Utilization and outcome disparities in allogeneic hematopoietic stem cell transplant in the United States.

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is increasingly being used in the United States (US) and across the world as a curative therapeutic option for patients with certain high-risk hematologic malignancies and non-malignant diseases. However, racial and ethnic disparities in utilization of the procedure and in outcome following transplant remain major problems. Racial and ethnic minority patients are consistently under-represented in the proportion of patients who undergo allo-HSCT in the US. The transplant outcomes in these patients are also inferior. The interrelated driving forces responsible for the differences in the utilization and transplant outcome of the medical intervention are socioeconomic status, complexity of the procedure, geographical barriers, and the results of differences in the genetics and comorbidities across different races. Bridging the disparity gaps is important not only to provide equity and inclusion in the utilization of this potentially life-saving procedure but also in ensuring that minority groups are well represented for research studies about allo-HSCT. This is required to determine interventions that may be more efficacious in particular racial and ethnic groups. Various strategies at the Federal, State, and Program levels have been designed to bridge the disparity gaps with varying successes. In this review paper, we will examine the disparities and discuss the strategies currently available to address the utilization and outcome gaps between patients of different races in the US.

Aortic dissection and multimodality imaging.

Aortic dissection is a life-threatening emergency warranting expeditious diagnosis. Computed tomographic angiography (CTA) is the established gold standard test but is not always fool proof. We report the case of an 18-year-old male patient with traumatic type A aortic dissection which was not evident on the CTA, suggestive on the transthoracic echocardiogram (TTE) and eventually confirmed with a transesophageal echocardiogram (TEE). When the clinical suspicion for dissection is high and in the presence of complications of type A dissection, such as aortic regurgitation, it would be prudent to obtain further imaging with a TTE/TEE to rule in or rule out the diagnosis.

Multiple Biomarkers to Assess the Pathophysiological State in Critically Ill Patients with Sepsis.

Sepsis is associated with various metabolic derangements as a consequence of inflammatory response, ischemia and oxidative stress. Four parameters of relevance are procalcitonin (PCT), ischemia modified albumin (IMA) pH and lactate. The study was carried out to highlight the concomitant occurrence of sepsis, ischemia and lactic acidosis, all of which could have deleterious effects on organ function. 26 critically ill patients with a provisional diagnosis of sepsis were the test subjects. The control group had 25 apparently healthy volunteers. PCT, lactate and IMA were assayed. PCT was estimated on an automated analyser using electro-chemiluminescence. Lactate and pH were estimated on a blood gas analyzer. Serum IMA was estimated spectrophotometrically by Albumin Cobalt Binding Test. Statistical tools like students 't' test and Venn diagram were employed to depict the outcome of the study. All critically ill patients had significantly higher IMA levels (0.96746 ± 0.73407) as compared to the control group (0.00728 ± 0.00895) with a p value of <0.0001. The Venn diagram was used to depict the finding that all 26 test subjects had elevated levels of IMA, of which PCT was elevated in 22 and lactate in 20. Both PCT and lactate were abnormal in 17 patients. The most significant observation was that all critically ill patients, irrespective of the presence of sepsis or lactic acidosis had elevated levels of IMA which is clearly indicative of the ubiquitous presence of oxidative stress. The Venn diagram is an elegant representation of the concurrent multiple pathophysiological processes which occur in critically ill patients.

Adjuvant Chemotherapy in Premenopausal Patients With Hormone-Positive Breast Cancer With a Recurrence Score of 16-25: A Retrospective Analysis Using the National Cancer Database.

PURPOSE: Results from the TAILORx trial revealed that the use of adjuvant chemotherapy along with endocrine therapy had no survival advantage in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2-negative (HER2-), node-negative (N0) breast cancer (BC) with an intermediate (11-25) 21-gene recurrence score (RS) in the overall population. However, in patients under age 50 years, adjuvant chemotherapy demonstrated a progression-free survival benefit when the RS ranged from 16-25. We studied this cohort with the population-based national database. METHODS: The 2010-2018 National Cancer Database was used to include patients with BC age 18-50 years, N0, M0, RS 16-25, ER+/progesterone receptor±, and HER2-. Patients were divided into two groups on the basis of adjuvant chemotherapy use, and the survival between them was compared. RESULTS: Adjuvant chemotherapy use was noted in 4,808/15,792 (30.45%) patients. Median RS was 18 and 21 in patients without and with adjuvant chemotherapy, respectively. Factors associated with adjuvant chemotherapy use were higher T stage, poor and moderately differentiated tumors, age <40 years, care at an academic center, Caucasian race, patients undergoing mastectomy, regional lymph node surgery, and radiation therapy. Kaplan-Meier survival at 10 years was better with adjuvant chemotherapy (96.2% v 91.6%). Patients without adjuvant chemotherapy had more adverse outcomes (hazard ratio [HR], 1.683 [95% CI, 1.392 to 2.036]; P < .0001). Subgroup analysis showed that the benefit was significant in patients with RS scores 21-25 (HR, 1.953 [95% CI, 1.295 to 2.945]), ductal histology (HR, 1.521 [95% CI, 1.092 to 2.118]), Caucasian race (HR, 1.655 [95% CI, 1.180 to 2.322]), and 41-50 years age group (HR, 1.732 [95% CI, 1.244 to 2.411]). CONCLUSION: Our study showed an overall survival benefit for adjuvant chemotherapy use in patients with ER-positive, N0 premenopausal BC patients, age less than 50 years, with an intermediate RS score, particularly 21-25.

A Quality Improvement Initiative for Echocardiogram Ordering Patterns in an Academic Hospital.

Background Appropriate Use Criteria (AUC) for echocardiography are a useful tool to deliver quality healthcare. Our quality-based interventional study was designed to assess the trends in appropriate utilization rates for echocardiography in our institution and improve adherence to the AUC criteria for transthoracic echocardiograms (TTE). Methodology A prospective, time series analysis was conducted at the Upstate University Hospital for the months of July 2019 and August 2020. A chart analysis was performed on 620 consecutive inpatients who underwent TTE for the month of July 2019. We assessed the trends of the appropriate ordering of TTEs. We then updated our order form incorporating the 42 most common appropriate indications. A post-intervention chart analysis was performed on all inpatient TTEs ordered for the month of August 2020 (n = 410). The appropriateness of the TTE for the entire group was determined based on the true indication per chart review. The primary outcome was the proportion of appropriate and inappropriate TTEs ordered. Secondary outcomes included assessing for concordance between the indication on the order requisition form and by chart review. A p-value <0.05 was considered significant. Results Using the 2011 AUC for the entire group, 81% of the pre-intervention TTEs and 79.5% of the post-intervention TTEs were appropriate (p = 0.55). There was a statistically significant reduction in the number of discordant TTE orders before and after the intervention (p < 0.01). In addition, we noted increased appropriateness of TTEs in the concordant group both pre and post-intervention. Conclusions Our study demonstrates a significant increase in the concordance between the TTE order sheet and actual indication per chart review with the intervention. This can translate into improved scanning and physician reading quality and time, thereby increasing focus on areas of interest according to the true indication. There was no significant increase in the appropriate TTEs ordered.

Descriptive Analysis and Factors Influencing Survival in Patients With Primary Cutaneous Gamma-Delta T Cell Lymphoma. A Retrospective National Cancer Database Study.

BACKGROUND: Gamma delta T cells gives rise to a rare malignancy called Primary cutaneous Gamma-Delta T cell lymphoma (PCGDTCL). METHODS: From the National Cancer Database (NCDB), 110 (0.015%) patients with PCGDTCL were identified. RESULTS: Males aged >60 years were the commonest cohort. Caucasian race was the most common (Caucasian: 79.09%, African American:16.36%). Most patients were diagnosed at stage 1 (52.33%), followed by stage 4 (30.23%). On analyzing income categories, <$48,000 group had 48.15% stage 4 (13/27) and 40.74% (11/27) stage 1. Overall survival (OS) of the study group at 3 years by Kaplan-Meier (KM) analysis was 46.6%. African American race (37.5%), income of <$48,000 (27.6%) and government insurance (38.8%) had lower survival rates in KM analysis. In the adjusted hazard ratio (HR) analysis, only age <=40 years compared to >60 years (0.165 [0.036, 0.768], P= .0217) reached significance. Although the group that did not receive any chemotherapy or radiation seemed to have a better survival by KM analysis at 74.3% at 3 years, significance was not seen in the adjusted HR estimates and majority of the patients in this group were stage 1. This group may have received topical treatments which may have not been captured in NCDB. Adjusted analysis also revealed chemoradiation to have a lower mortality risk compared to chemotherapy alone (0.229 [0.079, 0.670], P = .0071), suggesting that aggressive strategies may be required for management when needed. CONCLUSION: Socioeconomic disparities significantly impact access to healthcare and are of particular importance in rare lymphomas.

Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss.

INTRODUCTION: Homozygous deletion of MTAP upregulates de novo synthesis of purine (DNSP) and increases the proliferation of neoplastic cells. This increases the sensitivity of breast cancer cells to DNSP inhibitors such as methotrexate, L-alanosine and pemetrexed. MATERIALS AND METHODS: 7,301 cases of MBC underwent hybrid-capture based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). RESULTS: 208 (2.84%) of MBC featured MTAP loss. MTAP loss patients were younger (p = 0.002) and were more frequently ER- (30% vs. 50%; p < 0.0001), triple negative (TNBC) (47% vs. 27%; p < 0.0001) and less frequently HER2+ (2% vs. 8%; p = 0.0001) than MTAP intact MBC. Lobular histology and CDH1 mutations were more frequent in MTAP intact (14%) than MTAP loss MBC (p < 0.0001). CDKN2A (100%) and CDKN2B (97%) loss (9p21 co-deletion) were significantly associated with MTAP loss (p < 0.0001). Likely associated with the increased TNBC cases, BRCA1 mutation was also more frequent in MTAP loss MBC (10% vs. 4%; p < 0.0001). As for immune checkpoint inhibitors biomarkers, higher TMB >20 mut/Mb levels in the MTAP intact MBC (p < 0.0001) and higher PD-L1 low expression (1-49% TPS) in the MTAP loss MTAP (p = 0.002) were observed. CONCLUSIONS: MTAP loss in MBC has distinct clinical features with genomic alterations (GA) affecting both targeted and immunotherapies. Further efforts are necessary to identify alternative means of targeting PRMT5 and MTA2 in MTAP-ve cancers to benefit from the high-MTA environment of MTAP-deficient cancers.

Radiation Recall Dermatitis Following Treatment With Pembrolizumab: A Case Report and Review of the Literature.

Radiation recall dermatitis is an inflammatory reaction of the skin that may infrequently occur in areas of the skin that have been previously treated with radiation therapy. This is thought to be due to a triggering agent administered after radiation therapy which leads to an acute inflammatory reaction, manifesting as a skin rash. We present the case of a 58-year-old male with recurrent invasive squamous cell carcinoma of the tongue, previously treated with chemotherapy and radiation therapy, who presented with progression of his disease. He was treated with pembrolizumab and subsequently developed a new-onset facial rash over the previously treated radiation field. The distribution of the rash was suggestive of radiation recall dermatitis. A biopsy showed dermal necrosis without evidence of dermatitis, vasculitis, or infectious process. This case highlights the incidence of a rare complication of immune checkpoint inhibitor therapy and emphasizes the need for careful monitoring for radiation recall dermatitis.

Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma.

Introduction: KRAS mutation is a common occurrence in Pancreatic Ductal Adenocarcinoma (PDA) and is a driver mutation for disease development and progression. KRAS wild-type PDA may constitute a distinct molecular and clinical subtype. We used the Foundation one data to analyze the difference in Genomic Alterations (GAs) that occur in KRAS mutated and wild-type PDA. Methods: Comprehensive genomic profiling (CGP) data, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 by Immunohistochemistry (IHC) were analyzed. Results and discussion: Our cohort had 9444 cases of advanced PDA. 8723 (92.37%) patients had KRAS mutation. 721 (7.63%) patients were KRAS wild-type. Among potentially targetable mutations, GAs more common in KRAS wild-type included ERBB2 (mutated vs wild-type: 1.7% vs 6.8%, p <0.0001), BRAF (mutated vs wild-type: 0.5% vs 17.9%, p <0.0001), PIK3CA (mutated vs wild-type: 2.3% vs 6.5%, p <0.001), FGFR2 (mutated vs wild-type: 0.1% vs 4.4%, p <0.0001), ATM (mutated vs wild-type: 3.6% vs 6.8%, p <0.0001). On analyzing untargetable GAs, the KRAS mutated group had a significantly higher percentage of TP53 (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001), CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001), CDKN2B (mutated vs wild-type: 28.9% vs 23%, p =0.007), SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001) and MTAP (mutated vs wild-type: 21.7% vs 18%, p =0.02). ARID1A (mutated vs wild-type: 7.7% vs 13.6%, p <0.0001 and RB1(mutated vs wild-type: 2% vs 4%, p =0.01) were more prevalent in the wild-type subgroup. Mean TMB was higher in the KRAS wild-type subgroup (mutated vs wild-type: 2.3 vs 3.6, p <0.0001). High TMB, defined as TMB > 10 mut/mB (mutated vs wild-type: 1% vs 6.3%, p <0.0001) and very-high TMB, defined as TMB >20 mut/mB (mutated vs wild-type: 0.5% vs 2.4%, p <0.0001) favored the wild-type. PD-L1 high expression was similar between the 2 groups (mutated vs wild-type: 5.7% vs 6%,). GA associated with immune checkpoint inhibitors (ICPIs) response including PBRM1 (mutated vs wild-type: 0.7% vs 3.2%, p <0.0001) and MDM2 (mutated vs wild-type: 1.3% vs 4.4%, p <0.0001) were more likely to be seen in KRAS wild-type PDA.

Genomic landscape of non-small-cell lung cancer with methylthioadenosine phosphorylase (MTAP) deficiency.

INTRODUCTION: New treatment strategies for advanced non-small-cell lung carcinoma (NSCLC) include synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of genomic loss of methylthioadenosine phosphorylase (MTAP). METHODS: Twenty nine thousand three hundred seventy nine advanced NSCLC cases underwent hybrid-capture based comprehensive genomic profiling between June 1, 2018 and May 31, 2020. PD-L1 expression was determined by immunohistochemistry (Dako 22C3 PharmDx assay). RESULTS: 13.4% (3928/29,379) NSCLC cases exhibited MTAP loss distributed in adenocarcinoma (59%), squamous cell carcinoma (22%), NSCLC not otherwise specified (16%), and 1% each for large-cell neuroendocrine, sarcomatoid, and adenosquamous carcinoma. Statistically significant differences in mitogenic driver alterations included more KRAS G12C mutations in MTAP-intact versus MTAP-lost (12% vs. 10%, p = 0.0003) and fewer EGFR short variant mutations in MTAP-intact versus MTAP-lost NSCLC (10% vs. 13%, p < 0.0001). Statistically significant differences in currently untargetable genomic alterations included higher frequencies of TP53 (70% vs. 63%, p < 0.0001) and RB1 inactivation (10% vs. 2%, p < 0.0001) in MTAP-intact compared to MTAP-lost NSCLC. SMARCA4 inactivation (7% vs. 10%, p < 0.0001) was less frequent in MTAP-intact versus MTAP-lost NSCLC. Alterations in ERBB2, MET, ALK, ROS1, and NTRK1 did not significantly differ between the two groups. Predictors of immunotherapy efficacy were higher in MTAP-intact versus MTAP-lost NSCLC including tumor mutational burden (9.4 vs. 8.6 mut/Mb, p = 0.001) and low (30% vs. 28%, p = 0.01) and high PD-L1 (32% vs. 30%, p = 0.01) expression. Alterations in biomarkers potentially predictive of immune checkpoint inhibitor resistance (STK11, KEAP1, and MDM2) were similar in the two groups. CONCLUSIONS: MTAP loss occurs in 13% of NSCLC, supporting the development of targeted therapies to exploit PRMT5 hyper-dependence. MTAP loss is accompanied by small differences in targeted and immunotherapy options which may impact future combination strategies.

Association of Molecular Profiles and Mutational Status With Distinct Histological Lung Adenocarcinoma Subtypes. An Analysis of the LACE-Bio Data.

BACKGROUND: Adjuvant chemotherapy (AC) is indicated for stage II and stage III lung adenocarcinomas (ADC). Using the LACE Bio II database, we analyzed the distribution of various mutations across the subtypes of ADCs and studied the prognostic and predictive roles of PD-L1, TMB, and Tumor Infiltrating Lymphocytes (TILs). MATERIALS AND METHODS: Clinical and genomic data from the LACE Bio II data were extracted. Patients were divided into ADC subtypes, in which the grouping was done based on their known clinical behavior (Lepidic [LEP], Acinar/Papillary [ACI or PAP], Micropapillary/Solid [MIP or SOL], Mucinous [MUC] and Others). Kaplan-Meier (KM) and log-rank test were used to compare survival based on PD-L1, TMB, TILs and combinations of TMB with PD-L1 and TILs. Adjusted Hazard Ratios (HR) were analyzed with Overall Survival (OS), Disease-Free Survival (DFS) and Lung Cancer-Specific Survival (LCSS) as endpoints. RESULTS: A total of 375 ADC patients were identified. MIP/SOL was the subtype most commonly positive for various biomarkers. PD-L1 Negative/high TMB was associated with better outcomes in terms of OS (HR = 0.46 [0.23-0.89], P = .021) and DFS (HR = 0.52 [0.30-0.90], P = .02), relative to PD-L1 Negative/low TMB. High TMB predicted worse outcome with AC use in terms of OS (ratio of hazard ratio rHR = 2.75 [1.07-7.04], P = .035). Marked TILs had better outcome with AC for DFS (rHR = 0.22 [0.06-0.87], P = .031 and LCSS (rHR = 0.08 [0.01-0.66], P = .019) respectively. There was also a beneficial effect of AC among patients with Marked TILs/low TMB in terms of DFS (rHR = 0.06 [0.01-0.53], P = .011). CONCLUSION: High TMB has a prognostic role in resectable lung ADC. The high TMB group had a poor outcome with AC, suggesting that this group may be better served with immune checkpoint therapy.

Metabolic syndrome is independently associated with improved overall survival to first-line therapy with immune checkpoint inhibitors in non-small cell lung cancer.

Background: Many co-existing medical conditions may affect the outcome in patients treated with immune checkpoint inhibitors for advanced cancer. There is currently not any information on whether metabolic syndrome (MetS) impacts the clinical outcome in patients treated with immune checkpoint inhibitors (ICIs) for advanced non-small cell line cancer (NSCLC). Methods: We carried out a single-center retrospective cohort study to determine the effects of MetS on first-line ICI therapy in patients with NSCLC. Results: One hundred and eighteen consecutive adult patients who received first-line therapy with ICIs and had adequate medical record information for the determination of MetS status and clinical outcomes were included in the study. Twenty-one patients had MetS and 97 did not. There was no significant difference between the two groups in age, gender, smoking history, ECOG performance status, tumor histologic types, pre-therapy use of broad-spectrum antimicrobials, PD-L1 expression, pre-treatment neutrophil:lymphocyte ratio, or proportions of patients who received ICI monotherapy or chemoimmunotherapy. With a median follow-up of 9 months (range 0.5-67), MetS patients enjoyed significantly longer overall survival (HR 0.54, 95% CI: 0.31-0.92) (p = 0.02) but not progression-free survival. The improved outcome was only observed in patients who received ICI monotherapy and not chemoimmunotherapy. MetS predicted for higher probability of survival at 6 months (p = 0.043) and 12 months (p = 0.008). Multivariate analysis indicated that, in addition to the known adverse effects of use of broad-spectrum antimicrobials and the beneficial effects of PD-L1 (Programmed cell death-ligand 1) expression, MetS was independently associated with improved overall survival but not progression-free survival. Conclusions: Our results suggest that MetS is an independent predictor of treatment outcome in patients who received first-line ICI monotherapy for NSCLC.

Current Trends in the Management of Epithelial Lacrimal Gland Tumors: A Retrospective National Cancer Database Analysis.

BACKGROUND: Lacrimal gland tumors are rare with data limited to very few large studies. Contemporary strategies like orbit sparing surgeries and neoadjuvant intraarterial chemotherapy remain controversial. METHODS: This is a retrospective cohort analysis of epithelial lacrimal gland tumors from the 2004-2016 National Cancer Database. Patients were stratified based on the type of surgery (limited vs destructive) and various treatment modalities employed. RESULTS: Squamous cell carcinoma (33.48%) and adenoid cystic carcinoma (29.45%) were the commonest histologies (N=669). Comparison of limited (46.33%) vs destructive procedures (53.11%) among 482 patients did not show any survival difference, nor the comparison between surgery vs ± chemotherapy vs ± radiotherapy among 472 patients. CONCLUSION: Squamous cell carcinoma and adenoid cystic carcinoma are the commonest types of lacrimal gland tumors seen in our study. Tumor spread from adjacent sites may have contributed to the higher percentage of squamous cell carcinomas seen. The type of surgery or chemoradiation use did not alter survival.

A Rare Cause of Chronic Hip Pain From PEComa: An Aggressive Mesenchymal Sarcoma.

Perivascular epithelioid cell tumors (PEComas) are related to the tuberous sclerosis complex (TSC) and are commonly benign. When malignant, they can be aggressive with local invasion and metastatic spread. Conventional PEComas do not have TFE3 gene rearrangement and are associated with TSC with a preference for an occurrence at a younger age. We report a case of a young male who had progressive chronic hip pain and was found to have a TFE3-associated PEComa in his pelvic region.

Liposomal Daunorubicin and Cytarabine, a Potential Therapy for Blastic Plasmacytoid Dendritic Cell Neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive malignancy with poor outcomes. Although novel options like tagraxofusp, a CD123-directed cytotoxin, has emerged and is promising, treatment options are very limited in the relapsed and recurrent setting. We present a case of refractory BPDCN in a 62-year-old man who showed a complete bone marrow response to liposomal daunorubicin and cytarabine (vyxeos).

Associated factors and outcomes of delaying adjuvant chemotherapy in breast cancer by biologic subtypes: a National Cancer Database study.

PURPOSE: Several studies have evaluated the role of delayed initiation of adjuvant chemotherapy (AC) in breast cancer (BC), but the results have remained controversial and an optimal time has not been defined. Our aim was to determine the effect of time to starting AC from the date of surgery on survival of BC patients, based on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, using data from the National Cancer Database (NCDB). METHODS: A total of 332,927 Stage I-III BC patients who received AC from 2010 to 2016 were analyzed. We included all ER, PR and HER2 statuses and excluded patients with stage 4 and stage 0 (DCIS) disease. The cohort was divided into five groups based on the time of initiating AC from the date of the most definitive surgery i.e., ≤ 30 days, 31-60 days, 61-90 days, 91-120 days and > 120 days. They were further divided into five subgroups based on the receptor status. RESULTS: Hazard ratio (HR) estimates and Kaplan-Meier (KM) analysis shows that starting AC by 31-60 days shows the best survival outcome in all the subtypes, except in hormone positive/HER2 negative BC in which 31-60 days and 61-90 days have similar outcomes. CONCLUSIONS: After surgery for BC, it takes around 4-6 weeks to begin AC and delay in initiating the same leads to poor outcomes. Our results are particularly significant in triple-negative breast cancer (TNBC), similar to prior studies showing a benefit to starting AC as early as possible after surgery.

Primary Neuroendocrine Tumor of the Scrotum: An Uncommon Site for a Rare Tumor.

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors developing from neural crest cells, with numerous sites of origin, commonly the gastrointestinal and genitourinary tracts. NETs of the genitourinary tract are more common in women. Small cell carcinoma of the prostate or testicular carcinoid are the NETs in male. In this article, we present a rare case of NET of the scrotum. Our patient was a 47-year-old male with a history of complicated pilonidal cysts resulting in chronic scrotal wounds. Biopsy of a large nonhealing scrotal wound revealed a high-grade neuroendocrine carcinoma with features most suggestive of small cell carcinoma. Presenting with advanced disease at diagnosis, he was started on systemic therapy and unfortunately progressed through multiple lines of treatment, including CAPTEM (capecitabine and temozolomide). Unfortunately, due to multiple logistical reasons, the patient was unable to receive the then off-label immunotherapy based on DART (Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors) trial. He, unfortunately, succumbed to his disease within months of diagnosis.

Predictive Biomarkers for Immune Checkpoint Inhibitors in Metastatic Breast Cancer.

We examined a large dataset of female metastatic breast cancers (MBCs) profiled with comprehensive genomic profiling (CGP) to identify the prevalence and distribution of immunotherapy responsiveness-associated biomarkers. DNA was extracted from 3831 consecutive MBCs: 1237 (ERpos /HER2neg ), 1953 ERneg /HER2amp , and 641 triple-negative breast cancer (TNBC). CGP was performed using the FoundationOne® or FoundationOne® CDx NGS assay. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined in a subset of cases. PD-L1 expression in immunocytes in a subset of cases was determined by immunohistochemistry using the companion diagnostic VENTANA PD-L1 SP142 Assay. The median age of the cohort was 54 years (range 20-89). Genomic alterations (GAs)/tumor were similar (range: 5.9-7.3). Markers of potential immune checkpoint inhibitor (ICPI) benefit included: CD274 (PD-L1) amplification (1%-3%), BRAF GA (1%-4%), TMB of ≥10 mutations/Mb (8%-12%), MSI-high (0.1%-0.4%), PBRM1 GA (1%), and positive PD-L1 staining of immunocytes ranging from 13% in ERpos /HER2neg and 33% in ERneg /HER2amp to 47% in the TNBC group. Potential markers of ICPI resistance included inactivating STK11 GA (1%-2%) and MDM2 amplification (3%-6%). MTOR pathway targets were common with lowest frequency in TNBC. ERBB2 short variant mutations were most frequent ERpos /HER2neg and absent in TNBC. BRCA1/2 GA were least frequent in ERneg /HER2amp . The demonstrations of clinical benefit of immunotherapy in MBC support the need for development and utilization of biomarkers to guide the use of ICPIs for these patients. In addition to guiding therapy selection, CGP shows potential to identify GA linked to response and resistance to ICPI in MBC.