Multi-institutional Study Research Articles

How far are we off? Analyzing the accuracy of surgical margin relocation in the head and neck.

Positive surgical margin rates remain high in head and neck cancer surgery. Relocation is challenging given the complex, three-dimensional (3D) anatomy. Prospective, multi-institutional study to determine accuracy of head and neck surgeons and pathologists relocating margins on virtual 3D specimen models using written descriptions from pathology reports. Using 3D models of 10 head and neck surgical specimens, each participant relocated 20 mucosal margins (10 perpendicular, 10 shave). A total of 32 participants, 23 surgeons and 9 pathologists, marked 640 margins. Of the 320 marked perpendicular margins, 49.7% were greater than 1 centimeter from the true margin with a mean relocation error of 10.2 mm. Marked shave margins overlapped with the true margin a mean 54% of the time, with no overlap in 44 of 320 (13.8%) shave margins. Surgical margin relocation is imprecise and challenging even for experienced surgeons and pathologists. New communication technologies are needed.

Association between consumption of small fish and all-cause mortality among Japanese: the Japan Multi-Institutional Collaborative Cohort Study.

Although small fish are an important source of micronutrients, the relationship between their intake and mortality remains unclear. This study aimed to clarify the association between intake of small fish and all-cause and cause-specific mortality. We used the data from a cohort study in Japan. The frequency of the intake of small fish was assessed using a validated food frequency questionnaire. The hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality according to the frequency of the intake of small fish by sex were estimated using a Cox proportional hazard model with adjustments for covariates. The Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. A total of 80,802 participants (34,555 males and 46,247 females), aged 35-69 years. During a mean follow-up of 9.0 years, we identified 2,482 deaths including 1,495 cancer-related deaths. The intake of small fish was statistically significantly and inversely associated with the risk of all-cause and cancer mortality in females. The multivariable-adjusted HRs (95% CIs) in females for all-cause mortality according to the intake were 0.68 (0.55-0.85) for intakes 1-3 times/month, 0.72 (0.57-0.90) for 1-2 times/week, and 0.69 (0.54-0.88) for ≥3 times/week, compared with the rare intake. The corresponding HRs (95% CIs) in females for cancer mortality were 0.72 (0.54-0.96), 0.71 (0.53-0.96), and 0.64 (0.46-0.89), respectively. No statistically significant association was observed in males. Intake of small fish may reduce the risk of all-cause and cancer mortality in Japanese females.

Abstract PO3-05-13: A Multi-Institutional Review of Contralateral Axillary Metastases: Time for Reclassification as Local-Regional Event?

Abstract Background Current American Joint Committee on Cancer (AJCC) breast cancer staging considers contralateral axillary metastasis (CAM) stage IV disease (M1). Retrospective studies suggest that women with CAM have improved overall survival (OS) compared to those with distant metastasis (M1) and/or comparable OS to locally advanced breast cancer (LABC). These studies support consideration of curative intent treatment; however, they contain heterogeneous cohorts with highly variable treatment strategies. We sought to evaluate treatment and outcomes in a well-defined CAM cohort treated with contemporary systemic and locoregional therapy. Methods We performed a retrospective multi-institution cohort study to compare OS of patients with CAM matched 1:3 on age +/- 5 years to LABC (defined as cN2-3 and/or pN2-3), and to non-CAM M1. CAM patients classified as type 1) de novo CAM, synchronous with the contralateral primary, 2) metachronous isolated CAM in the setting of prior surgical and/or radiation treatment to primary index cancer, 3) synchronous with, or 4) metachronous after an in-breast or axillary nodal recurrence of the primary index cancer. The M1 cohort included de novo and recurrent metastasis with varied sites and number of metastasis. OS was defined as time from CAM diagnosis to death or last follow-up for CAM patients; time from primary diagnosis to death or last follow-up for LABC; and time from metastatic diagnosis to death or last follow-up for M1. Unadjusted OS was estimated with the Kaplan-Meier method, and Cox proportional hazards models were used to estimate the association of group with OS after adjustment for covariates Results We identified 57 CAM and 155 LABC from 8 institutions (2016-2022), and 632 M1 from a single institution. The median age was similar between groups (CAM=59 years, LABC=58, M1=57, p=0.44), and there were no statistically significant differences in hormone receptor status (p=0.25). There were more Non-Hispanic Black patients in the M1 cohort compared to CAM or LABC (p< 0.001). The majority of CAM cases were delayed metachronous from the index cancer (type 2, 35.1%), or synchronous with a recurrence (type 3, 33.3%). Type 1 (de novo, 14%) and type 4 (delayed metachronous after breast cancer recurrence, 17.5%) were less frequent. Among CAM patients, 49.1% were hormone receptor positive (HR+)/HER2-negative (HER2-), 22.8% HR-/HER2-, 10.5% HR+/HER2+, and 5.3% HR-/HER2+. Comparing CAM versus LABC, invasive ductal carcinoma (IDC) was more commonly seen in CAM (82.5% vs 66.5%), as was grade 3 (45.6% vs 35.5%), and triple negative (22.8% vs 13.5%). Conversely, in LABC, treatment of the primary index cancer more frequently included chemotherapy (CAM=71.9%, LABC=92.3%), mastectomy (CAM=54.4%, LABC 74.2%), and adjuvant radiation (CAM=73.7%, LABC=90.3%). On multivariable analysis adjusting for age, race/ethnicity, and hormone receptor status, both CAM and M1 had inferior survival to LABC (Table 1), but with a 2.4-fold difference for CAM (95% CI 1.42-4.07, p=0.001) versus a 6.3-fold difference for M1 (95% CI 4.29-9.23, p=< 0.001). Discussion In this contemporary, multi-institution study, we demonstrated that CAM patients selected for presumed curative intent treatment experienced improved OS when compared to stage IV (M1) patients. Our data adds additional support for re-evaluating the current stage IV designation, in favor of N3, and consideration of curative intent treatment in this disease. Table. Adjusted* Overall Survival Comparing Patients with Breast Cancer Contralateral Axillary Metastasis (CAM) to those with Locally Advanced Breast Cancer (LABC) and Metastatic Disease (M1) *Adjusted for age, race/ethnicity, hormone receptors. Citation Format: Meghan R. Flanagan, Stephanie Downs-Canner, Samantha Thomas, Astrid Botty van de bruele, Margaret Lillie, Kristalyn Gallagher, Tammeza Gibson, James Jakub, Alexandra Verosky, Sarah Tevis, Malia Brennan, Francys Verdial, Jennifer Q. Zhang, Leisha Elmore, Jennifer Plichta, Laura Rosenberger. A Multi-Institutional Review of Contralateral Axillary Metastases: Time for Reclassification as Local-Regional Event? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-13.

Abstract PO3-06-10: Real World Outcomes with Sacituzumab Govitecan in Metastatic Triple Negative Breast Cancer Patients: A Multi-Institution Study

Abstract Background Sacituzumab govitecan (SG) is approved for treatment of metastatic triple negative breast cancer (mTNBC) in the second line and beyond. Little is known about the real-world outcomes of SG. We aim to evaluate the real-world effectiveness and toxicity outcomes of SG in heterogenous heavily pretreated mTNBC patients (pts) to investigate the consistency of the outcomes in comparison to the clinical trial population. Methods A multi-center retrospective study of pts with mTNBC treated with SG in the US from January 2021 until May 2023 was conducted. Demographics and clinicopathological variables including site of metastases, prior lines of therapy, relative dose intensity (RDI), adverse events (AEs), HER2 immunohistochemistry (IHC) score at time of metastasis, clinical response, clinical benefit rate (CBR) defined as (complete response, partial response (PR) or stable disease (SD) > 6 months) and last follow-up were collected. For continuous variables, Mann-U Whitney and Kruskal Wallis tests were used to compare mean, median, standard deviation, and range. For categorical variables, Fisher's exact tests and Pearson Chi-square tests were used. Univariate and multivariate cox regression models examined RDI and survival outcomes. SAS v9.4 was used to perform statistical analysis at a significance level of 0.05. Results A total of 111 pts were analyzed. The median age was 58 years (range 29-84). The majority of pts were heavily pretreated: 59.1% received >3 prior lines of treatment (Tx) in the metastatic setting, 54.1% received prior immune checkpoint inhibitor (ICI), 8.1% received prior olaparib. 55% of pts had significant disease burden defined by >=3 organs involved by metastatic disease, with 22.5% having brain metastasis at the time of initiation of SG. Of note, 51% had primary refractory disease defined as relapse within 12 months of completion of adjuvant chemotherapy. 98.1% experienced any grade AEs, with the most common being anemia 63.1%. Grade 3 AEs occurred in 51.4% pts with neutropenia being the highest 32.4% followed by anemia 14.4%, diarrhea 7.2% and fatigue 7.2%. Tx interruptions and dose reductions due to AEs occurred in 52.3% of patients and Tx discontinuation rate due to AEs was 11.8%. Elderly pts (defined as >65 years) did not have higher rates of dose reductions due to AEs compared to young pts (< = 65 years) (37.8% vs 59.7 %), p=0.043). The median RDI is 92% (interquartile range (IQR) 33%-100%). The median RDI in elderly pts was 94% (IQR 50%-100%). Among pts in which response was assessed, objective response rate (ORR) was 26.6% (25 pts had PR), and 38.3% had SD. Interestingly, the rate of alopecia was higher in pts who had PR as the best response (28%), compared to 5.6% in pts who had SD, and 3% in progressive disease (PD) p=0.004. The median prior line of therapy in pts who had PR and SD as best response was 2 (IQR 1, 5) (IQR1, 12), respectively, compared to a median of 3 (IQR 1, 7) in pts with PD, p< 0.001. The CBR was 49% (46/94). The median duration of clinical benefit was 7 months IQR (2, 16) with median overall survival of 13 months IQR (2.5, 39) compared to 5.7 months IQR (0.03, 27) in pts without clinical benefit (p< 0.001). 56.9% (62/109) of pts had HER2 low disease and the clinical benefit rate in this subgroup was 14.3% (23/62). Conclusion: In a heavily pretreated cohort, SG retains clinical activity and tolerability in mTNBC. This is reassuring given pts on clinical trials tend to be healthier compared to real-world clinical practice. Citation Format: Sabah Alaklabi, Arya Mariam Roy, Paola Zagami, Nicole Held, Saba Shaikh, Lubna Chaudhary, Yara Abdou, Shipra Gandhi. Real World Outcomes with Sacituzumab Govitecan in Metastatic Triple Negative Breast Cancer Patients: A Multi-Institution Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-10.

Abstract PS08-03: Sequencing Antibody-Drug Conjugate after Antibody-Drug Conjugate in Metastatic Breast Cancer (A3 study): Multi-Institution Experience and Biomarker Analysis

Abstract Background: Antibody-drug conjugates (ADCs) improve survival in patients with metastatic breast cancer (MBC) and offer the potential for targeted delivery of highly potent therapy. Many patients are now candidates for multiple ADCs, but optimal strategies for sequencing are unknown. We previously reported on a single institution experience of patients receiving multiple ADCs for MBC (Abelman, ASCO 2023). Here we report a multi-institution update with biomarker analysis. Methods: We included all patients treated at three academic medical institutions who received multiple ADCs for MBC. Patients were included if they had hormone receptor positive, HER2-negative (HR+/HER2-) breast cancer or triple-negative breast cancer (TNBC); patients with HER2+ metastatic breast cancer were excluded. Clinical information was determined by chart review. The metric of “cross-resistance” to the second ADC was defined as patients with progressive disease on first restaging assessment or progression within 60 days of treatment initiation. Every subsequent ADC beyond the first was compared against the prior ADC for presence of identical “antibody target” and “payload”. Comparisons across ADCs were performed using Fisher’s exact test. Significance was determined to be a type I error less than 0.05. A subset of patients had available whole exome tissue sequencing through commercially available sequencing platforms (BostonGene and Caris) performed around the time of receipt of ADC. All sequencing reports were examined for presence of pathogenic variants, variants of uncertain significance, and currently undefined variants and fusions as defined by each sequencing platform. Results: 68 patients were identified who received two or more ADCs for metastatic HR+/HER2- breast cancer or TNBC from August 2014-June 2023. 30 patients (44.1%) had HR+/HER2- disease and 38 patients (55.9%) had TNBC; 50 patients (73.5%) had HER2-low disease. Median age at time of second ADC was 59.6 (range 29.9-88.6). Patients had received a median of 4 lines of treatment in the metastatic setting prior to initiation of the second ADC. At time of first restaging, cross-resistance was present in 38/64 evaluable cases (59.4%). When the antibody target of the latter ADC was the same as the prior, cross-resistance was present in 11/14 cases (78.5%) compared to 26/49 cases (53.1%) when the later ADC targeted a different tumor-associated antigen. Relatively similar patterns of cross-resistance were observed regardless of whether the later ADC contained an identical payload to prior (6/10 cases, 60%) versus a different payload (22/42, 52.4%). Sequencing information was available for 20 patients who received multiple ADCs with 15 unique reports performed at the time of resistance to ADC1, prior to initiation of ADC2, or after ADC2 if presence of cross-resistance. Variants in topoisomerase-I associated genes (TOP1, TOP2A, TOP3A, TOP3B) were identified in a subset of patients mediating cross-resistance to the second ADC with a topoisomerase-I inhibitor payload. Conclusions: In this multi-institution study, cross-resistance to the second ADC appears to be driven by the antibody target in some patients versus the payload in others, highlighting the heterogeneity of mechanisms related to ADC resistance. Tumor sequencing revealed candidate resistance mutations that may guide optimal sequencing for patients with MBC. Citation Format: Rachel Occhiogrosso Abelman, Laura Spring, Geoffrey Fell, Andrew Davis, Whitney Hensing, Phoebe Ryan, Neelima Vidula, Seth Wander, Arielle Medford, Jennifer Shin, Elizabeth Abraham, Steven Isakoff, Beverly Moy, Leif Ellisen, Aditya Bardia. Sequencing Antibody-Drug Conjugate after Antibody-Drug Conjugate in Metastatic Breast Cancer (A3 study): Multi-Institution Experience and Biomarker Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-03.

Outcome of video-assisted thoracoscopic treatment of idiopathic chylothorax in 15 cats.

To evaluate the outcomes and complications of video-assisted thoracoscopic (VATS) treatment of chylothorax in cats. Multi-institutional retrospective study. Fifteen client-owned cats. The medical records of cats undergoing thoracoscopic thoracic duct ligation (TDL) for treatment of idiopathic chylothorax were reviewed. Cats undergoing additional procedures including thoracoscopic pericardectomy and/or laparoscopic cisterna chyli ablation (CCA)_were included. Follow up was obtained through communication with the referring veterinarian or owner. All cats underwent thoracoscopic TDL. Thirteen cats underwent simultaneous pericardectomy and two cats underwent laparoscopic CCA without pericardectomy. Conversion from a thoracoscopic to open approach was necessary in 2/15 (13%) of thoracic duct ligations and 1/11 (9%) of pericardectomies. The most common postoperative complication was persistent pleural effusion in five cats (33%). Four of 15 cats (27%) died or were euthanized prior to hospital discharge following surgery. Recurrence of effusion occurred in 1/7 (14%) of cats that sustained resolution of the effusion at the time of surgery with a median follow up of 8 months. The overall mortality attributed to chylothorax was 47%. Thoracoscopic treatment of idiopathic chylothorax resulted in a low incidence of intraoperative complications or conversion in the study population; however, mortality related to feline idiopathic chylothorax remained high. While VATS treatment of idiopathic chylothorax is technically feasible, further consideration of the underlying pathology and current treatment algorithm is needed to improve outcomes as this remains a frustrating disease to treat in the feline population.

Abstract PO3-03-01: Impact of Environmental Temperature on Clinical Outcomes and Tumor Microenvironment of Early-Stage Breast Cancer

Abstract Background Preclinical evidence using mouse model suggests that thermal/cold stress increases tumor growth by modulating the tumor microenvironment (TME); however, the clinical relevance of temperature on breast cancer (BC) outcomes is unknown. Studies show that residing in cold regions is associated with higher incidence of BC. We aim to study the impact of environmental temperature on the pathological complete response (pCR) and survival of early-stage BC patients (pts). Methodology A multi-institutional study was conducted within the Oncology Research Information Exchange Network (ORIEN). We analyzed the clinical and genomic data for early-stage BC pts from 12 centers in different environment zones (5 warm and 7 cold) (based on average annual regional temperature obtained from National Centers for Environmental Information). Cox regression was used to measure the association of climate and overall/relapse-free survival (OS/RFS) after adjusting for age, race, body mass index, grade, stage, treatments, comorbidities, and subtype. Raw feature counts were normalized, and differential expression analysis was carried out using DESeq2, while adjusting for all of the covariates. Differential expression rank order was used for subsequent gene set enrichment analysis (GSEA), performed using the cluster profile package in R. Gene sets queried included the Hallmark, Canonical pathways, and GO Biological Processes Ontology collections available through the Molecular Signatures Database (MSigDB). Results Out of the 1,304 early-stage BC pts, 271 pts received neoadjuvant chemotherapy (NAC) (186 warm, 85 cold). Higher clinical T- and N-stages were observed in pts from warm compared to cold regions (p< 0.001). Pts residing in cold regions had more comorbidities (57.6% vs 4.8%, p< 0.001). Pts in warm regions had higher pCR, though not statistically significant (8% vs 2.5%, p= 0.1). In the overall population, the OS (univariate (UV) HR= 0.48, 95% CI 0.27-0.64, p < 0.001; adjusted HR (aHR)= 0.56, 95% CI 0.32 - 0.96, p= 0.03) and RFS (UV HR= 0.51, 95% CI 0.38 - 0.68, p< 0.001; aHR= 0.52, 95% CI 0.36 - 0.75, p= 0.0005) were higher in pts from warm compared to cold regions (Table 1). Among the patient subgroup treated with NAC, the OS (aHR= 0.35, p= 0.02) and RFS (aHR= 0.49, p= 0.02) of pts from warmer regions was also higher than cold regions. RNA sequencing was performed on 826 tumors (443 warm, 383 cold) using pre-treatment samples. Naïve B-cells (mean: 0.09 vs 0.08, p=0.004), CD4 naïve T cells (0.03 vs 0.02, p= 0.0008), CD4+ memory T cells (0.03 vs 0.02, p= 0.04), gamma-delta T-cells (0.007 vs 0.004, p= 0.006) were higher in pts residing in cold compared to warm regions while CD8 T cells, T regulatory cells, macrophages, dendritic cells, natural killer cells were similar in both regions. Macrophage signaling, cholesterol metabolism and the pathway for negative regulation of cell migration in angiogenesis were upregulated in pts living in warm compared to cold regions. Conclusion Early-stage BC pts living in cold have worse OS and RFS compared to warm regions. Our study is the first to report significant differences in the TME among these pts. However, it is important to acknowledge that the limited availability of comprehensive data regarding patients' relocation to different environmental temperature zones during treatments, and individual temperature preferences may be considered a potential limitation of our study. To ensure the validity and robustness of these intriguing findings, larger multi-center studies should be conducted, encompassing detailed information on the duration of exposure to both warm and cold weather conditions. Table 1: OS and RFS of patients living in warm vs cold environments Citation Format: Arya Mariam Roy, Spencer Rosario, Anthony George, Qiang Hu, Brian Czerniecki, John Carpten, Virginia Borges, Bryan Schneider, Jill Kolesar, Christopher Moskaluk, Craig Shriver, Cindy Matsen, Shridar Ganesan, Sneha Phadke, Wajeeha Razaq, Kristopher Attwood, Shipra Gandhi. Impact of Environmental Temperature on Clinical Outcomes and Tumor Microenvironment of Early-Stage Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-03-01.

Abstract PO4-27-08: A Phase II Multi-Institutional Study of Concurrent Radiotherapy, Palbociclib, and HormoneTherapy for Treatment of Bone Metastasis in Breast Cancer Patients

Abstract Background: This Phase II study aimed to determine the efficacy and safety of administering palliative radiotherapy (RT) to bone metastases (mets) in patients (pts) receiving concurrent palbociclib and hormone therapy (HT) for hormone receptor positive, Her2/neu negative breast cancer. The primary endpoint was response rate 3 months after RT. Methods: Pts with painful bone mets or asymptomatic bone mets with risk for impending clinical event were treated with RT to 30 Gy in 10 fractions or 20 Gy in 5 fractions with concurrent palbociclib and HT. Change in maximum pain score on the Brief Pain Inventory was used to assess pain response 3 months post RT relative to baseline. Among pts with asymptomatic bone lesions, response was defined as prevention of a clinical event (e.g., bone fracture) without evidence of local tumor growth on surveillance imaging. Patient reported outcomes (PROs) of fatigue, depression, anxiety, and quality of life were collected. Blood-based biomarkers were examined to determine their relationship with response and PROs. Using a non-inferiority study design, a sample size of at least 33 pts was needed to achieve 80% power to detect a non-inferiority proportion of 60% using a one-sided binomial test and assuming a Type I error of 0.05. Results: Among 38 patients enrolled, 79% had painful bone mets. 35 pts completed baseline and 3-month post RT assessments. 61% and 37% of pts received aromatase inhibitors and fulvestrant, respectively, with palbociclib. Median age was 60 years (31-83) and 25% of pts were non-Hispanic Black. The majority (72%) of pts received 5 fraction RT and 69% received RT to one bone region. 29 patients (83%) were responders [95% CI: 66%-93%, p=.003]. Median progression free survival (PFS) was 30.4 months (1.3 - 44.0). Three-year PFS and overall survival were 45.6% and 67.2%, respectively. Grade 3 neutropenia developed in 4 (11%), 4 (11%), and 7 (20%) pts at end of RT, 1 month, and 3 months post RT, respectively. No pts developed Grade 4 neutropenia. One patient developed Grade 3 gastrointestinal toxicity during RT, another developed Grade 3 dyspnea 1 month post XRT, and another developed a bone fracture 6 months after RT. >While patient reported measures of fatigue, depression, and overall quality of life did not significantly change during or after RT relative to baseline, pain scores (i.e., BPI pain severity and interference, BM22 pain characteristics and pain site subscales, EORTC C15 pain) significantly decreased 3 months post XRT relative to baseline. Heightened inflammatory marker levels (e.g., TNFRII, IL1ra, CRP, TNF alpha) were significantly associated with worse symptoms of fatigue (MFI) and depression (HADS), increased pain interference (BPI), and lower overall quality of life (SF-36), controlling for age and time using mixed effect models. Patients with improved pain symptoms and lower pain scores had significantly lower inflammatory marker levels relative to baseline (e.g., interleukin-6). Conclusions: Our study demonstrated high rates of response to concurrent RT with palbociclib and HT with acceptable levels of toxicity. These results suggest that RT to bone mets effectively alleviates pain in patients taking palbociclib and pain response to treatment is associated with decreased inflammatory markers. RT may be given to pts receiving palbociclib and HT for breast cancer. Clinical Trial Identification: NCT03691493 Citation Format: Mylin Torres, Jolinta Lin, Sarah Friend, Canhua Xiao, Yichun Cao, Shannon Kahn, Karen Godette, Sheela Hanasoge, David Yu, Tony Eng, Matthew Cheney, Nancy Wiggers, Andrew Pippas, Keerthi Gogineni, Jane Meisel, David Schuster, Aditya Bardia, Andrew Miller, Jennifer Felger, Jeffrey Switchenko, Amelia Zelnak, Kevin Kalinsky, Manali Bhave. A Phase II Multi-Institutional Study of Concurrent Radiotherapy, Palbociclib, and HormoneTherapy for Treatment of Bone Metastasis in Breast Cancer Patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-27-08.

Abstract PO1-22-10: Long term outcomes of breast cancer patients with local recurrence after mastectomy undergoing immediate breast reconstruction: A retrospective multi-institutional study of 4153 cases

Abstract Background: The number of breast cancer patients in Japan undergoing immediate breast reconstruction (IBR) has increased and the postoperative follow-up period has been extended. This study was conducted to clarify the clinical aspects of and factors associated with local recurrence (LR) after IBR. Methods: This was a multicenter study which included 4153 early breast cancer patients who underwent IBR. Clinicopathological characteristics were examined and factors potentially contributing to LR were analyzed. Risk factors for LR were examined separately for non-invasive and invasive breast cancers. Results: The median follow-up period was 75 months. The 7-year LR rates were 2.1% and 4.3% for non-invasive and invasive cancers, respectively (p < 0.001). The proportions of LR detected by palpation, subjective symptoms, and ultrasonography were 40.0%, 27.3%, and 25.9%, respectively. Overall, 75.7% of LR were solitary, and 92.7% of these cases had no further recurrences during the observational period. Multivariate analysis of LR for invasive cancer showed that skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM), the presence of lymphovascular invasion, cancer at the surgical margin, and not receiving radiation therapy were factors related to LR. The 7-year overall survival rates of the patients with LR and non-LR of invasive cancers were 92.5% and 97.3%, respectively, (p=0.002). Conclusions: The rate of LR after IBR was acceptably low and IBR can thus be performed safely for early breast cancer patients. Invasive cancer, SSM/NSM, lymphovascular invasion, and/or cancer at the surgical margin should prompt awareness of the possibility of LR. Citation Format: Akiko Ogiya, Naomi Nagura, Ayaka Shimo, Hiroko Nogi, Kazutaka Narui, Hirohito Seki, Hiroki Mori, Shinsuke Sasada, Makoto Ishitobi, Naoto Kondo, Chikako Yamauchi, Kohei Akazawa, Tadahiko Shien. Long term outcomes of breast cancer patients with local recurrence after mastectomy undergoing immediate breast reconstruction: A retrospective multi-institutional study of 4153 cases [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-22-10.

Unrecognized Focal Nonmotor Seizures in Adolescents Presenting to Emergency Departments.

Many adolescents with undiagnosed focal epilepsy seek evaluation in emergency departments (EDs). Accurate history-taking is essential to prompt diagnosis and treatment. In this study, we investigated ED recognition of motor vs nonmotor seizures and its effect on management and treatment of focal epilepsy in adolescents. This was a retrospective analysis of enrollment data from the Human Epilepsy Project (HEP), an international multi-institutional study that collected data from 34 sites between 2012 and 2017. Participants were 12 years or older, neurotypical, and within 4 months of treatment initiation for focal epilepsy. We used HEP enrollment medical records to review participants' initial diagnosis and management. A total of 83 adolescents were enrolled between 12 and 18 years. Fifty-eight (70%) presented to an ED before diagnosis of epilepsy. Although most ED presentations were for motor seizures (n = 52; 90%), many patients had a history of nonmotor seizures (20/52 or 38%). Adolescents with initial nonmotor seizures were less likely to present to EDs (26/44 or 59% vs 32/39 or 82%, p = 0.02), and nonmotor seizures were less likely to be correctly identified (2/6 or 33% vs 42/52 or 81%, p = 0.008). A history of initial nonmotor seizures was not recognized in any adolescent who presented for a first-lifetime motor seizure. As a result, initiation of treatment and admission from the ED was not more likely for these adolescents who met the definition of epilepsy compared with those with no seizure history. This lack of nonmotor seizure history recognition in the ED was greater than that observed in the adult group (0% vs 23%, p = 0.03) and occurred in both pediatric and nonpediatric ED settings. Our study supports growing evidence that nonmotor seizures are often undiagnosed, with many individuals coming to attention only after conversion to motor seizures. We found this treatment gap is exacerbated in the adolescent population. Our study highlights a critical need for physicians to inquire about the symptoms of nonmotor seizures, even when the presenting seizure is motor. Future interventions should focus on improving nonmotor seizure recognition for this population in EDs.

A Multi-Institutional Study Comparing Stoma Location in Neonates With Intestinal Perforation

IntroductionNeonates with intestinal perforation often require laparotomy and intestinal stoma creation, with the stoma placed in either the laparotomy incision or a separate site. We aimed to investigate if stoma location is associated with risk of postoperative wound complications. MethodsA multi-institutional retrospective review was performed for neonates ≤3 mo who underwent emergent laparotomy and intestinal stoma creation for intestinal perforation between January 1, 2009 and April 1, 2021. Patients were stratified by stoma location (laparotomy incision versus separate site). Outcomes included wound infection/dehiscence, stoma irritation, retraction, stricture, and prolapse. Multivariable regression identified factors associated with postoperative wound complications, controlling for gestational age, age and weight at surgery, and diagnosis. ResultsOverall, 79 neonates of median gestational age 28.8 wk (interquartile range [IQR]: 26.0-34.2 wk), median age 5 d (IQR: 2-11 d) and median weight 1.4 kg (IQR: 0.9-2.42 kg) had perforated bowel from necrotizing enterocolitis (40.5%), focal intestinal perforation (31.6%), or other etiologies (27.8%). Stomas were placed in the laparotomy incision for 41 (51.9%) patients and separate sites in 38 (48.1%) patients. Wound infection/dehiscence occurred in 7 (17.1%) neonates with laparotomy stomas and 5 (13.2%) neonates with separate site stomas (P = 0.63). There were no significant differences in peristomal irritation, stoma retraction, or stoma stricture between the two groups. On multivariable regression, separate site stomas were associated with increased likelihood of prolapse (odds ratio 6.54; 95% confidence interval: 1.14-37.5). ConclusionsStoma incorporation within the laparotomy incision is not associated with wound complications. Separate site stomas may be associated with prolapse. Patient factors should be considered when planning stoma location in neonates undergoing surgery for intestinal perforation.

Prognostic value of preoperative combined neutrophil, monocyte, and lymphocyte scores in patients with renal cell carcinoma undergoing laparoscopic nephrectomy: A retrospective study.

In a multi-institutional clinical study, we assessed the prognostic significance of a novel indicator preoperative peripheral blood immune (PBIS) scores that combined ratios of preoperative lymphocyte, monocyte, and neutrophil of renal cell carcinoma (RCC) patients undergoing laparoscopic nephrectomy. Between January 2014 and December 2019, 438 patients with RCC were retrospectively analyzed in three centers. We used X-tile software to obtain the optimum cut-off values for neutrophils, monocytes, and lymphocytes to classify the patients. To assess the relationship between PBIS score and overall survival (OS), and cancer-specific survival (CSS) in patients with RCC by Kaplan-Meier survival curves and Cox regression analyses. In addition, predictive OS and CSS nomograms were constructed. The discriminative ability of nomogram and predictive performance accuracy were verified with consistency index (C-index), calibration curves, receiver operating curve (ROC) curves, decision curve analysis (DCA) curves, and time-dependent ROC curves. The optimum cutoff values for monocytes, lymphocytes, and neutrophils were 0.46, 1.01, and 4.50, respectively. We divided patients into four subgroups according to PBIS scores, which were significantly associated with M-stage (p = 0.008), T-stage (p < 0.001), N-stage (p = 0.006), and AJCC stage (p < 0.001). Multivariate Cox regression analysis revealed that RCC patients with lower PBIS scores showed a worse postoperative prognosis and served as an independent predictor of OS (p = 0.002) and CSS (p < 0.001). Ultimately, the nomograms based on PBIS scores demonstrated excellent predictive performance for OS (C-index: 0.770) and CSS (C-index: 0.828) through the analysis of calibration curves, ROC curves, DCA curves, and time-dependent ROC curves. PBIS score served as novel and effective predictor to accurately predict OS and CSS in patients with RCC receiving laparoscopic nephrectomy.

Preoperative CECT-Based Multitask Model Predicts Peritoneal Recurrence and Disease-Free Survival in Advanced Ovarian Cancer: A Multicenter Study

ObjectivePeritoneal recurrence is the predominant pattern of recurrence in advanced ovarian cancer (AOC) and portends a dismal prognosis. Accurate prediction of peritoneal recurrence and disease-free survival (DFS) is crucial to identify patients who might benefit from intensive treatment. We aimed to develop a predictive model for peritoneal recurrence and prognosis in AOC. MethodsIn this retrospective multi-institution study of 515 patients, an end-to-end multi-task convolutional neural network (MCNN) comprising a segmentation convolutional neural network (CNN) and a classification CNN was developed and tested using preoperative CT images, and MCNN-score was generated to indicate the peritoneal recurrence and DFS status in patients with AOC. We evaluated the accuracy of the model for automatic segmentation and predict prognosis. ResultsThe MCNN achieved promising segmentation performances with a mean Dice coefficient of 84.3% (range: 78.8%-87.0%). The MCNN was able to predict peritoneal recurrence in the training (AUC 0.87; 95% CI 0.82–0.90), internal test (0.88; 0.85–0.92), and external test set (0.82; 0.78–0.86). Similarly, MCNN demonstrated consistently high accuracy in predicting recurrence, with an AUC of 0.85; 95% CI 0.82–0.88, 0.83; 95% CI 0.80–0.86, and 0.85; 95% CI 0.83–0.88. For patients with a high MCNN-score of recurrence, it was associated with poorer DFS with P<0.0001 and hazard ratios of 0.1964 (95% CI: 0.1439-0.2680), 0.3249 (95% CI: 0.1896-0.5565), and 0.3458 (95% CI: 0.2582-0.4632). ConclusionsThe MCNN approach demonstrated high performance in predicting peritoneal recurrence and DFS in patients with AOC.

The real-world data of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study.

The real-world efficacy, feasibility, and prognostic factors of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer are not fully established. This multi-institutional retrospective cohort study evaluated 71 consecutive patients treated with immune-checkpoint inhibitor combination therapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, safety, and long-term survival. In patients with measurable lesions, the response rate was 58%, and the disease control rate for all enrolled patients was 80%. Five patients (7.0%) underwent successful conversion surgery. Grade 3 or higher immune-related adverse events occurred in 13% of patients, and one patient (1.4%) died due to cholangitis. Median progression-free survival was 9.7 (95% confidence interval: 6.5-not reached). C-reactive protein levels and performance status were identified as significant predictors of progression-free survival through Cox proportional hazards analysis. Immune-checkpoint inhibitor combination therapy for esophageal cancer demonstrated comparable tumor response, safety, and long-term survival to previous randomized clinical trials. Patients with good performance status and low C-reactive protein levels may be suitable candidates for this treatment.

Assessing Uveitis Risk following Pediatric Down Syndrome Diagnosis: A TriNetX Database Study

Background and Objectives: The risks of uveitis development among pediatric patients with Down syndrome (DS) remain unclear. Therefore, we aimed to determine the risk of uveitis following a diagnosis of DS. Materials and Methods: This multi-institutional retrospective cohort study utilized the TriNetX database to identify individuals aged 18 years and younger with and without a diagnosis of DS between 1 January 2000 and 31 December 2023. The non-DS cohort consisted of randomly selected control patients matched by selected variables. This included gender, age, ethnicity, and certain comorbidities. The main outcome is the incidence of new-onset uveitis. Statistical analysis of the uveitis risk was reported using hazard ratios (HRs) and 95% confidence intervals (CIs). Separate analyses of the uveitis risk among DS patients based on age groups and gender were also performed. Results: A total of 53,993 individuals with DS (46.83% female, 58.26% white, mean age at index 5.21 ± 5.76 years) and 53,993 non-DS individuals (45.56% female, 58.28% white, mean age at index 5.21 ± 5.76 years) were recruited from the TriNetX database. Our analysis also showed no overall increased risk of uveitis among DS patients (HR: 1.33 [CI: 0.89–1.99]) compared to the non-DS cohort across the 23-year study period. Subgroup analyses based on different age groups showed that those aged 0–1 year (HR: 1.36 [CI: 0.68–2.72]), 0–5 years (HR: 1.34 [CI: 0.75–2.39]), and 6–18 years (HR: 1.15 [CI: 0.67–1.96]) were found to have no association with uveitis risk compared to their respective non-DS comparators. There was also no increased risk of uveitis among females (HR: 1.49 [CI: 0.87–2.56]) or males (HR: 0.82 [CI: 0.48–1.41]) with DS compared to their respective non-DS comparators. Conclusions: Our study found no overall increased risk of uveitis following a diagnosis of DS compared to a matched control population.

Impact of radiation therapy for breast cancer with involved surgical margin after immediate breast reconstruction: A multi-institutional observational study

IntroductionInvolved surgical margins are risk factors for local recurrence and re-excision is often difficult, particularly in patients with breast cancer undergoing immediate breast reconstruction (IBR). However, the magnitude of the effect of radiation therapy on preventing local recurrence for breast cancers with involved margins has not been sufficiently assessed. Materials and methodsWe retrospectively assessed sites of involved surgical margins and local recurrence after mastectomy with IBR in patients with early breast cancer between 2008 and 2016. The effect of postoperative radiation therapy was evaluated in patients with involved margins, adjusted for nuclear grade, lymphatic invasion, surgical procedures, and primary systemic therapy. ResultsA total of 274 (5.8 %) out of 4726 patients who underwent mastectomy with IBR had involved surgical margins: 133, 68, 88, and 26 had involvement of the skin, deep margin, lateral margins, and nipple, respectively (including duplicates). Radiation therapy was administered to 54 patients with involved margins. In patients with involved margins, 7-year cumulative incidences of local recurrence were 1.9 % and 12.6 % with and without radiation therapy, respectively (adjusted hazard ratio, 0.17; 95 % CI, 0.04–0.80). Local recurrence occurred in 28 patients, and the sites were skin, subcutaneous tissue, muscle, and nipple-areola complex in 7, 17, 1, and 3 patients, respectively. Among them, 23 (82.1 %) were associated with involved margin sites. ConclusionsRadiation therapy meaningfully reduced the incidence of local recurrence in patients with breast cancer with margin involvement after mastectomy with IBR. Most local recurrences occurred at involved margin-related sites.

Inter- and intra-observer variability of qualitative visual breast-composition assessment in mammography among Japanese physicians: a first multi-institutional observer performance study in Japan.

Visual assessment of mammographic breast composition remains the most common worldwide, although subjective variability limits its reproducibility. This study aimed to investigate the inter- and intra-observer variability in qualitative visual assessment of mammographic breast composition through a multi-institutional observer performance study for the first time in Japan. This study enrolled 10 Japanese physicians from five different institutions. They used the new Japanese breast-composition classification system 4th edition to subjectively evaluate the breast composition in 200 pairs of right and left normal mediolateral oblique mammograms (number determined using precise sample size calculations) twice, with a 1-month interval (median patient age: 59years [range 40-69years]). The primary endpoint of this study was the inter-observer variability using kappa (κ) value. Inter-observer variability for the four and two classes of breast-composition assessment revealed moderate agreement (Fleiss' κ: first and second reading = 0.553 and 0.587, respectively) and substantial agreement (Fleiss' κ: first and second reading = 0.689 and 0.70, respectively). Intra-observer variability for the four and two classes of breast-composition assessment demonstrated substantial agreement (Cohen's κ, median = 0.758) and almost perfect agreement (Cohen's κ, median = 0.813). Assessments of consensus between the 10 physicians and the automated software Volpara® revealed slight agreement (Cohen's κ; first and second reading: 0.104 and 0.075, respectively). Qualitative visual assessment of mammographic breast composition using the new Japanese classification revealed excellent intra-observer reproducibility. However, persistent inter-observer variability, presenting a challenge in establishing it as the gold standard in Japan.

Technology Characterization Through Diverse Evaluation Methodologies: Application to Thoracic Imaging in Photon-Counting Computed Tomography

Objective Different methods can be used to condition imaging systems for clinical use. The purpose of this study was to assess how these methods complement one another in evaluating a system for clinical integration of an emerging technology, photon-counting computed tomography (PCCT), for thoracic imaging. Methods Four methods were used to assess a clinical PCCT system (NAEOTOM Alpha; Siemens Healthineers, Forchheim, Germany) across 3 reconstruction kernels (Br40f, Br48f, and Br56f). First, a phantom evaluation was performed using a computed tomography quality control phantom to characterize noise magnitude, spatial resolution, and detectability. Second, clinical images acquired using conventional and PCCT systems were used for a multi-institutional reader study where readers from 2 institutions were asked to rank their preference of images. Third, the clinical images were assessed in terms of in vivo image quality characterization of global noise index and detectability. Fourth, a virtual imaging trial was conducted using a validated simulation platform (DukeSim) that models PCCT and a virtual patient model (XCAT) with embedded lung lesions imaged under differing conditions of respiratory phase and positional displacement. Using known ground truth of the patient model, images were evaluated for quantitative biomarkers of lung intensity histograms and lesion morphology metrics. Results For the physical phantom study, the Br56f kernel was shown to have the highest resolution despite having the highest noise and lowest detectability. Readers across both institutions preferred the Br56f kernel (71% first rank) with a high interclass correlation (0.990). In vivo assessments found superior detectability for PCCT compared with conventional computed tomography but higher noise and reduced detectability with increased kernel sharpness. For the virtual imaging trial, Br40f was shown to have the best performance for histogram measures, whereas Br56f was shown to have the most precise and accurate morphology metrics. Conclusion The 4 evaluation methods each have their strengths and limitations and bring complementary insight to the evaluation of PCCT. Although no method offers a complete answer, concordant findings between methods offer affirmatory confidence in a decision, whereas discordant ones offer insight for added perspective. Aggregating our findings, we concluded the Br56f kernel best for high-resolution tasks and Br40f for contrast-dependent tasks.

Prognostic Significance of Bulky Nodal Disease in Anal Cancer Management: A Multi Institutional Study.

This study aimed to assess the prognostic significance of bulky nodal involvement in patients with anal squamous cell carcinoma treated with definitive chemoradiotherapy. We retrospectively analyzed medical records of patients diagnosed with anal squamous cell carcinoma who underwent definitive chemoradiotherapy at three medical centers between 2004 and 2021. Exclusion criteria included distant metastasis at diagnosis, 2D radiotherapy, and salvage treatment for local relapse. Bulky N+ was defined as nodes with a long diameter of 2 cm or greater. A total of 104 patients were included, comprising 51 with N0, 46 with non-bulky N+, and 7 with bulky N+. The median follow-up duration was 54.0 months (range, 6.4-162.2 months). Estimated 5-year progression-free survival (PFS), loco-regional recurrence-free survival (LRRFS), and overall survival (OS) rates for patients with bulky N+ were 42.9%, 42.9%, and 47.6%, respectively. Bulky N+ was significantly associated with inferior PFS, LRRFS and OS compared to patients without or with non-bulky N+, even after multivariate analysis. We proposed a new staging system incorporating bulky N+ as N2 stage, with estimated 5-year LRRFS, PFS, and OS rates of 81.1%, 80.6%, and 86.2% for stage I, 67.7%, 60.9%, and 93.3% for stage II, and 42.9%, 42.9%, and 47.6% for stage III disease, enhancing the predictability of prognosis. Patients with bulky nodal disease treated with standard chemoradiotherapy experienced poor survival outcomes, indicating the potential necessity for further treatment intensification.

Enhancing NSCLC recurrence prediction with PET/CT habitat imaging, ctDNA, and integrative radiogenomics-blood insights

While we recognize the prognostic importance of clinicopathological measures and circulating tumor DNA (ctDNA), the independent contribution of quantitative image markers to prognosis in non-small cell lung cancer (NSCLC) remains underexplored. In our multi-institutional study of 394 NSCLC patients, we utilize pre-treatment computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to establish a habitat imaging framework for assessing regional heterogeneity within individual tumors. This framework identifies three PET/CT subtypes, which maintain prognostic value after adjusting for clinicopathologic risk factors including tumor volume. Additionally, these subtypes complement ctDNA in predicting disease recurrence. Radiogenomics analysis unveil the molecular underpinnings of these imaging subtypes, highlighting downregulation in interferon alpha and gamma pathways in the high-risk subtype. In summary, our study demonstrates that these habitat imaging subtypes effectively stratify NSCLC patients based on their risk levels for disease recurrence after initial curative surgery or radiotherapy, providing valuable insights for personalized treatment approaches.