Browse Articles

Safety and efficacy of combining PD-L1 and CTLA-4 blockade with transarterial chemoembolization in intermediate-stage hepatocellular carcinoma: A phase II study.

609 Background: Transarterial chemoembolization (TACE) is the standard treatment for intermediate-stage hepatocellular carcinoma (HCC) defined as Barcelona Clinic Liver Cancer (BCLC) B, but the benefit of adding systemic therapy remains unclear. While durvalumab and tremelimumab are approved for advanced HCC, the safety and efficacy in combination with TACE for intermediate-stage disease is undefined. Combining these PDL1 and CTLA4 inhibitors with TACE may enhance anti-tumor activity by leveraging TACE’s proinflammatory effects while blocking immune evasion and reducing immune suppression. This phase IIb study evaluates the safety and efficacy of this combination in BCLC-B HCC. Methods: We enrolled patients with intermediate-stage HCC that are also unresectable and ineligible for transplant. All patients received drug-eluting bead TACE (DEB-TACE) followed by durvalumab (1500 mg Q4W) and tremelimumab (300 mg once). Durvalumab monotherapy was continued until disease progression or unacceptable toxicity, for a maximum of 13 cycles. Primary endpoints include objective response rate (ORR) based on mRECIST. Secondary endpoints were overall survival (OS), and safety/adverse events (AEs). The trial is designed to rule out ORR of 30%. We obtained 3 serial biopsies and plasma for participating patients prior and one week after TACE and after the administration of immunotherapy for correlative studies. Results: 21 patients were enrolled. Of these, 20 patients were considered evaluable after receiving at least one dose of TACE and immunotherapy. ORR was 55% (95% CI: 32%-77%, CR 10% (n=2), PR 45% (n=9), meeting the primary endpoint. Five patients had PD (25%) per mRECIST, of which two were unconfirmed on repeat imaging and continued treatment beyond progression. Three patients received curative intent treatment as the result of treatment: surgical resection (n=1) and transplant (n=2). At a median follow-up of 18.4 months, median OS was 28.8 mo (95% CI: 15.1, NA) and mPFS was 6.1mo (95% CI: 3.3, NA). Grade 3 or higher immune related adverse events were rash (n=2), diarrhea, myalgia, nausea, elevated AST/ALT. One patient developed multiple irAEs after first dose (myocarditis, myositis, pericarditis) and was taken off study. Conclusions: The combination of DEB-TACE with PD-L1/CTLA-4 blockade is safe and shows promising activity in patients with BCLC-B HCC. The ongoing immune analysis and biomarker studies on serial blood and tissue biopsies will provide further insights into the mechanistic effects of this combination approach and inform future therapeutic strategies. Clinical trial information: NCT03638141 .

Comparison of mutational landscape in primary and metastatic pancreatic tumors.

781 Background: Genomic profiling has brought to the forefront the clinical relevance of intratumoral heterogeneity. Oncogenic KRAS mutation is the most common driver event in pancreatic ductal adenocarcinoma (PDAC), but little is known about how KRAS alteration may cooperate with other genetic lesions to support dissemination and growth of metastatic disease. Therefore, an improved understanding of molecular events affecting the clinical course of KRAS -altered PDAC is needed to identify biomarkers of early disease and expand the repertoire of targeted therapies. Methods: We retrospectively analyzed tissue samples from PDAC patients using the OncoExTra tumor-normal whole exome and whole transcriptome test between April 2018 and May 2024. The prevalence of actionable somatic alterations was determined overall and by specimen location (primary vs. metastatic). Fisher’s exact test with FDR-based correction for multiple testing was used to identify co-alterations with KRAS and 19 DNA damage response (DDR) gene alterations. Results: PDAC samples from 434 patients (51.2% female; mean age 65.4±10.9 years) were analyzed. KRAS alterations were detected in 369 (85.0%) samples: 198 (45.6%) primary and 239 (55.1%) metastatic. KRAS G12D (32.7%) and KRAS G12V (29.5%) were the most common KRAS mutations. The frequency of KRAS alterations was 85.9% and 84.5% in primary and metastatic samples, respectively. TP53 alterations occurred in 68.2% samples overall and in 64.6% and 71.1% of primary and metastatic samples, respectively. Examination of co-alterations in KRAS -altered versus KRAS -WT samples uncovered enrichment of TP53 alterations in KRAS -altered (277 samples, 75.1%) compared to KRAS -WT samples (19 samples, 29.2%) ( p <0.001). Also, BRAF mutations and SND1:BRAF fusions exclusively occurred in metastatic KRAS -WT samples, although the number of events was small ( n =4 and n =2, respectively). We also found that MTAP was significantly co-altered in metastatic KRAS -WT samples (n=6, 16.2%) compared to KRAS -altered samples (6 samples, 3.0%) ( p =0.004). A total of 21.9% of all PDAC samples had an alteration in at least 1 DDR gene. No associations were observed between KRAS alteration status and alteration in DDR genes. However, TP53 alterations were more frequent in non-DDR-altered samples ( p <0.001), while CDKN2B alterations were enriched in DDR-altered samples ( p =0.025). Conclusions: We observed expected rates of alterations in known PDAC driver genes and uncovered higher co-occurrence of KRAS and TP53 alteration in metastatic samples. Additionally, TP53 alterations were less frequent in DDR-altered samples. Our findings suggest that a number of therapy approaches including BRAF, WEE1, PARP, and KRAS inhibitors as well as epigenetic modulators, alone or in combination, could improve clinical outcomes in PDACs with specific mutational profiles.

Characterization of the tumor immune microenvironment (TIME) and somatic landscape in gastrointestinal (GI) malignancies with <i>MTAP</i> deletions (del).

835 Background: PRMT5 is a synthetic lethality target in patients (pts) with MTAP del and early phase trials are underway with PRMT5 inhibitors. Additionally, MTAP del are associated with a less immunogenic TIME and reduced efficacy of immunotherapy, but research has primarily not been focused on GI malignancies. Thus, we investigated the TIME and somatic landscape in GI malignancies with MTAP del. Methods: From the Tempus Database, we retrospectively analyzed de-identified next-generation sequencing data from pts across GI malignancies, including pancreatic (n=11,217), gastroesophageal (GEJ, n=5,803), cholangiocarcinoma (CCA, n=3,244), and colorectal (CRC, n=17,537) cancers. Tumors were sequenced with the Tempus xT DNA (648-gene panel) and xR RNA assays. MTAP del were defined as two-copy losses. Somatic alterations (alt), immune cell infiltration predicted from gene expression patterns, PD-L1 from IHC, TMB, and MSI were evaluated. Chi-squared/Fisher’s Exact tests or Kruskal-Wallis tests were used to assess statistical significance (p&lt;0.05, q&lt;0.05 for false discovery rate correction for multiple testing). Results: MTAP del were identified in 14.8%, 11.3%, 0.9%, and 7.3% of pancreatic, CCA, CRC, and GEJ cancers, respectively. Of these, 98/93%, 99/91%, 92/89%, and 98/89% had co-occurring CDKN2A/B loss. In pancreatic, CCA, and CRC pts, MTAP del was associated with a reduced proportion of B cells and CD4 T cells, and there were higher percentages of macrophages vs pts with MTAP WT status (p&lt;0.001 for all). Reductions in proportion of CD8 T cells were also associated with MTAP del in pancreatic and CCA pts (p&lt;0.001 for both). Lower TMB (p=0.036) and MSI-H status (p=0.009) were found in CRC pts with MTAP del. GEJ with MTAP del also exhibited significantly lower MSI-H status than MTAP WT GEJ (p=0.014). SMAD4 alterations , a marker of reduced immune infiltrates, were more prevalent in pts with MTAP del across GI malignancies (q&lt;0.005). In the CCA cohort, there was a higher percentage of BRAF alt and FGFR2 fusions in pts with MTAP loss (q&lt;0.001, q=0.028), while KRAS alt were higher in pancreatic cases with MTAP loss (q&lt;0.001). Conclusions: This is the largest analysis of the TIME and somatic landscape of MTAP loss across GI malignancies. In pts with MTAP del and pancreatic cancer, CCA, and CRC, we observed a less immunogenic TIME pattern, indicating the evaluation of immunotherapy implications in these GI malignancies with MTAP del is warranted. Our findings are hypothesis-generating, providing further rationale to study synthetic lethality and novel combinatorial therapeutic strategies in GI malignancies with MTAP del.

Real-world clinical outcomes of locally advanced unresectable and de-novo metastatic pancreatic ductal adenocarcinoma: A multicenter retrospective study from Saudi Arabia.

691 Background: Pancreatic ductal adenocarcinoma (PDAC) has dismal clinical outcomes, even with existing treatment regimens. This study evaluates the clinical characteristics and outcomes of patients with locally advanced unresectable or de-novo metastatic PDAC in Saudi Arabia to provide real-world data that can be compared to international benchmarks. Methods: This is a retrospective, multicenter study. Patients diagnosed with unresectable locally advanced or de-novo metastatic PDAC between January 2015 and November 2023 were included. Data were collected from 10 oncology centers across Saudi Arabia. Patient characteristics, treatment regimens, and clinical outcomes, including progression-free survival (PFS) and overall survival (OS), were analyzed using univariate and multivariate analyses. Results: A total of 350 patients were identified, with a median age of 60 years at time of diagnosis, 63% of patients presenting with multiple metastatic sites, primarily in the liver (66.3%). Among patients tested, 7.1% had deficient mismatch repair (d-MMR), and 5.8% harbored BRCA mutations. FOLFIRINOX was the most common first-line treatment (55.1%), followed by gemcitabine plus nab-paclitaxel (15.1%). The median PFS for first-line treatment was 5.3 months, with FOLFIRINOX achieving the longest PFS (6.5 months). The median OS was 10.34 months for the entire cohort, with better survival outcomes observed in patients receiving FOLFIRINOX (12.3 months). Independent prognostic factors for PFS and OS included performance status, type of first-line regimen, and neutrophil-lymphocyte ratio (NLR). Conclusions: This real-world study confirms that clinical outcomes for locally advanced unresectable and metastatic PDAC in Saudi Arabia are consistent with international data, with trend of FOLFIRINOX showing superior outcomes over gemcitabine-based regimens. However, both treatments reflect the persistent poor prognosis of PDAC, underscoring the need for novel therapeutic strategies. Further research is warranted to optimize treatment selection and improve survival outcomes in this population.

One-step fabrication of sharp platinum/iridium tips via amplitude-modulated alternating-current electropolishing

The platinum/iridium (Pt/Ir) alloy tip for scanning probe microscopy was fabricated by amplitude-modulated alternating-current electropolishing. The clean tips with a radius of curvature less than 100 nm were reproducibly obtained by applying the sinusoidal voltage in the frequency (f0) of 900 Hz≤f0≤1500 Hz with amplitude modulation by the sinusoidal wave in the modulation frequency (fs) of fs=0.1f0 in CaCl2/H2O/acetone solution. The analyses by scanning electron microscopy with an energy-dispersive x-ray analyzer and atom probe tomography showed that a uniform Pt/Ir alloy was exposed on the tip surface as a clean surface without O or Cl contamination. The scanning tunneling microscopy (STM) imaging using the fabricated tip showed that it is more suitable for investigating rough surfaces than conventional as-cut tips and applicable for atomic-resolution imaging. Furthermore, we applied the fabricated tip to qPlus atomic force microscopy (AFM) analysis in liquid and showed that it has atomic resolution in both the horizontal and vertical directions. Therefore, it is concluded that the amplitude-modulated AC etching method reproducibly provides sharp STM/AFM tips capable of both atomic resolution and large-area analyses without complex etching setups.

Evolutionary scenarios for the specific recognition of nonhomologous endogenous peptides by G protein–coupled receptor paralogs

Effect of marital status and race on survival of patients with well differentiated neuroendocrine tumors (NETs).

654 Background: Socioeconomic status factors (SES) such as marital status, income, and race can influence and enhance disparities in cancer incidence and outcomes. Marriage has documented positive impacts on overall survival of numerous cancer types. Consequences of divorce have been less explored. The unique indolent, secretory nature of NETs may be differentially affected by SES factors. This study identifies implications of marital status and sex on 5-year survival rates of different racial groups diagnosed with NETs within the Surveillance, Epidemiology, and End Results (SEER) database between 2000-2020 while controlling broadly for the type of treatment received. Methods: Within the SEER data base patients with reported sex, race, marital status and treatment who were diagnosed with well differentiated NETs were selected excluding carcinomas. Relative and disease specific 5-year survival analyses were calculated with 95% confidence intervals and age standardized. Three groupings were analyzed single, separated/divorced/widowed and domestic-partner/married. Results: For all races and sexes, relative survival for individuals in a union was higher than those who were single, or separated, divorced/widowed [86.9% (CI 86.1% - 87.7%); 79.3% (77% to 81.3%); and 79.2% (78% to 80.3%) respectively]. When individuals of each marital status group were compared by matching sex and race, there were no significant differences in relative survival. But males of any race who left a union had lower chances of survival than corresponding females [72.4% (69.7% to 74.9%) vs 81.6% (80.3% to 82.8%)]. As expected, all groupings who received surgical treatment had a higher relative survival than those who did not. Those who received surgical treatment while in a partnership had a higher relative survival then those who were separated [94.5% (93.6% to 95.3%) vs 88.7% (87.3% to 89.9%)]. All marital groupings who underwent surgery or did not, had comparable relative survival between races; except, black individuals in a partnership had improved outcomes compared to the white population. More specifically, when accounting for race, sex, marital status and treatment received, black men who did not undergo surgery had a higher relative survival compared to white men [69.9% (62.2% to 76.3%) vs 59.4% (56.6% to 62.1%)]. All the same conclusions were statistically significant for disease specific survival. Conclusions: Due to NETs slow growing nature SES factors play a major role in the care of patients living with them. Our findings demonstrate generally, irrespective of race, sex, or surgical treatment, being involved in a union is advantageous, showing a protective effect on patient survival, while parting from a union could be deleterious as it is tied to less favorable outcomes. These findings underscore the importance of considering these factors in treatment and care strategies.

Personalized frailty risk assessment in long-term survivors of colorectal cancer.

65 Background: Frailty, a pathologic form of aging, is associated with reduced quality of life and increased risk of death. Its incidence increases with age. Frailty is a concern for cancer survivors, especially since this population is surviving longer and increasing in size. There is a need to predict which patients are at risk of frailty to tailor preventative measures, particularly in early-stage colon and rectal cancer survivors, the largest group in gastrointestinal cancer survivors. Methods: This was a retrospective cohort study of individuals aged 66 and older in the SEER-Medicare linked database, diagnosed with stage I-III colon or rectal cancer between 2003-2012. Patients included in the study received definitive surgical treatment and survived for at least 5 years after diagnosis. Frailty was assessed using administrative claims codes with the Kim frailty index. Patients already frail at year 5 were excluded from the analysis. An increase in frailty score, indicating the onset of frailty or worsening to moderate or severe frailty, occurring within 5-10 years following cancer diagnosis was the primary outcome. Predictors of frailty were identified using restricted mean survival time (RMST) regression, with results less than 1 indicating a shorter time to frailty, and significant factors were used to develop a clinical prediction model and stratify patients into risk tertiles. Results: At 10 years or end of available follow-up, 58% of the patients had developed new onset or worsening frailty. There were no significant differences in RMST by patient race, sex, cancer stage and grade. Receipt of systemic therapy 4-5 years after diagnosis, having an ostomy present in years 4-5, advancing age, comorbidities, and living in an area with a greater proportion of residents below the federal poverty line were all associated with shorter time to frailty; the largest effects were seen with advancing age and comorbidities (Table). Our clinical prediction model incorporated age&gt;85 and having multiple comorbidities for both cohorts and ostomy in years 4-5 for the colon cohort. Conclusions: Our population level analysis provided a clinical prediction model for frailty 5-10 years after cancer diagnosis in colon and rectal cancer survivors and may help inform long-term survivorship management. RMST for selected variables. Selected Variables RMST for Colon Cohort (95% CI) RMST for Rectal Cohort (95% CI) Age 85-89 (ref: age 71-74) 0.76 (0.73, 0.79) 0.79 (0.74, 0.84) Age 90+ (ref: age 71-74) 0.67 (0.64, 0.70) 0.74 (0.66, 0.82) 20-100% area-level poverty (ref: 0-&lt;5%) 0.95 (0.92, 0.98) 0.96 (0.91, 1.02) Receiving systemic therapy in years 4-5 0.89 (0.85, 0.92) Not selected Ostomy in years 4-5 0.80 (0.69, 0.92) 0.97 (0.92, 1.02) Elixhauser Comorbidity Index (ECI) 1-2 (reference: ECI 0) 0.77 (0.75, 0.79) 0.79 (0.76, 0.82) ECI 3 (ref: ECI 0) 0.60 (0.57, 0.64) 0.67 (0.59, 0.76)

Thoracic Radiotherapy Improves the Survival in Patients With <i>EGFR</i> -Mutated Oligo-Organ Metastatic Non–Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors: A Multicenter, Randomized, Controlled, Phase III Trial

PURPOSE This multicenter, randomized, phase III clinical trial (Northern Radiation Oncology Group of China-002) focused on patients with oligo-organ metastatic non–small cell lung cancer (NSCLC) who have epidermal growth factor receptor ( EGFR ) mutations. We aimed to investigate whether first-line concurrent thoracic radiotherapy (TRT) and EGFR-tyrosine kinase inhibitors (TKIs), compared with TKIs alone, could achieve better survival. MATERIALS AND METHODS The patients in the TKI plus TRT group received 60 Gy to primary lung tumor and positive regional lymph nodes. Radiotherapy for metastases to other sites was determined by clinicians. The primary end point was the progression-free survival (PFS). Secondary end points included overall survival (OS) and treatment-related adverse events (TRAEs). The first and second interim analyses were performed in March 2021 and March 2022. RESULTS Between April 14, 2016, and February 25, 2022, a total of 118 patients were enrolled. Compared with the TKI alone group, the TKI plus TRT group achieved significantly better PFS (hazard ratio [HR], 0.57; P = .004) and OS (HR, 0.62; P = .029). The median PFS was 10.6 months in the TKI alone group and 17.1 months in the TKI plus TRT group. The median OS was 26.2 months and 34.4 months in the TKI alone group and TKI plus TRT group, respectively. The TKI plus TRT group showed better local control but was associated with a higher incidence of severe TRAEs (11.9% v 5.1%). CONCLUSION For patients with EGFR -mutated oligo-organ metastatic NSCLC treated with first-line EGFR-TKIs, concurrent TRT improves the PFS and OS, and TRAEs are acceptable and tolerable.

Factors and timing of decreased adherence to S-1 in postoperative docetaxel + S-1 therapy for gastric cancer.

403 Background: The combination of docetaxel + S-1 (DS) therapy in postoperative adjuvant treatment for gastric cancer has proven to be effective and has become a standard therapy. Clarification of factors involved in and the timing of S-1 non-adherence is important to minimize non-adherence. Methods: Among 92 patients who started DS treatment as postoperative adjuvant chemotherapy for gastric cancer between November 1, 2015 and April 30, 2021 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 90 were eligible for this study. The S-1 adherence rate per cycle was defined as the number of times a patient took S-1 divided by 28. In this study, adherence to S-1 was assessed through pill counts and by asking patients about reasons for non-adherence in interviews at a pharmaceutical outpatient clinic. Elicited reasons for non-adherence were categorized and analyzed. Results: Percentage of remaining S-1 was 3.9% in the first cycle, 7.4% in the second cycle, and 2.0% in the seventh cycle. Median relative dose intensity of S-1 was 80.9%. As reasons for non-adherence, patients most commonly cited nausea/vomiting (18.9%), missed dose (17.6%), and diarrhea (9.9%). From the first to the seventh course, the highest percentage of remaining S-1 was in the second course. Conclusions: Nausea/vomiting, missed dose, and diarrhea were identified as the most common factors for decreased adherence to S-1 in postoperative DS therapy for gastric cancer. Between the first and seventh courses, S-1 adherence decreased the most during the second course, when docetaxel was started. Using this information, we intend to develop methods to improve S-1 adherence in the future.

Signal-noise analysis of miniaturized delta-E effect magnetic field sensors

Delta-E effect sensors developed for detecting small amplitude and low-frequency magnetic fields have shown potential for miniaturization. However, a comprehensive signal-and-noise analysis of such miniaturized sensors is lacking. Here, we present an in-depth study of the key performance characteristics of sub-millimeter-sized delta-E effect sensors with a double-wing resonator geometry. Several resonance modes are evaluated for their sensitivity, noise, and limit of detection (LoD) as functions of the excitation voltage amplitude and magnetic bias flux density. We identify and discuss the optimal conditions for sensor operation and compare the performance to that of the reported macroscopic devices. While all investigated resonance modes behave qualitatively similar, quantitative differences in signal and noise lead to an almost sevenfold difference in LoD s. The performance is limited by magnetic noise at large excitation amplitudes and, unlike reported macroscopic delta-E effect sensors, by noise from the excitation signal and charge amplifier at low excitation amplitudes. The best performance is achieved in the third resonance mode excited at 683 kHz with a LoD≤7.4±3 nT/Hz between 10 and 1000 Hz and a minimum of 2.8 nT/Hz at 195 Hz. This demonstrates an improvement over previously reported values for miniaturized delta-E effect sensors in this frequency range. Moreover, the sensors show a −3 dB bandwidth of ≈440 Hz, which is significantly wider compared to macroscopic delta-E effect sensors. Reducing electronic noise and employing advanced magnetic multilayers can further improve the LoD, making these miniaturized sensors promising candidates for compact arrays.

The RecA-NT homology motif in ImuB mediates the interaction with ImuA′, which is essential for DNA damage–induced mutagenesis

Changes in peri-operative chemotherapy and radiation use among patients with resected pancreatic ductal adenocarcinoma (PDAC) between 2004-2021 in the US SEER dataset.

697 Background: PDAC peri-operative management changed over 20 years. Randomized data supports adjuvant and multiagent chemotherapy (CT), while peri-operative chemoradiotherapy (RT) was used selectively in the US. We examined recent trends in treatment with outcomes in surgically resected PDAC patients. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) 17 dataset, we identified surgically resected primary M0/MX PDAC cases from 2004-2021 over 3-year periods (P1-P6). Neoadjuvant (NCT), adjuvant (ACT), or multiagent (MACT) CT scheduling was included. χ² analysis assessed cohort characteristics over time and multinomial logistic regression assessed odds of CT allocation adjusted by cohort characteristics. Multivariable Cox proportional hazards model assessed treatment-related overall survival (OS) adjusted for cohort characteristics. Results: Among 55,293 cases of M0/MX PDAC, 21,904 (40%) completed surgery. Median age was 66 years; stages were T1/T2/T3/T4 (8.0/25/59/6.0%) and N0/N+ (38/54%). RT use declined (P1:P6, 41%-&gt;18% p&lt;0.001) while CT use increased (P2:P6, 63%-&gt;79%, p&lt;0.001). NACT (P2:P6, 4.1%-&gt;23% p&lt;0.001) and MACT (P2:P6, 1.6%-&gt;20%, p&lt;0.001) use increased while ACT decreased (P2:P6, 58%-&gt;36%, p&lt;0.001). CT is likely to be allocated to young patients (&lt;65yo) with Stage II-III tumors located at the pancreatic head (OR&gt;1.00, p&lt;0.001). Median OS increased over time (P1:P6, 18mo-&gt;32mo, p&lt;0.001). Multivariable analysis shows that Adjuvant RT (HR 0.84 [0.81-0.87], p&lt;0.001) and all CT (NCT: HR 0.71 [0.66-0.77], p&lt;0.001; ACT: HR 0.63 [0.60-0.66], p&lt;0.001; MACT: HR 0.65 [0.60-0.71], p&lt;0.001) improved OS. Conclusions: This study shows decreased RT and increased CT adoption from 2004-2021. Median OS improved over the years, potentially due to peri-operative advances during this study period. Trends in treatment use over 3-year periods. RTN (%) CTN (%) Neo CTN (%) MACTN(%) P1: 2004-2006N=2661 1087 (41) 0 (0) a 0 (0) a 0 (0) a P2: 2007-2009N=3185 1185 (37) 2021 (63) 129 (4.1) 50 (1.6) P3: 2010-2012N=3536 1226 (35) 2460 (70) 267 (7.6) 138 (3.9) P4: 2013-2015N=3947 1210 (31) 2880 (73) 434 (11) 244 (6.2) P5: 2016-2018N=4224 971 (23) 3256 (77) 676 (16) 491 (12) P6: 2019-2021N=4351 787 (18) 3430 (79) 1003 (23) 857 (20) a No cohorts reported chemotherapy use during period 1. RT: Radiation Therapy; CT: Chemotherapy; NCT: Neoadjuvant Chemotherapy; MACT: Multiagent Chemotherapy.

Impact of intrathecal targeted drug delivery (ITDD) on oral morphine equivalents and pain scores in advanced pancreatic cancer pain.

686 Background: Pancreatic cancer accounts for approximately 3% of all cancers and affects ~64,000 adults in the United States each year. Seventy five percent of patients present with abdominal pain, leading to diagnosis. This is one of the most painful cancers, with pain severity strongly correlating to prognosis. Severe intractable abdominal pain negatively impacts quality of life. Traditionally, opioids have been used as the first line agent for the treatment of severe abdominal pain. However, opioids carry significant risk and often unwarranted side effects. With escalating doses to treat refractory pain there is also potential for unintentional overdose. Intrathecal targeted drug delivery (ITDD) provides pain medications directly to the intrathecal space limiting systemic side effects. Our study aimed to determine the impact ITDD has on pain scores as well as the amount of systemic opioid needed in patients with advanced pancreatic cancer. Methods: A retrospective review was conducted on 217 advanced cancer patients that underwent ITDD placement from March 2019 through July 2024. Thirty- five patients with a diagnosis of pancreatic cancer met inclusion criteria. Pain scores and oral morphine equivalent (OME) use was evaluated at baseline (prior to ITDD), at 1 month and 3 months post ITDD implant. A numeric scale of 0-10 was used to determine pain scores, while a comprehensive chart review and patient response was used to determine OME use. Results: We found that post ITDD placement, pain scores were reduced on average by 4.55 points at 1month and 4 points at 3-months after implantation. This was statistically significant with a two-paired t-test analysis (p &lt;0.05). Post ITDD placement, there was a 96.7% reduction in OME at 1-month (p &lt;0.005) and 98.1% reduction in OME at 3 months (p &lt;0.04). Conclusions: Despite the small sample size of patients, ITDD showed a significant reduction in pain scores and OME use compared to baseline with systemic opioid use only in patients with advanced pancreatic cancer. This reduction appeared to be maintained for 3 months post ITDD placement. Further studies conducted on a larger sample size would be beneficial to demonstrate statistical outcomes of ITDD therapy on pain scores and OME use.

Clinical relevance of tumor fraction assessment from circulating tumor DNA in metastatic colorectal cancer.

237 Background: Both tissue (TBx) and liquid (LBx) biopsies are indicated for detecting actionable alterations in metastatic colorectal cancer (mCRC). LBx is easier to obtain and often has faster turnaround time, but its informative results depend on the ctDNA tumor fraction (TF) content. We aimed to (1) evaluate the concordance between LBx and TBx in CRC; and (2) determine baseline lab and clinical factors associated with TF. Methods: CRC patients (pts) with both tissue and liquid Foundation Medicine comprehensive genomic profiling within an interval of up to 90 days between samples collection were analyzed. Positive percent agreement (PPA) and negative predictive value (NPV) for RAS (KRAS/NRAS) and BRAFV600E detection were calculated with tissue as reference. Clinical data was obtained by the US-wide de-identified Flatiron Health-Foundation Medicine real-world clinicogenomic CRC database, from ~280 cancer clinics (~800 sites of care) between 1/2011-12/2023. mCRC pts with LBx collected up to 60 days prior to therapy (Tx) start were analyzed for association between TF and baseline factors using logistic regression with TF≥1% as the binary outcome. Baseline factors include age, ECOG, race/ethnicity, line of therapy, practice type, metachronous vs. synchronous disease, tumor side, albumin, alkaline phosphatase (AP), serum creatinine, hemoglobin, lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio, opioid and steroid pre-Tx. Foundation Medicine’s ctDNA TF is a composite algorithm prioritizing aneuploidy at higher levels to avoid germline signal and prioritizing variant allele frequency of canonical alterations at lower levels to maximize dynamic range. Results: A total of 402 pts had TBx and LBx (268 [67%] TF≥1% and 134 [33%] TF&lt;1%). Without accounting for TF, the overall PPA for RAS and BRAFV600E was 77% and 83%, and the NPV was 65% and 99%. In LBx with TF≥1%, the PPA for RAS and BRAFV600E was 99% and 100%, and NPV was 98% and 100%. In contrast, for TF&lt;1% samples, the PPA for RAS and BRAFV600E was 37% and 50%, and NPV was 57% and 97%. Of the 633 pts with LBx collected prior to Tx, 474 (75%) had TF≥1%. TF≥1% was independently associated with ECOG 1+ (odds ratio [OR]: 1.58, p=0.038), community oncology care site (OR: 2.58, p=0.002), elevated levels of AP (OR: 3.00, p&lt;0.001) and LDH (OR: 3.97,p=0.002). TF≥1% was less likely to occur in right-side tumors (OR: 0.53, p=0.012) and metachronous disease (OR: 0.48, p&lt;0.001). Conclusions: Approximately 70% of LBx samples from CRC pts have TF≥1%, with near-perfect concordance for RAS/BRAFV600E. For LBx with TF&lt;1%, interpretation of negative results can be challenging due to low tumor shedding, especially for RAS mutations, where 43% may be false negatives and a subsequent TBx will provide more confidence in the negative results. Clinical factors such as right-sided tumors and metachronous disease may help anticipate low TF and guide decisions to pursue TBx.

Correlation between immune-related adverse events and clinical outcomes in patients treated with first-line nivolumab plus chemotherapy for advanced gastric or gastroesophageal junction cancer: A multi-center retrospective study in Japan.

439 Background: The CheckMate 649 trial and ATTRACTION-4 trial showed the efficacy of first-line nivolumab plus chemotherapy (Nivo-CT) for advanced gastric or gastroesophageal junction (GEJ) cancer. Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with survival benefit in patients with solid tumors. However, there were few data on correlation between irAEs and efficacy of first-line Nivo-CT for advanced gastric or GEJ cancer. Methods: This multi-center retrospective study included patients with histologically confirmed advanced gastric or GEJ adenocarcinoma who were started on first-line Nivo-CT between December 2021 and December 2023. We divided the patients into two groups according to occurrence of irAEs; those with irAEs (irAE group) or those without (non-irAE group) and assessed the efficacy in both groups. Efficacy was evaluated by overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Landmark analysis at 2 months after initiating Nivo-CT was performed to adjust effects of early progression or death, in which patients who had events up to 2 months were excluded. Results: A total of 271 patients were included (median age, 70 [range 18–85] years; male/female, 64/36%; performance status (PS) 0/1/2, 47/49/4%; primary tumor site gastric/GEJ, 90/10%; status unresectable/recurrent, 81/19%; histology intestinal/diffuse, 30/70%; PD-L1 CPS &lt;1/1~5/&gt;5, 15/33/53%). Median follow-up time was 11.3 (range 1-30) months, and 80 (30%) patients developed irAE. In the landmark analysis, the median PFS was 11.1 months in the irAE group and 7.2 months in non-irAE group (HR 0.70 [95%CI 0.50-0.97], p = 0.034), and the median OS was 22.5 months in the irAE group and 17.9 months in non-irAE group (HR 0.77 [95%CI, 0.50-1.17], p = 0.219). The ORR were 67.4% in the irAE group and 66.7% in non-irAE group (p = 0.934). Multivariate analysis indicated that PS ≥1 (HR 1.66 [95%CI, 1.20-2.30], p = 0.02), elevated ALP (HR 1.61 [95%CI, 1.13-2.27], p = 0.008), and absence of irAEs (HR 1.55 [95%CI, 1.08-2.22], p = 0.018) were associated with poor prognosis. The most frequent irAEs were pneumonitis (n = 16), and grade ≥3 irAEs were observed in 26 (9.6%) patients: pneumonitis (n = 6), hepatitis/hypophysitis (n = 5). Conclusions: Development of irAEs was associated with improved outcomes in advanced gastric or GEJ cancer patients receiving first-line Nivo-CT.

Visible-blind bipolar response photodetector based on GaN/ZnO:Ga/GaAs double heterojunctions for dual-band optoelectronic logic operation

Bipolar response photodetectors have sparked considerable interest in optical switches, smart chips, and artificial neuroscience, but invisible ones are still scarce. Here, a visible-blind bipolar response photodetector based on GaN/ZnO:Ga/GaAs double heterojunctions is proposed. Under self-powered conditions, the designed photodetector only shows dual-band photoresponse in the ultraviolet (UV) and infrared (IR) spectrum. Specifically, originating from the absorption characteristics and suitable energy band of multilayered structures, it exhibits positive (negative) photocurrents under UV (IR) illumination. The maximum responsivity of 4.7 mA/W (−1.8 mA/W) under the UV (IR) illumination and fast response time (19.6/36.8 μ s) are achieved. Dual-band optoelectronic logic operations, including OR, AND, NOR, NOT, and NAND, are realized with a single photodetector by precisely regulating the UV and IR illumination. This work paves an approach for the development of visible-blind bipolar photodetection and all-in-one optoelectronic logic gates.

Disruption of deoxyribonucleotide triphosphate biosynthesis leads to RAS proto-oncogene activation and perturbation of mitochondrial metabolism

Real-world clinical outcomes of trifluridine-tipiracil monotherapy (FTD-TPI) and FTD-TPI + bevacizumab combination therapy (FTD-TPI+bev) in 639 black patients (pts) with metastatic colorectal cancer (mCRC).

81 Background: In the phase 3 SUNLIGHT trial, FTD-TPI+bev improved overall survival (OS) as compared to FTD-TPI in treatment-refractory mCRC. Out of 492 pts in the study, only 7 (1.4%) pts self-identified as Black; therefore, the potential benefit of FTD-TPI+bev in this pt population was not well-examined. We present the largest analysis to date of real-world clinical outcomes of FTD-TPI and FTD-TPI+bev in Black pts with mCRC. Methods: We retrospectively identified Black adult pts with a documented exposure to FTD-TPI and diagnosis of mCRC at or prior to the initiation of FTD-TPI using United States-based electronic medical records and claims in the ConcertAI RWD360 dataset. Pts were categorized as having received FTD-TPI or FTD-TPI+bev. Kaplan-Meier analyses were used to compare the real-world overall survival (rwOS) and time to discontinuation (rwTTD) from the date of first exposure to FTD-TPI (index). Multivariate Cox regression analyses were used to control for pt characteristics including demographics, ECOG performance status (PS), comorbidities, metastatic sites, time from mCRC diagnosis to index, lab results, and prior receipt of regorafenib. Results: Out of 639 Black pts included in our study, 551 received FTD-TPI and 88 received FTD-TPI+bev. Index years were 2021-2023 for 26% and 92% pts receiving FTD-TPI and FTD-TPI+bev, respectively. Pts receiving FTD-TPI had median age 61 years; male 51.2%; any comorbidities 43.9%; ECOG PS 0-1 36.7%; median time from mCRC diagnosis to index 632 days. Pts receiving FTD-TPI+bev had median age 59 years; male 50.0%; any comorbidities 42.0%; ECOG PS 0-1 60.3 %; median time from mCRC diagnosis to index 579.5 days. The rwOS was significantly improved with FTD-TPI+bev as compared with FTD-TPI (10.8 vs 6.2 months, respectively; p=0.0001), similar to the SUNLIGHT study (Table). In the adjusted model, pts who received FTD-TPI+bev had a significantly lower risk of death as compared to pts who received FTD-TPI (hazard ratio [HR]=0.45; p&lt;0.0001). The rwTTD was also significantly prolonged with FTD-TPI+bev as compared with FTD-TPI (3.8 vs 2.4 months, respectively; p&lt;0.0001). In the adjusted model, pts who received FTD-TPI+bev had about half the risk of discontinuation as compared with pts who received FTD-TPI (HR=0.51; p&lt;0.0001). Conclusions: This is the first study to compare the clinical outcomes with FTD-TPI vs. FTD-TPI+bev in Black pts with mCRC in the real-world setting. Our study confirmed OS improvement with FTD-TPI+bev as compared to FTD-TPI in Black pts with mCRC, as seen in the overall population of the SUNLIGHT trial. Current Study SUNLIGHT Black n rwOS months (95% CI) Black n OS months (95% CI) FTD-TPI 551 6.2 (5.7-6.9) 3 7.5 (6.3-8.6) FTD-TPI+bev 88 10.8 (7.8-16.0) 4 10.8 (9.4-11.8) HR 0.45 (95% CI 0.33-0.63; p&lt;0.0001) HR 0.61 (95% CI 0.49-0.77; p&lt;0.001)

Utilization of <i>SDC2</i> gene in conjunction with <i>SEPTIN9</i> gene methylation analysis for the diagnosis and efficacy assessment of colorectal cancer.

240 Background: SDC2 gene encodes the transmembrane proteoglycan molecule Syndecan-2. Syndecan-2 protein affects the proliferation, migration and invasion of colorectal cancer cells by participating in the regulation of cell adhesion, tissue differentiation and angiogenesis. Plasma methylated SEPTIN9 gene has been shown to be a sensitive and specific biomarker for the detection of CRC, which is involved in apoptosis, pseudopod projection, tumor cell migration and invasion. The aim of this study is to validate the value of SDC2 and S9 gene methylation detection in the diagnosis and efficacy evaluation of CRC. Methods: A total of 102 patients were enrolled in the study. The methylation levels of fecal SDC2 gene and blood SEPTIN9 gene were detected by fluorescence PCR. The clinical diagnostic accuracy of SDC2 kit was evaluated by patients with benign gastrointestinal lesions, gastrointestinal tumors and healthy subjects. Combined detection of SDC2 and S9 to improve the detection rate of CRC. SDC2m levels were analyzed in 26 patients with partial remission or stable disease after palliative treatment and 32 patients with complete remission after radical surgery. Results: The detection rate of SDC2 in patients was 0.0% for UC and CD, 66.7% for AA and 60.0% for NA, 25.0% for HOP. For 8 healthy subjects with negative colonoscopies, the true negative rate was 100%. The detection rates of GC and EC were 50.0% and 0.0%, respectively. Data from 72 patients with CRC were evaluated, with a sensitivity of 89.1% (41/46,95%CI 0.798-0.985) for patients with untreated CRC. The sensitivity of SDC2 was 46.2% (12/26,95%CI 0.256-0.667) in patients with partial response or stable disease after palliative treatment. The difference was statistically significant (P &lt; 0.001). The sensitivity of S9 for CRC detection was 88.2% (15/17, 95%CI 0.712-1.053). By two tests, 94.1%(16/17, 95%CI 0.816-1.066) of CRC cases could be detected.The sensitivity was 89.1% (41/46 95%CI 0.798-0.985) in untreated CRC and 46.2% (12/26 95%CI 0.256-0.667) in patients with PR and SD after chemotherapy/radiotherapy/targeted/immunotherapy. The difference rate of SDC2m between two groups was statistically significant (P &lt; 0.001). Among 46 untreated patients with CRC, 32 patients with positive SDC2m underwent radical surgery, of which 30 CR patients turned SDC2m test negative after surgery. We found reduced SDC2m in stool from patients with clinical benefit (CR+PR+SD). Conclusions: Detection of SDC2m in untreated CRC patients has high sensitivity and has the potential to become a non-invasive diagnostic tool for CRC. Combination of S9 and fecal SDC2 could improve the detection rate of SDC2 in non-dominant population. The methylation level of SDC2 may be helpful for postoperative follow-up of CRC after radical surgery, prediction of recurrence, and monitoring the efficacy of a series of palliative treatments for CRC.