Search

Uncontrolled chemotherapy-induced nausea and vomiting (CINV) can reduce patients’ quality of life and may result in premature discontinuation of chemotherapy. Although nausea and vomiting are commonly grouped together, research has shown that antiemetics are clinically effective against chemotherapy-induced vomiting (CIV) but less so against chemotherapy-induced nausea (CIN). Nausea remains a problem for up to 68% of patients who are prescribed guideline-consistent antiemetics. Despite the high prevalence of CIN, relatively little is known regarding its etiology independent of CIV. In this review paper, we summarize a metagenomics approach to the study and treatment of CIN with the goal of encouraging future research. Metagenomics focuses on genetic risk factors, encompassing both human (i.e., host) and gut microbial genetic variation. Little work to date has focused on metagenomics as a putative biological mechanism of CIN. Metagenomics has the potential to be a powerful tool in advancing scientific understanding of CIN by identifying new biological pathways and intervention targets. Investigation of metagenomics in the context of well-established demographic, clinical, and patient-reported risk factors may help to identify patients at risk and facilitate prevention and management of CIN.

Purpose Estrogen receptor–positive (ER+) breast cancer (BC) is a heterogeneous disease with an ongoing debate regarding the optimal cutoff point for clinically relevant ER expression. We used a real-world database to assess prognostic and predictive values of lower ER expression levels on treatment outcomes with endocrine therapy. Methods We used a nationwide electronic health record– (EHR-) derived deidentified database. Descriptive statistics were used to evaluate the correlation between ER expression, tumor characteristics, and treatment patterns among patients with early-stage BC. We used Kaplan-Meier survival curves to estimate relapse-free survival (RFS) and overall survival (OS). To assess an optimal ER expression level cut point, correlations between ER+ expression and clinical outcomes were performed. Results Among 4697 patients with early-stage BC, 83 (1.76%) had ER+-low BC (ER expression, 1%-9.99%), and 36 (0.8%) had ER+-intermediate BC (10%-19.9%). ER+-low tumors were associated with higher tumor grade, larger size and higher axillary tumor burden than ER+-high tumors (≥ 20% ER expression). African Americans had a higher prevalence of both triple-negative BC (TNBC; 21%) and ER+-low BC (22%) than ER+-high tumors (8%). Patients with ER+-low and ER+-intermediate tumors had survival outcomes similar to patients with TNBC and worse survival outcomes than patients with ER+-high tumors (P +-low or ER+-intermediate BCs. Further tumors with

Background Delayed hemolytic transfusion reaction (DHTR) with hyperhemolysis is a potentially fatal complication resulting from alloimmunization that can cause severe hemolysis of both transfused and intrinsic red blood cells (RBCs). Patients with sickle cell disease often receive multiple RBC units during their lifetime and thus are likely to develop alloantibodies that increase the risk for DHTR. Treatment to decrease hemolysis includes intravenous immunoglobulin (IVIG), steroids, eculizumab, rituximab, and plasmapheresis in addition to erythropoietin (EPO), intravenous (IV) iron, vitamin B12, and folate to support erythropoiesis. RBC transfusion is preferably avoided in DHTR due to an increased risk of exacerbating the hemolysis. Case report We report a rare case of anti-N and anti-Doa immunoglobulin (Ig)G alloantibody-mediated life-threatening DHTR with hyperhemolysis in a patient with hemoglobin SS after RBC transfusion for acute chest syndrome who was successfully treated with eculizumab and HBOC-201 (Hemopure) in addition to steroids, IVIG, EPO, IV iron, and vitamin B12. HBOC-201 (Hemopure) was successfully used as a RBC alternative in this patient. Conclusion Anti-N and anti-Doa IgG alloantibodies can rarely cause severe life-threatening DHTR with hyperhemolysis. HBOC-201 (Hemopure) can be a lifesaving alternative in this scenario. Our report also supports the use of eculizumab in DHTR; however, prospective studies are needed to determine the appropriate dose and sequence of eculizumab administration.

Due to HAART and consequent decline in mortality from infectious complications, HIV patients have an increasing burden of non-AIDS defining cancers. Data on their safety and efficacy is unknown as these patients were excluded from clinical trials due to concern of unforeseen side effects. Objectives. The main objective of our study was to evaluate the efficacy and safety profile of PD-1 and PD-L1 inhibitors in HIV patients being treated for advanced cancers and to assess the impact of these drugs on HIV status of the patients specifically CD4 count and HIV viral load. Materials and Methods. This was a retrospective analysis of data of 17 patients HIV treated with one of the PD-1/PD-L1 inhibitors (Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, or Avelumab) for advanced cancer. Results. 10 out of 17 patients responded to therapy. 7 patients, all of whom had shown response to therapy, were alive and 4 were still on checkpoint inhibitor. 10 patients including all 7 nonresponders had died. Responders had minimum of 15 weeks of response while one had ongoing continued response at 34 weeks. Side effects were seen in 7 patients and only one patient needed cessation of therapy. CD4 counts were stable on treatment while HIV RNA remained undetectable. Conclusion. PD-1 and PD-L1 inhibitors appear to have comparable efficacy and tolerable side effect profile and have no effect on HIV markers when used in HIV patients with advanced cancers.

There is well-established evidence of a therapeutic role for immune checkpoint inhibitors (ICIs) in mismatch repair deficient (MMR-D) metastatic colorectal cancer (mCRC). However, factors associated with receipt and response to ICIs in the real-world setting are not well-characterized. Using electronic health record-derived, de-identified data from the nationwide Flatiron Health database, we selected 568 patients diagnosed with mCRC between January 2013 and December 2019 who received at least one line of ICI therapy in their treatment course (median age: 62.9 years, 50.2% male, 69.4% White, 44% stage IV at diagnosis, 41.2% MMR-D). Overall survival (OS) was defined as the time period from start of ICI therapy until death or last patient activity. Differences in sociodemographic (e.g. age, sex), clinical (e.g. stage at diagnosis, anatomic site) and molecular (e.g. MMR status) characteristics between patients who did and did not receive ICI therapy were compared using chi-square or t-tests. Univariate and multivariate Cox regression models were used to identify predictive factors associated with OS among patients treated with ICIs. Median OS from start of ICI therapy was 8.95 months, while the 1-year probability of survival was 42.6%. Compared to patients who did not receive ICI therapy (n=18,366), patients who received ICIs were initially diagnosed at earlier stage (I-III), were more likely to have MMR-D tumors (p2) or ICIs alone (p=0.0074 and 0.0057, respectively). In the multivariable model, high albumin level (HR=0.27, 95%CI=0.16-0.45, p=5x10-7) and antibiotic intake (HR=0.46, 95%CI=0.29-0.74, p=0.001) remained statistically significantly associated with higher OS among patients with MMR-P tumors. Our findings support that MMR status is a key predictor for OS in mCRC patients treated with ICI therapy and provide insights into additional specific clinical features that may predict response to ICIs in a real-world setting. Citation Format: Shahla Bari, Marco Matejcic, Richard Kim, Hao Xie, Estrella Carballido, Ibrahim Sahin, Benjamin Powers, Seth Felder, Stephanie Schmit. Immune checkpoint inhibitor therapy for metastatic colorectal cancer: Real-world practice patterns and predictors of overall survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 484.

Programmed cell death-1 (PD-1) ligand inhibitors have gained popularity in the treatment of advanced non-small-cell lung cancer. The immune system is regulated by stimulatory and inhibitory signaling and aims to achieve the balance between activation and inhibition. Treatment with immune checkpoint inhibitors enhances immune response, but is also known to diminish immune tolerance and increase autoimmune toxicity. Here we present a case of a patient with advanced squamous cell lung cancer who developed type I diabetes and thyroiditis after treatment with PD-1 checkpoint inhibitor nivolumab. The presence of autoimmune diabetes mellitus and thyroiditis were confirmed by markedly elevated titers of the glutamic acid decarboxylase autoantibody and thyroid peroxidase antibody, respectively. This report serves to heighten awareness of potential autoimmune toxicities related to anti-PD-1 therapy, especially as these toxicities are manageable if identified in a timely manner.

525 Background: Estrogen receptor (ER) positive breast cancer (BC) is a heterogeneous disease, with ongoing debate on the optimal cut off point for clinically relevant ER expression. Tumors harboring ≤10% ER expression are associated with poor outcomes. We used a real-world database to assess prognostic and predictive value of an alternative ER expression cut points. Methods: This retrospective cohort study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. During the study period, the de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). We evaluated the association between ER expression (assessed locally by immunohistochemistry according to ASCO/CAP guidelines) with tumor characteristics, and treatment patterns of patients with early-stage BC (stage I-III) using descriptive statistics. Recurrence free survival and overall survival was defined as time in months from date of surgery until the data of documented cancer recurrence or death respectively. We used Kaplan Myer survival curves to calculate recurrence free (RFS) and overall survival (OS) of patients with ER low, ER intermediate and ER high tumors. To define an alternative ER expression cut point, the data set was divided into 2/3 training and 1/3 test data. A cut point analysis was performed on the training data set to find the optimum cut point of ER+ staining based on correlation with recurrence free survival as the outcome. Results: Among 4,697 ER positive early-stage BC patients, 83 (1.8%) had ER low (ER expression :1-10%) and 36 (0.8%) had ER intermediate BC (11-20%). Median follow up time was 63 months (range 24-84). ER low tumors were associated with higher tumor grade, larger size, and higher axillary tumor burden compared to ER high positive tumors ( > 20% ER expression). African American patients had a higher prevalence of both triple negative and ER low positive BCs compared to ER high tumors- 21%, 22%, and 8% respectively. No significant differences in patient- or tumor-associated characteristics were observed between Low ER and intermediate-ER positive BC patients. Both ER low and intermediate positive tumor patients had survival outcomes similar to patients with TNBC and worse than ER high positive tumors (p < 0.001). No significant correlations between endocrine therapy and RFS or OS were observed among patients with either ER low or intermediate BCs (HR 1.47 and 2.57, p > 0.05; respectively). Sensitivity analysis showed that tumors with ≤ 20% ER expression were associated with worse RFS in both univariate and multivariate analyses (p < 0.05). Conclusions: These findings suggest that patients with ER expression rates ≤ 20% have poor outcomes and derive minimal benefit from endocrine therapies.

Simple Summary Even with recent advances, there are urgent needs for novel therapies to improve overall survival and decrease toxicities in the management of head and neck squamous cell carcinoma (HNSCC). This article reviews historical data to provide a context and highlights recent data in understanding of epidemiology and pathophysiology and supporting changes in treatments of HNSCC, particularly in patients with recurrent and/or metastatic disease. For use of immune checkpoint modulators such as programmed cell death protein 1 (PD-1) inhibitors, potential predictive biomarkers of clinical benefits are also summarized. In addition, this article reviews currently ongoing clinical trials and provides a perspective on future research directions. Abstract Head and neck squamous cell carcinoma (HNSCC) is the most common cancer arising in the head and neck region. The most common risk factors are smoking, excessive drinking, and human papillomavirus (HPV) infection. While the overall incidence of smoking is decreasing, the incidence of HPV-related HNSCC is increasing in the United States and Western Europe, which led to a shift in understanding of the pathophysiology, treatment, and prognosis of this disease. The outcomes for non-metastatic HNSCC remains very encouraging and continues to improve. Advances in radiation technology and techniques, better organ preserving surgical options, and multidisciplinary treatment modalities have improved cure rates for locally advanced HNSCC patients. The treatment of metastatic disease, however, remains an area of need. The advancement of immune checkpoint inhibitors has provided significantly better outcomes, but only a small proportion of patients obtain benefits. Most recurrent and/or metastatic HNSCC patients continue to have poor survival. This has led to the vigorous investigation of new biomarkers and biomarker-based therapies. Novel therapeutic options including adaptive cellular therapy and therapeutic vaccines are also on the horizon. In this review, we highlight the latest advances in the field of HNSCC and the future direction of research.

1548 Background: LS is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2 (d-MMR). A minority of LS patients have MMR proficient tumors (p-MMR). ICI therapy has dramatically changed outcome of d-MMR (majority of LS patients. However, data about response to ICI in LS patients, irrespective of their tumor MMR status is scarce. The aim of this study was to evaluate outcomes of ICI therapy in all LS associated Cancer. Methods: This was a retrospective analysis of LS associated cancers treated with one of the 6 ICIs at our center. We also looked at age, sex, microsatellite status, response and survival. Results: Out of 262 LS patients analyzed, 194 had cancer and 22 received ICIs. Among the patients analyzed, the mean age at diagnosis of 1st cancer was 51 yrs. There were 10 females (47%). 10 patients had colorectal (45%), 3 urothelial (14%), 2 renal cell, 2 cholangiocarcinoma and one each of esophageal, ovarian, uterine, glioblastoma multiforme and pancreatic cancer. One patient died from progressive disease after receiving a single dose and was not included in the analysis. 17 patients (80%) received Pembrolizumab, 11 patients were microsatellite unstable (MSI), 3 were microsatellite stable (MSS) while 7 were unknown. 2 patients achieved complete response (CR) (10%), 1 patient had partial response (PR) (5%), 13 had stable disease (62%) while 5 had progressive disease (23%) leading to a disease control rate (DCR) of 76%. Of the 3 known MSS Lynch syndrome patients, 2 did not respond while the 3rd continues to respond at 9 months of therapy. Of the 5 patients who had PD, 2 were MSS, 2 unknown and 1 MSI. Among the 16 patients who responded, 15 of 16 (94%) had sustained response and have not experienced disease progression or relapse. 3 of these patients have been off therapy (1 due to immune related adverse evet) and have had no relapse. One responder progressed after 18 cycles of therapy. The DCR was 71% at 12 months as well as 48 months of follow up. Median progression survival has not been reached. Similarly, median overall survival has not been reached. Conclusions: Our study is the one of the largest reported analysis of LS associated cancer patients treated with ICIs and included LS patients with both MSI and MSS tumors. Though small, our data suggests robust DCR and prolonged responses in Lynch associated MSS tumors treated with ICI. This encouraging response in MSS tumors along with higher response rates in LS associated cancers as compared to non-LS MSI tumors, suggests that there may be additional drivers of response to ICI in LS patients leading to superior responses.

Castration-resistant prostate cancer is an incurable disease. To date, six agents-abiraterone, enzalutamide, docetaxel, cabazitaxel, radium-223 and sipuleucel-T- have shown clinical efficacy in phase III clinical trials, leading to their FDA approval. Patients are typically sequenced through most or all of these agents, and then eventually succumb to their disease. Development of new treatments remains an unmet need. We report a case of a patient who progressed on enzalutamide with a single enlarging metastatic lesion, was treated with ablative stereotactic body radiation therapy while maintaining the same systemic treatment, who then had durable complete remission. Our findings have important clinical implications and suggest novel clinical trials for this difficult to treat disease.

Objective Colorectal cancer (CRC) develops from precancerous adenomatous polyps to malignant lesions of adenocarcinoma. Elucidating inhibition mechanisms for this route in patients with a risk of developing CRC is highly important for a potential diagnostic or prognostic marker. Differential expression of nuclear-encoded cytochrome c oxidase subunit 4 (COXIV) seems to contribute to a more unregulated respiration due to loss of ATP inhibition. Majority of energy for tumor transformations are mitochondrial origin. Differences in mitochondrial efficiency may be reflected in the progression of colorectal adenomatous polyps to adenocarcinomas. Here, we evaluate expression levels of COXIV isoform 1 (COXIV-1) and Mitochondrial (MT)-ATP synthase Subunit 6 (ATPase6) in adenomas of tubular, tubulovillous and villous tissues as compared to adenocarcinoma tissues. Method Both RT-qPCR and western blot techniques were used to assess COXIV-1 and ATPase6 expression levels in 42 pairs of patients' tissue samples. Protein carbonyl assay was performed to determine levels of oxidized proteins, as a measurement of ROS productions, in the tissue samples. Results Differential RNA expression levels of COXIV-1 and ATPase6 from whole tissues were observed. Interestingly, RNA expression levels obtained from mitochondrial for COXIV-1 were significantly decreased in tubulovillous, villous adenomas and adenocarcinoma, but not in the tubular-polyps. Moreover, mitochondrial ATPase6 RNA expression levels decreased progressively from adenopolyps to adenocarcinoma. In mitochondrial protein, expression levels of both genes progressively decreased with a three folds from adenomatous polyps to adenocarcinoma. Whilst the ATPase6 protein expression significantly decreased in adenocarcinoma compared to villous, conversely, the levels of oxidized carbonyl proteins were considerably increased from adenomatous polyps to adenocarcinoma. Conclusion Our findings provide evidence that decreased mitochondrial protein expression of COXIV-1 and ATPase6 correlates with increased ROS production during colorectal adenomatous polyps' progression, suggesting the pivotal role of COXIV-1 in energy metabolism of colorectal cells as they progress from polyps to carcinoma.

Diamond Blackfan anemia (DBA), a syndrome primarily characterized by anemia and physical abnormalities, is one among a group of related inherited bone marrow failure syndromes (IBMFS) which share overlapping clinical features. Heterozygous mutations or single-copy deletions have been identified in 12 ribosomal protein genes in approximately 60% of DBA cases, with the genetic etiology unexplained in most remaining patients. Unlike many IBMFS, for which functional screening assays complement clinical and genetic findings, suspected DBA in the absence of typical alterations of the known genes must frequently be diagnosed after exclusion of other IBMFS. We report here a novel deletion in a child that presented such a diagnostic challenge and prompted development of a novel functional assay that can assist in the diagnosis of a significant fraction of patients with DBA. The ribosomal proteins affected in DBA are required for pre-rRNA processing, a process which can be interrogated to monitor steps in the maturation of 40S and 60S ribosomal subunits. In contrast to prior methods used to assess pre-rRNA processing, the assay reported here, based on capillary electrophoresis measurement of the maturation of rRNA in pre-60S ribosomal subunits, would be readily amenable to use in diagnostic laboratories. In addition to utility as a diagnostic tool, we applied this technique to gene discovery in DBA, resulting in the identification of RPL31 as a novel DBA gene.

1532 Background: LS is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2. Inappropriate immune responses as seen in chronic inflammatory conditions as well as immunodeficiency states confer increased risk of developing cancer. This aim of this study was to evaluate the effect of immune dysfunction on the characteristics of LS associated cancers. Methods: This was a retrospective analysis of LS patients and carriers at two institutions listed above. We evaluated mutational profiles, immune status, age of onset of first and subsequent cancers in this cohort. Results: 106 patients with mutations consistent with LS were included. 72 patients had at least one cancer while 34 were carriers. 44% patients were Caucasian female, 18% white males, 14% African American males, 11% African American females and 10% Hispanic females. Colon cancer (CRC) was the most common cancer (44%) and PMS2 was the most common mutation, noted in 35 patients (33%). Of the 72 patients with LS associated cancer, 18 patients were either immunosuppressed or had an autoimmune condition. Of the 10 patients who had an autoimmune condition ,7 had multiple cancers. Of the 9 patients who were immunosuppressed, 5 had multiple cancers. Out of a total of 18 out of 72 patients who had multiple cancers, 12 (66%) had either an autoimmune condition or were immunosuppressed. CRC was the index cancer in 42% and breast in 33% of patients with multiple cancers. Patients with MSH2 were most likely to have an immune related condition (32%) and accounted for 41% of patients with multiple cancers. The median age of first cancer in this group was 46 years while it was 48.5 years in the population without immune dysfunction (p = 0.2). There was a high prevalence of breast cancer (24%) as a LS associated cancer in our study population. 66% of the patients with PMS2 mutation had breast cancer with a median age of onset of 48 years (62 years for sporadic cancer). Conclusions: Our study is the first to look at the effect of immune dysfunction in LS patients. Immune dysfunction was associated with a higher rate of multiple cancers and was more commonly associated with the MSH2 mutation. It also highlights importance of aggressive screening for breast cancer in LS patients (especially with PMS2 mutation).

Background Due to HAART and consequent decline in mortality from infectious complications, HIV patients have an increasing burden of non-AIDS defining cancers. Immunotherapy, consisting of PD1/PDL1 inhibitors, has revolutionized the treatment of cancers but data on their safety and efficacy is unknown in HIV patients, as they were excluded from clinical trials due to concern for unforeseen side effects. Methods This is the largest retrospective study, involving 17 patients with HIV, treated with one of the 4 PD-1/PD-L1 inhibitors (Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab or Avelumab) for cancer.The objective of our study was to evaluate the efficacy and safety profile of PD-1 and PD-L1 inhibitors in Cancer patients with HIV and also to assess the impact of these drugs on HIV infection control, specifically CD4 count and HIV viral load. Results Ten out of 17 patients responded to therapy. Of the 10 patients who responded to therapy, seven were alive and four were still on therapy. Ten patients including all seven non-responders died; nine died from cancer progression and one from sepsis after discontinuing HAART. The minimum duration of response was 15 weeks with one ongoing response at 34 weeks (similar to non HIV patients). Adverse events (Grade 1 or 2) were noted in seven patients while one stopped therapy due to pneumonitis. CD4 count was stable on treatment and HIV RNA was undetectable (became undetectable in one patient with initial low HIV viremia) (Table1). Conclusion PD-1 and PD-L1 inhibitors have transformed cancer treatment. Our data shows that they have equal efficacy, tolerable side effects with no effect on HIV markers when used in HIV patients with cancer. We strongly advocate inclusion of HIV cancer patients in clinical trials and support the use of PD1/PDL1 inhibitors in them. Table 1: HIV Markers While on PD-1 or PD-L1 Inhibitor Therapy Patient CD4 Count at Initiation of T Viral Load at Initiation of Therapy CD4 Count at 12 Weeks of Therapy Viral Load at 12 Weeks of Therapy 1 573 0 NA* NA* 2 624 500 NA* NA* 3 242

e15634Background: MSI status remains an important clinical and prognostic marker and has been associated with better outcomes in CRC. AA patients are known to have more aggressive CRC at diagnosis ...

e15080Background: The African American (AA) population has been under-represented in clinical trials for PD-1/PDL-1 inhibitors, constituting less than 5% of patients in these trials. Therefore, dif...