Citations

PURPOSE: Clinical trials are important for managing older patients with AML. We investigated differences in outcomes of older patients with AML on the basis of whether patients participated in intensive chemotherapy trials at community versus academic cancer centers. METHODS: We used data from the Alliance for Clinical Trials in Oncology phase III trials that enrolled patients age ≥ 60 years with newly diagnosed AML between 1998 and 2002 in the Cancer and Leukemia Group B (CALGB) 9720 trial and between 2004 and 2006 in the CALGB 10201 trial. Centers funded by the NCI Community Oncology Research Program were identified as community cancer centers; others were designated as academic cancer centers. Logistic regression models and Cox proportional hazards models were used to compare 1-month mortality and overall survival (OS) by center type. RESULTS: Seventeen percent of the 1,170 patients were enrolled in clinical trials in community cancer centers. The study results demonstrated comparable rates of grade ≥3 adverse events (97% v 93%), 1-month mortality (19.1% v 16.1%), and OS (43.9% v 35.7% at 1 year) between community versus academic cancer centers, respectively. After adjusting for covariates, 1-month mortality (odds ratio, 1.40; 95% CI, 0.92 to 2.12; P = .11) and OS (hazard ratio, 1.04; 95% CI, 0.88 to 1.22; P = .67) were not statistically different among patients treated in community versus academic cancer centers. CONCLUSION: An older patient population, who have complex health care needs, can be successfully treated on intensive chemotherapy trials in select community cancer centers with outcomes comparable with that achieved at academic cancer centers.

Abstract Alloreactive memory T cells, unlike naive T cells, fail to be restrained by transplantation tolerance protocols or regulatory T cells, and therefore represent a critical barrier to long-term graft acceptance. Using female mice sensitized by rejection of fully-mismatched paternal skin allografts, we show that subsequent semi-allogeneic pregnancy successfully reprograms memory fetus/graft-specific CD8+ T cells (TFGS) towards hypofunction in a manner that is mechanistically distinct from naive TFGS. Post-partum memory TFGS were durably hypofunctional, exhibiting enhanced susceptibility to transplantation tolerance induction. Furthermore, multi-omics studies revealed that pregnancy induced extensive phenotypic and transcriptional modifications in memory TFGS reminiscent of T cell exhaustion. Strikingly, at loci transcriptionally modified in both naive and memory TFGS during pregnancy, chromatin remodeling was observed exclusively in memory and not naive TFGS. These data reveal a novel link between T cell memory and hypofunction via exhaustion circuits and pregnancy-mediated epigenetic imprinting. This conceptual advance has immediate clinical relevance to pregnancy and transplantation tolerance.

Abstract Background: Recent studies support that high levels of tumor-infiltrating lymphocytes (TILs) were associated with better prognosis in HPV(+) oropharyngeal squamous cell carcinoma (OPSCC). While these studies provide a potential role for TILs as a prognostic biomarker, the analyses were relied on manual quantification performed by pathologists, resulting in inter-observer variability. Deep Learning (DL)-based whole slide hematoxylin and eosin (H&E) image analyses may overcome these challenges. However, this analysis only provides the presence of cell types without consideration for the functional roles of each cell within the tumor immune microenvironment (TME). In this work, we develop a computational pipeline to integrate paired H&E and immunohistochemistry (IHC) images to functionally characterize TILs and investigate their prognostic utility. Methods: We analyzed 88 patients: 42 stage I, 39 stage II, and 7 stage III. Our data contain both H&E and IHCs examining FoxP3, CD3, PD-L1, CD20, etc. on serial sections of the tissue. In-house DL-based H&E analysis used to identify TILs, tumors, and stroma in each tumor, then performed registration between adjacent H&E and IHC images from the same tissue. The patients were then classified into three basic immune phenotypes: immune inflamed (IN; high TILs in the tumor region), immune excluded (EX; TILs are mostly localized in stroma), and immune desert (ID; few/no TILs) based on TIL enrichment in the TME. To functionally characterize TILs, we quantified protein expression from the adjacent IHCs. For example, we further classified each patient into different subtypes based on enriched protein expression (e.g., FoxP3 high IN, FoxP3 low IN). We used the Kaplan-Meier method and multivariate Cox analysis to evaluate the prognostic value of different subtypes enriched with different proteins to predict disease-free survival (DFS). Results: The IN group with 43 patients was significantly associated with good prognosis. Interestingly, further stratification of the IN subgroup based on Foxp3 quantification on TIL regions (i.e., high FoxP3 IN and low FoxP3 IN) showed that high protein expression of FoxP3 in TILs in the IN subgroup is significantly associated with a better prognosis compared to other immune subgroups (HR, 0.16; p-value, 0.003). Multivariate analysis, including other clinical covariates showed that the immune subtypes associated with high FoxP3 are independently associated with DFS. These results demonstrate that DL-based integrative IHC and H&E image analysis could be used to identify subgroups with distinct clinical outcomes. Furthermore, our results reveal unknown roles for Foxp3 expression in the TILs in HPV(+) OPSCC as a prognostic biomarker, a finding which should be evaluated in a larger cohort. Citation Format: Sumanth Reddy Nakkireddy, Inyeop Jang, Minji Kim, Linda X. Yin, Michael Rivera, Joaquin J. Garcia MD, Kathleen R. Bartemes, David M. Routman, Eric J. Moore, Daniel J. Ma, Kathryn M. Van Abel, Tae Hyun Hwang. Integrative spatial analysis of paired IHC and H&E images identifies Foxp3 enriched tumor-infiltrating lymphocytes associated with disease-free survival in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma. [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 4638.

Abstract Context Chronic hypoparathyroidism is conventionally treated with oral calcium and active vitamin D to reach and maintain targeted serum calcium and phosphorus levels, but some patients remain inadequately controlled. Objective To assess long-term safety and efficacy of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) treatment. Methods This was an open-label extension study at 12 US centers. Adults (n = 49) with chronic hypoparathyroidism were included. The intervention was rhPTH(1-84) for 6 years. The main outcome measures were safety, biochemical measures, oral supplement doses, bone indices. Results Thirty-eight patients (77.6%) completed the study. Throughout 72 months, mean albumin-adjusted serum calcium was within 2.00 to 2.25 mmol/L (8.0-9.0 mg/dL). At baseline, 65% of patients with measurements (n = 24/37) were hypercalciuric; of these, 54% (n = 13/24) were normocalciuric at month 72. Mean serum phosphorus declined from 1.6 ± 0.19 mmol/L at baseline (n = 49) to 1.3 ± 0.20 mmol/L at month 72 (n = 36). Mean estimated glomerular filtration rate was stable. rhPTH(1-84)-related adverse events were reported in 51.0% of patients (n = 25/49); all but 1 event were mild/moderate in severity. Mean oral calcium supplementation reduced by 45% ± 113.6% and calcitriol by 74% ± 39.3%. Bone turnover markers declined by month 32 to a plateau above pretreatment values; only aminoterminal propeptide of type 1 collagen remained outside the reference range. Mean bone mineral density z score fell at one-third radius and was stable at other sites. Conclusion 6 years of rhPTH(1-84) treatment was associated with sustained improvements in biochemical parameters, a reduction in the percentage of patients with hypercalciuria, stable renal function, and decreased supplement requirements. rhPTH(1-84) was well tolerated; no new safety signals were identified.

Infectious diseases contribute significantly to the global disease burden. Sensitive and accurate screening methods are some of the most effective means of identifying sources of infection and controlling infectivity. Conventional detecting strategies such as quantitative polymerase chain reaction (qPCR), DNA sequencing, and mass spectrometry typically require bulky equipment and well-trained personnel. Therefore, mass screening of a large population using conventional strategies during pandemic periods often requires additional manpower, resources, and time, which cannot be guaranteed in resource-limited settings. Recently, emerging microfluidic technologies have shown the potential to replace conventional methods in performing point-of-care detection because they are automated, miniaturized, and integrated. By exploiting the spatial separation of detection sites, microfluidic platforms can enable the multiplex detection of infectious diseases to reduce the possibility of misdiagnosis and incomplete diagnosis of infectious diseases with similar symptoms. This review presents the recent advances in microfluidic platforms used for multiplex detection of infectious diseases, including microfluidic immunosensors and microfluidic nucleic acid sensors. As representative microfluidic platforms, lateral flow immunoassay (LFIA) platforms, polymer-based chips, paper-based devices, and droplet-based devices will be discussed in detail. In addition, the current challenges, commercialization, and prospects are proposed to promote the application of microfluidic platforms in infectious disease detection.

Abstract Background Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas. Methods Targeted gene expression profiling was performed on 173 meningiomas and an optimized gene expression biomarker (34 genes) and risk score (0 to 1) was developed to predict clinical outcomes. Clinical and analytical validation was performed on independent meningiomas from 12 institutions across 3 continents (N = 1856), including 103 meningiomas from a prospective clinical trial. Gene expression biomarker performance was compared to 9 other classification systems. Results The gene expression biomarker improved discrimination of postoperative meningioma outcomes compared to all other classification systems tested in the independent clinical validation cohort for local recurrence (5-year area under the curve [AUC] 0.81) and overall survival (5-year AUC 0.80). The increase in area under the curve compared to the current standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval [CI] 0.07–0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% CI 0.37–0.78, P = 0.0001) and re-classified up to 52.0% meningiomas compared to conventional clinical criteria, suggesting postoperative management could be refined for 29.8% of patients. Conclusions A targeted gene expression biomarker improves discrimination of meningioma outcomes compared to recent classification systems and predicts postoperative radiotherapy responses.

Abstract Background: Previous studies demonstrated that activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). Further in vivo study showed that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors (ICIs). Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were treated with pembrolizumab 200 mg every 3 weeks plus an oral MEK inhibitor binimetinib. Treatment was started with a 2-week run-in period with single-agent binimetinib. There were 2 dose levels in phase I, including dose level 0 (DL 0) with binimetinib at 45 mg orally twice daily continuously and dose level -1 (DL -1) at 30 mg twice daily. A standard 3+3 design was used in phase I to identify the recommended phase II dose (RP2D) and Simon’s two-stage Optimal design was used in phase II. Results: A total of 22 patients were enrolled. The median age was 58 years old (range 37-77). 14 (63.6%) patients had no prior systemic therapy in the metastatic setting and 8 (36.4%) patients had 1-2 prior lines of therapy. There were 4 patients treated in DL 0. Dose-limiting toxicity (DLT) was observed in 2 out of 4 patients in DL 0 with grade 3 ALT abnormality in one patient and grade 3 flank pain together with grade 3 nausea and vomiting &gt; 48 hours despite anti-emetic therapy in the other patient. Binimetinib dose was reduced to DL -1. In the next 6 patients, there was 1 DLT observed with grade 3 AST/ALT abnormality. Thus, DL -1 was the RP2D, and an additional 12 patients were treated with DL -1 in phase II. Overall, 18 patients were treated in DL -1 and were included in phase II efficacy evaluation. 17 patients were evaluable for response. Objective responses were observed in 5 patients (29.41% 55.96) with 1 complete response (CR) and 4 partial responses (PR). The clinical benefit rate (CBR) was 35.29% (95% CI: 14.21 - 61.67) with 6 out of 17 having had CR, PR, or stable disease &gt;= 24 weeks. Since previous studies showed poor responses to ICIs in patients with liver metastases due to macrophage-mediated T cell elimination, we further conduct exploratory analysis to evaluate responses among patients with and without liver metastases. Among all 5 patients with liver metastases, no response was observed. The objective response rate (ORR) in patients without liver metastases was 55.56% (95% CI: 21.20 - 86.30) and CBR was 66.67% (95% CI: 29.93-92.51), when excluding 3 patients who discontinued treatment due to adverse events prior to follow-up scans. Median progression-free survival in DL 0 was 2.4 (95%CI: 0.5-NE) and in DL -1 was 8.3 (95% CI: 3.9-NE) months. Median overall survival in DL 0 was 7 (95%CI: 0.5-NE) and in DL -1 was 33.2 (95% CI: 10.3-NE) months. Among patients who responded, 3 out of 5 (60%) had a duration of response greater than 12 months and ongoing even after stopping treatment (range: 5.4 - 32.0 months). Adverse events (AEs) were mostly grade 1-2 including anemia, CPK increase, fatigue, diarrhea, nausea, peripheral neuropathy, acneiform rash, AST increase, cardiac troponin increase, and constipation. Additional correlative studies are ongoing and will be presented at the meeting. Conclusions: Pembrolizumab in combination with binimetinib at 30 mg twice daily appears to be safe with manageable toxicities. Promising activity with durable responses was observed with this combination without chemotherapy, particularly in patients without liver metastases. Future studies are warranted to further evaluate the efficacy of this combination. Citation Format: Saranya Chumsri, Joseph J. Larson, Kathleen S. Tenner, Jun He, Mei-Yin Polley, Morgan T. weidner, Amanda N. Arnold, Dana Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, Edith A. Perez, Keith L. Knutson. Phase I/II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-17.

It is well established that Cholangiocarcioma (CCA) drug resistance plays a crucial role in the spread and survival of cancer cells. The major enzyme in the nicotinamide-adenine dinucleotide (NAD+)-mediated pathways, nicotinamide phosphoribosyltransferase (NAMPT), is essential for cancer cell survival and metastasis. Previous research has shown that the targeted NAMPT inhibitor FK866 reduces cancer cell viability and triggers cancer cell death; however, whether FK866 affects CCA cell survival has not been addressed before. We show herein that NAMPT is expressed in CCA cells, and FK866 suppresses the capacity of CCA cells to grow in a dose-dependent manner. Furthermore, by preventing NAMPT activity, FK866 significantly reduced the amount of NAD+ and adenosine 5′-triphosphate (ATP) in HuCCT1, KMCH, and EGI cells. The present study’s findings further show that FK866 causes changes in mitochondrial metabolism in CCA cells. Additionally, FK866 enhances the anticancer effects of cisplatin in vitro. Taken together, the results of the current study suggest that the NAMPT/NAD+ pathway may be a possible therapeutic target for CCA, and FK866 may be a useful medication targeting CCA in combination with cisplatin.

AbstractObjectiveOtolaryngology residency is highly competitive, and applicant academic metrics are scrutinized. The predictive value of preresidency academic metrics on applicants’ future research productivity and career aspirations remains largely undefined.Study DesignRetrospective cohort studySettingAcademic otolaryngology department, 2014 to 2015.MethodsApplicant demographics, publication history, and United States Medical Licensing Examination (USMLE) scores were downloaded from Electronic Residency Application Service archives. Publications during residency were tallied from all PubMed articles indexed between July 1, 2015 and June 30, 2020. Postresidency career paths were examined by 2 investigators (D.J.C. and L.X.Y.) using Google searches with an emphasis on program websites, Doximity, and LinkedIn profiles. Associations with publication potential and postresidency positions were evaluated with Spearman rank correlation coefficients and Kruskal‐Wallis, Wilcoxon rank sum, and χ2 tests.ResultsOf 321 applicants, 226 (70%) matched, and 205 (64%) completed residency by June 2020. Matched residents published a median of 4 (range: 0‐41) manuscripts during residency. USMLE scores, Alpha Omega Alpha status, and the number of preresidency publications did not significantly correlate with publication potential during residency. The number of research experiences had a significant positive correlation with publications during residency (p < 0.001). Asian race (p = 0.002) and geographical region of residency (p < 0.001) also had significant associations with publication potential. Of the 205 graduates, 118 (58%) enrolled in fellowship. Age and female sex (74% vs 48%; p = 0.002) were the only factors significantly associated with pursuing a fellowship.ConclusionIn otolaryngology, not all preresidency academic metrics are associated with publication potential during residency or propensity for fellowship training. Programs should not use academic metrics alone to predict an applicant's future research productivity or career trajectory.

Mixed acinar neuroendocrine carcinoma of the pancreas (MANEC-P) is an extremely rare malignancy with a poor prognosis. However, epidemiological estimates of MANEC-P remain unknown. This study aimed to estimate and compare the incidence, prevalence, and cancer-specific survival (CSS) of MANEC-P in the United States (US). Patients with MANEC-P were identified through the Surveillance, Epidemiology, and End Results (SEER) and National Program of Cancer Registries databases between 2000–2017. The primary outcomes included age-adjusted incidence rate, limited-duration prevalence, and CSS. A total of 630 patients were identified for the incidence analysis and 149 for the prevalence and CSS analyses. The MANEC-P incidence rate was 0.011 per 100,000 individuals, which was the lowest among pancreatic cancer histologic subtypes. The incidence rate was significantly higher in men and Black races and peaked at 75–79 years of age. The incidence rate was the lowest in the midwestern region (0.009) and the highest in the northeastern US (0.013). The 17-year prevalence was 0.00005%, indicating that 189 patients were alive in the United States at the beginning of 2018. The median CSS of MANEC-P was estimated to be 41 (23, 69) months. In conclusion, MANEC-P is very rare, and its incidence rate has been steady in the US over the last two decades. MANEC-P has a poor prognosis and is the 5th leading cause of pancreatic cancer-related death in the US.