Citations

Abstract Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with deficient DNA mismatch repair (d-MMR) metastatic colorectal cancer (CRC), yet less than half of patients receive clinical benefit. We hypothesized that immune contexture including spatial distribution of cells expressing immune molecules in the tumor microenvironment may predict immunotherapy outcome. Methods: Primary CRC tissues from consecutive patients with d-MMR metastatic CRC (N=33) were treated with anti-PD-1 antibodies at Mayo Clinic Comprehensive Cancer Center (2015-2018). Tumors were stained for PD-L1, PD-1, CD8, CD3, CD68, LAG3, TGFβR2, MHC-I, CD14, B2M, DAPI and pan-cytokeratin in 5 compartments (overall tumor, tumor epithelia, tumor stroma, peritumor inside vs outside) by multiplex immunofluorescence with digital image analysis. Features computed within each image analysis region included positive cell density, fraction of positive cell types, intensity of positive cells, and spatial distribution between distinct cell types (distances measured using image analysis software). Prior to model fitting, feature selection was performed using regularized Cox regression with LASSO. Regularization parameter was chosen based on 5-fold cross validation. A Cox proportional hazards model was fitted to predict patient progression-free survival (PFS). Results: Among patients with d-MMR CRCs, 16/33 (48.4%) were female, 10 received first-line ICI therapy, and 23 had received > 1 prior chemotherapy regimen. Median age was 61.6 years (IQR of 49.4, 73.7). Eight patients (24.2%) harbored BRAFV600E, 9 (27.2%) had mutant KRAS, and median PFS was 22.2 months (95% CI: 11.8, NR) with 20 events. PD-L1 was expressed in tumor cells, CD68+ macrophages, and CD3+ T lymphocytes. PD-1 expression on CD8+ T lymphocytes was also observed. By univariate analysis, only cell-cell distance readouts achieved statistical significance. Multivariable feature selection identified the mean number of PD-1+ cells within 10 microns of a PD-L1+ cell in the overall tumor as the strongest predictor of anti-PD-1 efficacy, and was significantly associated with PFS (HR=0.87, 95% CI: 0.79-0.95, p< 0.001). In contrast, the ratio of PD-1+/PD-L1+ cells was not predictive of treatment efficacy (p= 0.47), thereby underscoring the importance of spatial distribution for PFS prediction. Conclusion: The mean number of PD-1+ cells in proximity to PD-L1+ cells in tumors was a predictive biomarker of anti-PD-1 efficacy. Confirmatory studies are warranted. Citation Format: Bahar Saberzadeh-Ardestani, Rondell P. Graham, Qian Shi, Eze Ahanonu, Sara McMahon, Crystal Williams, Antony Hubbard, Wenjun Zhang, Andrea Muranyi, Dongyao Yan, Kandavel Shanmugam, Frank A. Sinicrope. Prediction of anti-PD-1 efficacy based on immune marker densities and their spatial distribution in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6648.

Abstract Background No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture–based vaccines. In January 2021, an 84-year-old male died from rabies 6 months after being bitten by a rabid bat despite receiving timely rabies PEP. We investigated the cause of breakthrough infection. Methods We reviewed medical records, laboratory results, and autopsy findings and performed whole-genome sequencing (WGS) to compare patient and bat virus sequences. Storage, administration, and integrity of PEP biologics administered to the patient were assessed; samples from leftover rabies immunoglobulin were evaluated for potency. We conducted risk assessments for persons potentially exposed to the bat and for close patient contacts. Results Rabies virus antibodies present in serum and cerebrospinal fluid were nonneutralizing. Antemortem blood testing revealed that the patient had unrecognized monoclonal gammopathy of unknown significance. Autopsy findings showed rabies meningoencephalitis and metastatic prostatic adenocarcinoma. Rabies virus sequences from the patient and the offending bat were identical by WGS. No deviations were identified in potency, quality control, administration, or storage of administered PEP. Of 332 persons assessed for potential rabies exposure to the case patient, 3 (0.9%) warranted PEP. Conclusions This is the first reported failure of rabies PEP in the Western Hemisphere using a cell culture–based vaccine. Host-mediated primary vaccine failure attributed to previously unrecognized impaired immunity is the most likely explanation for this breakthrough infection. Clinicians should consider measuring rabies neutralizing antibody titers after completion of PEP if there is any suspicion for immunocompromise.

Objectives: Osteochondritis dissecans (OCD) of the humeral capitellum is an often painful condition that typically affects the adolescent athlete. There is little consensus on treatment and a scarcity of long-term outcomes data. The purpose of this study was to (1) report the long-term outcomes associated with both operative and non-operative management of capitellar OCD, (2) identify factors associated with failure of non-operative management, and (3) determine whether delay in surgery affects final outcomes. Methods: All patients diagnosed with OCD of the capitellum from 1995-2020 within a defined geographic cohort were included. Medical records, imaging studies, and operative reports were manually reviewed to record demographic data, treatment strategies, and outcomes. Surgical treatment was considered delayed if it occurred more than 6 months after symptom onset. Results: A total of 50 elbows with a mean follow-up of 9.4 years were included. Of these, 7 (14%) were treated non-operatively and never underwent surgery during follow-up, while 43 (86%) underwent surgical intervention: 27 had early surgery and 16 underwent delayed surgery after ≥ 6 months of non-operative treatment. When compared to non-operative management, surgical management resulted in superior MEPI scores (90 vs 83, p=0.05), decreased persistence of mechanical symptoms (9% vs 50%, p<0.01), and better elbow flexion (141° vs 131°, p=0.01) at long-term follow up. Older patients had a trend toward increased failure of non-operative management (p=0.06). The presence of an intra-articular loose body strongly predicted failure of non-operative management (p=0.01; OR 13). Plain radiography and MRI had poor sensitivities for identifying loose bodies (27% and 40%, respectively). Differences in outcomes following early versus delayed surgical management were not demonstrated. Conclusions: Patients with capitellar OCD initially treated nonoperatively failed nonoperative management 70% of the time. Elbows that did not undergo surgery had slightly increased symptoms and decreased functional outcomes compared to those treated surgically. In this cohort, the greatest predictors for failure of non-operative treatment were older age and presence of a loose body; however, an initial trial of non-operative treatment did not adversely impact the success of future surgery at long term follow-up. [Table: see text][Table: see text][Table: see text][Table: see text]

Abstract Background The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci. Methods We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci. Results We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci. Conclusions Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.

Abstract Background With data demonstrating benefit, the prevalence of home enteral nutrition (HEN) has increased significantly over the last few decades. Despite this increase, there remains a paucity of data regarding real‐world use of HEN including clinical outcomes and complications. Methods Descriptive analysis of prospectively maintained database of our specialized HEN program was undertaken. Patients who received care in our program with HEN initiation date between January 1, 2018, and December 31, 2020, were included in the analysis. Data regarding demographic information, anthropometrics, enteral nutrition (EN) regimen, electrolytes, and nutrition therapy history were included and tracked until July 31, 2021. Results During the study period, 1600 patients initiated HEN treatment under our care. Majority of the study population needed EN therapy due to malignancy and its complications, including malignant dysphagia or mechanical obstruction (60.6%) followed by neurodegenerative diseases (7.5%). By the end of the study period, a majority of the patients (82%) stopped HEN treatment. Of these, 44.2% achieved EN goals and/or oral autonomy. Patients continued HEN treatment for a median of 100 (interquartile range, 32–301) days. Overall, 53.2% of patients experienced/reported at least one HEN‐related complication that was clinically managed by the HEN team. Complications included tube‐related, enteral feeding intolerance (EFI), and electrolyte shifts. Conclusion In our study population, HEN was most utilized to manage malignancy‐related complications, including dysphagia. Unfortunately, complications, including EFI and tube‐related complications, remained quite prevalent. Further evaluation regarding risk factors for complications and preventive mechanisms, such as increased education, is indicated.

To determine the sensitivity and specificity of velar notching seen on nasopharyngoscopy for levator veli palatini (LVP) muscle discontinuity and anterior positioning. Nasopharyngoscopy and MRI of the velopharynx were performed on patients with VPI as part of their routine clinical care. Two speech-language pathologists independently evaluated nasopharyngoscopy studies for the presence or absence of velar notching. MRI was used to evaluate LVP muscle cohesiveness and position relative to the posterior hard palate. To determine the accuracy of velar notching for detecting LVP muscle discontinuity, sensitivity, specificity, and positive predictive value (PPV) were calculated. A craniofacial clinic at a large metropolitan hospital. Participants Thirty-seven patients who presented with hypernasality and/or audible nasal emission on speech evaluation and completed nasopharyngoscopy and velopharyngeal MRI study as part of their preoperative clinical evaluation. Among patients with partial or total LVP dehiscence on MRI, presence of a notch accurately identified discontinuity in the LVP 43% (95% CI 22-66%) of the time. In contrast, the absence of a notch accurately indicated LVP continuity 81% (95% CI 54-96%) of the time. The PPV for the presence of notching to identify a discontinuous LVP was 78% (95% CI 49-91%). The distance from the posterior edge of the hard palate to the LVP, known as effective velar length, was similar in patients with and without notching (median 9.8 mm vs 10.5 mm, P = 1.00). The observation of a velar notch on nasopharyngoscopy is not an accurate predictor of LVP muscle dehiscence or anterior positioning.

This essay describes a physician’s experience of completing medical education and postgraduate clinical training in Ireland vs adjusting to residency in the US.