 11 TLS events; 2 pts developed TLS in more than one escalation. Incidence of TLS was 15% for those escalated exclusively IP, 5.7% for those with any prophylactic hospitalization and 2.7% for those escalated exclusively OP. Those who developed TLS were more likely to have a higher TLS risk at baseline, preceding isolated hyperuricemia, or CrCl measurement &lt; 60 mL/min (Table). Conclusions: In this single institution retrospective cohort study, lab TLS was observed, though clinical TLS was not. Baseline hyperuricemia and impaired renal function were more common among those who developed lab TLS compared to those who did not. Prophylactic measures, including use of IV hydration, may have contributed to low rates of observed TLS in the outpatient setting. [Table: see text]

Pan-cancer proteogenomics expands the landscape of therapeutic targets

Fewer than 200 proteins are targeted by cancer drugs approved by the Food and Drug Administration (FDA). We integrate Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomics data from 1,043 patients across 10 cancer types with additional public datasets to identify potential therapeutic targets. Pan-cancer analysis of 2,863 druggable proteins reveals a wide abundance range and identifies biological factors that affect mRNA-protein correlation. Integration of proteomic data from tumors and genetic screen data from cell lines identifies protein overexpression- or hyperactivation-driven druggable dependencies, enabling accurate predictions of effective drug targets. Proteogenomic identification of synthetic lethality provides a strategy to target tumor suppressor gene loss. Combining proteogenomic analysis and MHC binding prediction prioritizes mutant KRAS peptides as promising public neoantigens. Computational identification of shared tumor-associated antigens followed by experimental confirmation nominates peptides as immunotherapy targets. These analyses, summarized at https://targets.linkedomics.org, form a comprehensive landscape of protein and peptide targets for companion diagnostics, drug repurposing, and therapy development.

Evaluating antitumor activity and response determinants to trastuzumab deruxtecan in pediatric solid tumors.

10049 Background: Trastuzumab deruxtecan (T-DXd) is an anti-HER2 antibody-drug conjugate (ADC) linked to a topoisomerase inhibitor FDA-approved for several indications, including the treatment of HER2+ breast and gastric cancer. Although HER2 amplification is uncommon in pediatric cancers, recent demonstration of T-DXd efficacy in HER2-low breast cancer patients prompted us to examine the potential clinical relevance of T-DXd in pediatrics by evaluating HER2 expression and activity of T-DXd in preclinical pediatric solid tumor models. Methods: Cell viability was assessed in a panel of histologically diverse pediatric solid tumor cell lines and 2 HER2-amplified adult cancer cell lines treated with T-DXd, payload (DXd), and a control IgG-ADC. HER2 protein expression in patient-derived xenograft (PDX) tumors was evaluated by immunohistochemistry (IHC) using 5 clinically validated anti-HER2 antibodies. RNAseq was performed on clinical (n=290) and PDX (n=184) tumors to determine relative expression of ERBB2. In vivo activity of T-DXd was evaluated in osteosarcoma (OS, n=10), Wilms tumor (WT, n=1) and malignant rhabdoid tumor (MRT, n=1) PDX models and a desmoplastic small round cell tumor (DSRCT) cell line xenograft model. Differences in tumor volume and time to disease progression was assessed and compared across treatments and models. Responses were correlated with HER2 expression by IHC. Results: In vitro, HER2-amplified control cell lines demonstrated a &gt;30-fold reduction of IC50 when comparing T-DXd to ADC control. In contrast, the ADC control IC50 was nearly identical to T-DXd across all pediatric cancer cell lines, consistent with the absence of HER2 amplification in these models. We observed focal and membranous staining of HER2 by IHC in PDXs but was quite variable across antibodies tested: WT 0-17% HER2+ cases (n=6), MRT 0-40% (n=5), DSRCT 0-33% (n=24), OS 0-7% (n=30). ERBB2 gene expression was highest in DSRCT followed by WT, OS and MRT. In vivo efficacy studies demonstrated complete and partial responses in OS, WT, and DSRCT and improved disease control rates (OS: 67%, p=0.006, Mann-Whitney; WT: 100%; DSRCT: 100%). However, T-DXd and ADC control demonstrated similar activity in all tumor types with no consistent correlation between in vivo response and HER2 expression. Consistent with these preclinical studies, 4 patients with progressive DSRCT were treated with T-DXd via compassionate/off-label access with signs of clinical and radiographic responses. Conclusions: T-DXd shows significant preclinical antitumor activity across multiple pediatric solid tumors but little correlation with HER2 expression suggesting a mechanism of action similar to the clinical activity observed in HER2-low breast cancer. Xenograft efficacy studies and preliminary clinical experience with T-DXd in DSRCT patients warrant formal clinical trial investigation in this largely incurable disease.

Pilot study to evaluate automated laboratory data transfer into Medidata Rave for NCI-supported pediatric cooperative group trials in the Pediatric Early Phase Clinical Trials Network (PEP-CTN) and Pediatric Brain Tumor Consortium (PBTC).

e23017 Background: Electronic data capture (EDC) has the potential to improve data accuracy and efficiency. As an initial step toward improvement in the accuracy and completeness of data acquisition for clinical trials, PEP-CTN and PBTC conducted a pilot project to assess the feasibility of automated transfer of laboratory data from participating institutions’ electronic health records to the NCI Medidata Rave EDC that is housed within each consortium’s Uniform Resource Locator (URL). The pilot aimed to assess feasibility of automated laboratory data extraction and transfer and to evaluate discrepancies between laboratory data obtained retrospectively through automated extraction and data manually ascertained during the original conduct of the study. Methods: Data from patients treated on 7 completed PEP-CTN or PBTC trials at 7 sites were included. Each consortium created a Rave EDC study to receive data. Sites used the ExtractEHR R package or local methods to map and extract laboratory data for designated patients. Post-extraction data were uploaded via a file transfer protocol (FTP) periodically polled by the Rave Batch Uploader (BU) that uploaded data into Rave EDC. After successful upload, extracted data (EHR) were compared to laboratory data that had been manually reported when patients were enrolled on the trials (MANUAL) and discrepancies were identified. Discrepancy types were categorized and 2 sites reviewed discrepancies at their sites to identify reasons. Results: Preparation and support for automated extraction and upload required significant central operations and local site effort. All sites successfully extracted specified laboratory data and had at least one complete upload via BU to Rave EDC. There were more laboratory data in the EHR datasets than MANUAL datasets across most sites. These results were due to multiple EHR results on a given day or from additional days in the study window than specified in MANUAL. Sites verified that laboratory data in MANUAL and not EHR were stored in un-extractable formats (e.g. PDFs) or outside laboratories. Most discrepant results in both EHR and MANUAL were mismatched values or units. Conclusions: This pilot demonstrated the feasibility of implementing automated laboratory data extraction and transfer in the cooperative group setting. Automated data transfer requires significant central operational support as well as detailed protocols, data specifications, and case report forms and engagement of site technical teams to be successful, but also permits collection of more comprehensive data with reduced manual data entry. Clinical trial information: NCT05020951 .

Inherited Germline Variants in Urinary Tract Cancer: A Multicenter Whole-Exome Sequencing Analysis and Correlation With Clinical Features and Tumor Genomics.

This study investigates a real-world multicenter cohort of patients with urinary tract cancer (UTC), with primary disease sites including the bladder, urethra, and upper tract, who enrolled for research molecular testing of their germline and tumor. The purpose of this study was to evaluate factors that could affect the likelihood of identifying a clinically actionable germline pathogenic variant (PV). Patients with UTC were identified from 10 cancer institutes of the Oncology Research Information Exchange Network consortium. The data set comprised abstracted clinical data with germline and tumor genomic data, and comparative analyses were conducted. Clinically actionable germline PVs in cancer predisposition genes were identified in 16 (4.5%) of 354 patients. A higher proportion of patients with the urethra and the upper tract as the primary sites of disease had PVs with a prevalence of 11% (5/45), compared with only 3.6% (11/308) in those with the bladder as the primary site of disease (P = .04). There were no significant differences in markers of genomic instability (such as tumor mutational burden, microsatellite instability [MSI], and loss of heterozygosity, copy number, and chromosomal instability) between those with PVs and those without (P > .05). Of the PVs identified, 10 (62%) were in homologous recombination repair (HRR) genes, three (19%) in mismatch repair (MMR) genes, and three (19%) in genes associated with other pathways. Tissue-based assessment of genomic instability, such as MSI, does not reliably indicate germline PV. A comprehensive clinical germline testing approach that includes HRR genes in addition to MMR genes is likely to yield PVs in approximately one of 10 patients with nonbladder primary disease sites such as the upper tract and the urethra.

Robot-assisted Partial Nephrectomy for Hilar and Nonhilar Renal Masses: Comparison of Perioperative, Oncological, and Functional Results in a Multicentre Prospective Cohort (NEPRAH Study, UroCCR 175)

Background and objectiveA hilar location for a renal tumour is sometimes viewed as a limiting factor for safe partial nephrectomy. Our aim was to evaluate perioperative, oncological, and functional outcomes of robot-assisted partial nephrectomy (RAPN) for hilar tumours (RAPN-H) in comparison to RAPN for nonhilar tumours (RAPN-NH). MethodsWe conducted an observational, multicentre cohort study using prospectively collected data from the French Research Network on Kidney Cancer (UroCCR). The registry includes data for 3551 patients who underwent RAPN for localised or locally advanced renal masses between 2010 and 2023 in 29 hospitals in France. We studied the impact of a hilar location on surgery, postoperative renal function, tumour characteristics, and survival. We also compared rates of trifecta achievement (warm ischaemia time [WIT] <25 min, negative surgical margins, and no perioperative complications) between the groups. Finally, we performed a subgroup analysis of RAPN without vascular clamping. Variables were compared in univariable analysis and using multivariable linear, logistic, and Cox proportional-hazards models adjusted for relevant patient and tumour covariates. Key findings and limitationsThe analytical population included 3451 patients, of whom 2773 underwent RAPN-NH and 678 underwent RAPN-H. Longer WIT (β = 2.4 min; p < 0.01), longer operative time (β = 11.4 min; p < 0.01) and a higher risk of postoperative complications (odds ratio 1.33; p = 0.05) were observed in the hilar group. Blood loss, the perioperative transfusion rate, postoperative changes in the estimated glomerular filtration rate, and trifecta achievement rates were comparable between the groups (p > 0.05). At mean follow-up of 31.9 mo, there was no significant difference in recurrence-free survival (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.58–1.2; p = 0.3), cancer-specific survival (HR 1.1, 95% CI 0.48–2.6; p = 0.79), or overall survival (HR 0.89, 95% CI 0.52–1.53; p = 0.69). Conclusions and clinical implicationsPatient and tumour characteristics rather than just hilar location should be the main determinants of the optimal surgical strategy for hilar tumours. Patient summaryWe found that kidney tumours located close to major kidney blood vessels led to a longer operation and a higher risk of complications during robot-assisted surgery to remove the tumour. However, tumours in these locations were not related to a higher risk of kidney function loss, cancer recurrence, or death.