Cancer Remission Research Articles

Breast cancer recurrence risk after hormonal contraceptive use in survivors of reproductive age

ObjectiveTo assess the risk of recurrence with hormonal contraceptive use in breast cancer survivors of reproductive age. Study designIn this retrospective study, women ages 18–51 years who were diagnosed with primary stage 0–3 breast cancer between 2006–2016 and subsequently entered remission were included. Patients with missing information within the cancer registry or electronic medical record and those with a history of hysterectomy and/or sterilization procedure prior to diagnosis were excluded. Hormonal contraception use was defined as being prescribed an oral contraceptive pill (OCP), patch, vaginal ring, medroxyprogesterone injection, etonogestrel implant, or levonorgestrel-releasing intrauterine device (IUD). Women were separated into two groups, hormonal contraceptive users and non-users. Basic descriptive and inferential statistics were used to compare groups as appropriate. The primary outcome reviewed was local or distant breast cancer recurrence. Secondary outcomes included all-cause mortality and pregnancy. ResultsFollowing exclusions, 1370 women remained in the cohort. Ninety-seven women (7.08 %) received a prescription for a form of hormonal contraception. When comparing groups, hormonal contraceptive users were more likely to be between 18−40 years of age (46.39 % vs. 17.99 % non-users;P < 0.01) and never smokers (68.04 % vs. 38.57 % non-users; P < 0.01). Patients did not differ between groups based on any other demographic or cancer-related characteristic, including tumor hormone receptor expression. Overall, 92 patients (6.72 %) experienced local or distant recurrence during the study period. Recurrence did not differ between groups (6.19 % users vs. 6.76 % non-users; P = 0.83). All-cause mortality and pregnancy rates also did not differ between hormonal contraceptive users and non-users. ConclusionThe study shows no increased risk of recurrence associated with hormonal contraceptive use after breast cancer diagnosis and remission.

Sarcoid-Like Reaction after Complete Remission of Malignancy: CT and 18F-FDG PET/CT Features for the Differential Diagnosis from Lymph Node Metastasis.

PurposeTo identify the imaging features indicative of sarcoid-like reactions in patients with intrathoracic lymphadenopathy after complete remission of malignancies.Materials and MethodsThis study enrolled five patients with histopathologically confirmed sarcoid-like reactions that developed after cancer remission. The clinical features and findings of CT and 18F-fluorodeoxyglucose (FDG) PET/CT were assessed.ResultsThe underlying malignancies included breast, nasopharyngeal, colon, and endometrial cancer and lymphoma. The time intervals between complete remission of malignancy and the diagnosis of sarcoid-like reaction ranged from 6 to 78 months. CT findings of sarcoid-like reaction included bilateral hilar and mediastinal lymphadenopathies (n = 5), pulmonary nodules (1–15 mm) with peribronchovascular, fissural, or subpleural distribution, and interlobular interstitial thickening in the lungs (n = 4). 18F-FDG PET/CT revealed hypermetabolic uptake in the mediastinal and hilar lymph nodes and both lungs in the absence of extrathoracic uptake (n = 3). The sarcoid-like reactions resolved in all patients after corticosteroid treatment.ConclusionIn patients with complete remission of malignancies, newly developed bilateral hilar and mediastinal lymphadenopathies with or without pulmonary nodules of perilymphatic distribution, in the absence of recurrence at the primary tumor site and extrathoracic metastasis, may suggest a sarcoid-like reaction. Such cases warrant histologic evaluation of the lymph nodes to prevent unnecessary systemic chemotherapy.

Rare Features of Dermatomyositis in a Patient with Ovarian Cancer

This case illustrates a mode of onset of dermatomyositis that could challenge its classification as a 'paraneoplastic' syndrome, as the dermatomyositis appeared when the patient was in complete metabolic remission.This case also raises questions about the observed relationship between IVIG administration and the onset of subcutaneous oedema and Evans' syndrome.

Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients.

Simple SummaryThis study provides new insights into the changing transcriptomic and epigenomic landscapes in chronic myeloid leukaemia (CML) patients who are receiving tyrosine kinase inhibitor (TKI) therapy (often life-long). Alternative splicing, vital for cellular homeostasis, is dysregulated in human cancers. Remarkably, we found abnormal splicing patterns despite molecular remission in peripheral blood cells of chronic-phase CML patients. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns.Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exemplar of targeted remission induction occurs in chronic myeloid leukaemia (CML) following tyrosine kinase inhibitor (TKI) therapy. Using RNA sequencing and whole-genome bisulfite sequencing, we profiled samples from chronic-phase CML patients at diagnosis and remission and compared these to healthy donors. Remarkably, our analyses revealed that abnormal splicing distinguishes remission samples from normal controls. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns. Most remarkable are the high intron retention (IR) levels that even exceed those observed in the diagnosis samples. Increased IR affects cell cycle regulators at diagnosis and splicing regulators at remission. We show that aberrant splicing in CML is associated with reduced expression of specific splicing factors, histone modifications and reduced DNA methylation. Our results provide novel insights into the changing transcriptomic and epigenomic landscapes of CML patients during remission. The conceptually unanticipated observation of widespread aberrant alternative splicing after remission induction warrants further exploration. These results have broad implications for studying CML relapse and treating minimal residual disease.

Extended Gumbel Type-2 Distribution: Properties and Applications

In this paper, we proposed a new four-parameter Extended Gumbel type-2 distribution which can further be split into the Lehman type I and type II Gumbel type-2 distribution by using a generalized exponentiatedGdistribution. The distributional properties of the proposed distribution have been studied. We derive thepth moment; thus, we generalize some results in the literature. Expressions for the density, moment-generating function, andrth moment of the order statistics are also obtained. We discuss estimation of the parameters by maximum likelihood and provide the information matrix of the developed distribution. Two life data, which consist of data on cancer remission times and survival times of pigs, were used to show the applicability of the Extended Gumbel type-2 distribution in modelling real life data, and we found out that the new model is more flexible than its submodels.

Phase 1 Trial of Prophylactic Donor-Derived IL-2 Activated NK Cell Infusion after Allogeneic Hematopoietic Stem Cell Transplantation from a Matched Sibling Donor

Background: Donor lymphocyte infusion (DLI) is commonly used to enhance T-cell mediated graft-versus-tumor (GVT) effect after allogeneic stem cell transplantation (allo-HSCT). It was showed that prophylactic DLI can produce promising outcome but is also associated with a high rate of graft-versus-host disease (GVHD), limiting its use as maintenance treatment. By contrast with T cells, there are clinical and biological evidences that NK cells can provide strong GVT effect without inducing GVHD, making post allo-HSCT NK cell-based immunotherapy appealing. Thus, we designed a phase 1 clinical trial evaluating the safety of donor-derived ex vivo IL-2 activated NK cells (DLI-NK) as maintenance immunotherapy after allo-HSCT (DLI-NK: NCT01853358). Methods: We included patients who were in morphologic remission of hematological cancers 2 months after allo-HSCT from a matched sibling donor after reduced intensity conditioning regimen, without history of acute GVHD. NK cells were purified from the donor (CD3 depletion / CD56 positive selection) and cultured ex vivo during 7 days with IL-2 before prior to infusion in patients between day+60 and day+90 after allo-HSCT. The study included a first phase of dose escalation (3+3 method) to determine the maximal tolerated dose (MTD) using 3 dose levels: 1.0 (dose 1), 5.0 (dose 2), 5.0-50 (dose 3) million cells/kg. A second phase allowed the treatment of subsequent patients to reach a total amount of 10 patients treated at the MTD. As ancillary studies, we performed: 1) preclinical evaluation of donor-derived IL-2 stimulated NK cell therapy in mice; 2) phenotypical and functional characterization of the NK cell therapy product before and after 7-day IL-2 stimulation, and 3) longitudinal immunomonitoring of NK cell phenotype in patients. Results: We treated 16 patients without observing any dose-limiting toxicity (grade 3-4 adverse events related to DLI-NK within 30 days after infusion). During the follow up, 4 patients developed chronic GVHD (1 mild, 2 moderate and 1 severe forms). All of them were in complete remission of GVHD without immunosuppressive treatment at last contact. We observed one non-relapse death due to idiopathic pneumonia. From the four patients who relapsed (3 AML and 1 CLL), 2 died from their disease and 2 were in complete response after salvage therapy. At last follow up, 11 out of 16 treated patients were alive in CR without GVHD features and immunosuppressive treatment. Ancillary studies showed that IL-2 stimulated allogeneic NK cells did not induce GVHD and displayed strong antitumor effect in mice against YAC-1 tumor cells, supporting the efficacy of this approach. In human, we observed that IL-2-activated NK cells expressed high levels of activating receptors (DNAM-1, NKG2A, NKp46, NKp30) and of the inhibitory receptor NKG2A, and exhibited increased degranulation and cytokine production when challenged by K562 tumor cells, as compared to freshly isolated NK cells. Immunomonitoring of patient NK cells after DLI-NK do not reveal significant phenotypic or functional dysfunction, with a pattern of NK cell recovery that is similar to what was previously observed after allo-HSCT. Conclusion: We showed that prophylactic DLI-NK after matched sibling donor allo-HSCT was feasible and safe. We observed low incidence of GVHD as compared to previous reports of conventional prophylactic DLI, reinforcing the rationale of NK cell role in GVHD prevention. In addition, promising disease-free survival supports the design of future clinical trials evaluating the efficacy of DLI-NK as disease relapse prevention. Disclosures Harbi: Sanofi: Honoraria. Olive:Imcheck Therapeutics: Other: Co-Founder &amp; shareholder; Emergence Therapeutics: Other: Co-Founder &amp; shareholder; Alderaan Biotechnology: Other: Co-Founder &amp; shareholder. Blaise:Jazz Pharmaceuticals: Honoraria.

Assessment of Molecular Remission in Oligometastatic Esophageal Cancer With a Personalized Circulating Tumor DNA Assay.

Assessment of Molecular Remission in Oligometastatic Esophageal Cancer With a Personalized Circulating Tumor DNA Assay.

Anthracycline-induced cardiotoxicity: molecular and genetic predictors for risk assessment

Abstract Objective The objective of this study was to evaluate the role of molecular and genetic biomarkers in the development of anthracycline-induced cardiotoxicity in women with breast cancer at the 12 months after polychemotherapy. Methods A total of 176 women, median age of 45,0 [42,0; 50,0] years with breast cancer without cardiovascular diseases who received anthracycline antibiotics as part of polychemotherapeutic treatment were enrolled in the study. Two-dimensional transthoracic echocardiography and 6-minute walk test were performed at baseline and at the 12 months after polychemotherapy. Serum levels of NT-proBNP, sFas-L were measured using an enzyme immunoassay after polychemotherapeutic treatment. Evaluation of gene polymorphisms of p53 protein (polymorphic marker-Arg72Pro exon 4, rs1042522) and nitric oxide synthase (NOS3, Glu298Asp, rs1799983) were carried out by polymerase chain reaction at baseline. Results After the 12 months of polychemotherapy all patients had breast cancer remission and were divided into 2 groups: group 1 (n=52) comprised patients with anthracycline-induced cardiotoxicity, group 2 (n=124) comprised those without it. After polychemotherapeutic treatment the median value of NT-proBNP in group 1 was higher (p&amp;lt;0,00001) by 52,4% than in group 2 (113 [101,8; 126,15] pg/mL and 53,8 [43,4; 63,0] pg/mL, respectively). The median value of sFas-L in group 1 was higher (p&amp;lt;0,00001) by 44,3% than in group 2 (125,3 [111,85; 133,95] pg/mL and 69,8 [59,8; 77,6] pg/mL, respectively). Based on ROC-analysis, sFas-L concentration of 95.8 pg/mL (sensitivity of 92.2%, specificity of 92.1%, and AUC=0,951; p=0,0001) and NT-proBNP concentration of 71.5 pg/mL (sensitivity of 99.9%, specificity of 91.9%, and AUC=0,951; p=0,0001) were identified as a cut-off values predicting the development of anthracycline-induced cardiotoxicity. The development of anthracycline-induced cardiotoxicity in women with breast cancer at the 12 months after polychemotherapy significantly was related to the presence of T/T genotype of NOS3 gene (OR = 3,059; p=0,018) and with Arg/Arg genotype of p53 protein gene (OR = 2,972; p=0,001). While, the presence of Pro/Pro the Pro53 gene genotype of p53 protein gene was related to the absence of anthracycline-induced cardiotoxicity. Conclusion Our data suggest that evaluation of polymorphisms gene of p53 (rs1042522) and NOS3 (rs1799983) can be recommended before polychemotherapy in women with breast cancer for the risk assessment of anthracycline-induced cardiotoxicity. The serum levels of NT-proBNP and sFas-L after polychemotherapy may be considered as non-invasive biomarkers for prediction of the development of anthracycline-induced cardiotoxicity in women with breast cancer during the 12 months after polychemotherapy. Funding Acknowledgement Type of funding source: None

Why we do what we do. A brief analysis of cancer therapies.

The goal of all medical activity is to preserve health in fit people, and to restore the sick into a state of complete physical, mental and social wellbeing. In an effort to determine whether we are achieving this last goal in oncology, herein we review the biological and clinical framework that has led to the foundations of the current anticancer treatment paradigm. Currently, cancer therapy is still based on the ancient axiom that states that the complete eradication of the tumor burden is the only way to achieve a cure. This strategy has led to a substantial improvement in survival rates as cancer mortality rates have dropped in an unprecedented way. Despite this progress, more than 9 million people still die from cancer every year, indicating that the current treatment strategy is not leading to a cancer cure, but to a cancer remission, that is “the temporary absence of manifestations of a particular disease”; after months or years of remission, in most patients, cancer will inevitably recur. Our critical analysis indicates that it is time to discuss about the new key challenges and future directions in clinical oncology. We need to generate novel treatment strategies more suited to the current clinical reality.

Asymptomatic abdominal wall and incisional hernias: Is therapeutic decision consensual? An international survey

IntroductionHernia pathology is one of the leading causes of surgery worldwide. For asymptomatic patients, surgery remains questionable. The objective of this study was to evaluate the practices of a large population of digestive surgeons with asymptomatic hernia. MethodsBetween October 2016 and March 2017, French-speaking digestive surgeons were invited to respond to an online survey consisting of 13 common clinical situations concerning primary or asymptomatic incisional hernia pathology where a therapeutic decision was requested. A consensual attitude was defined by identical care by at least 75% of surgeons. ResultsOf the 204 surgeons responding to the study, 44% were under 45 years of age. The therapeutic attitude was consensual in 2 out of 13 clinical cases: surgical abstention was chosen consensually for inguinal hernia in the elderly with comorbidities while surgical treatment was consensually chosen for incisional hernia in a young patient in remission of pancreatic cancer. The under-45s were more likely to undergo surgical repair (5 cases of 13 vs 4 cases of 13, p = 0.03). ConclusionAlthough frequent, the management of primary and incisional hernias of the abdominal wall does not reach consensus in the surgical community. Specific recommendations for indications of surgical management or watchful waiting are required.

Complete Remission of Colon Cancer with Ipilimumab Monotherapy.

Complete Remission of Colon Cancer with Ipilimumab Monotherapy.

Variability in clinical decision-making for ventricular assist device implantation in pediatrics.

Minimal data exist on clinical decision-making in VAD implantation in pediatrics. This study aims to identify areas of consensus/variability among pediatric VAD physicians in determining eligibility and factors that guide decision-making. An 88-item survey with clinical vignettes was sent to 132 pediatric HT cardiologists and surgeons at 37 centers. Summary statistics are presented for the variables assessed. Total respondents were 65 (72% cardiologists, 28% surgeons) whose centers implanted 1-5 (34%), 6-10 (40%), or >10 (26%) VADs in the past year. Consensus varied by patients' age, diagnosis, and Pedimacs profile. Highest agreement to offer VAD (97%) was a mechanically ventilated teenager with dilated cardiomyopathy. Patients stable on inotropes were less likely offered VAD (11%-25%). SV infant with Pedimacs profile 2 had the most varied responses: 37% offered VAD; estimated survival ranged from 15% to 90%. Variables considered for VAD eligibility included mild developmental delays (100% offered VAD), moderate-severe behavioral concerns (46%), cancer in remission >2years (100%), active malignancy with good prognosis (68%) or uncertain prognosis (36%), and BMI >35 (74%) or <15 (69%). Most respondents (91%) would consider destination therapy VADs in pediatrics, though not currently feasible at 1/3 of centers. Factors with greatest influence on decision-making included HT candidacy, families' goals of care, and risks of complications. Significant variation exists among pediatric VAD physicians when determining VAD eligibility and estimating survival, which can lead to differences in access to emerging technologies across institutions. Further work is needed to understand and mitigate these differences.

VANISHING PLEURAL EFFUSION: DRESSLER-LIKE SYNDROME IN PATIENT WITH FOREIGN BODY REACTION

SESSION TITLE: Fellows Disorders of the Pleura Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: We describe a patient who developed bilateral right greater than left pleural effusions after surgical alteration of her prior silicone breast implants. She had near-complete resolution of her effusion with a course of non-steroidal anti-inflammatory drugs (NSAIDs). CASE PRESENTATION: We describe a 42 y/o lady, former 5.5 pack-year smoker, triple-negative breast cancer in remission, status-post bilateral mastectomy and silicone breast implantation. She since had bilateral breast reconstruction, involving superior gluteal artery perforator (SGAP) flap. She developed dyspnea and pleuritic pain within 2 weeks of her SGAP procedure, and presented to our center. She had stable vitals on admission, and did not require supplemental oxygen; however, her dyspnea and pleuritic pain were affecting her daily activities. Chest X-ray revealed a moderate right and a small left pleural effusion, confirmed on PE protocol CT scan, which was negative for PE. She was initially treated with diuretics which failed to improve her symptoms or pleural effusion size. Right thoracentesis was then performed, yielding 800 mL of serous yellow fluid. Fluid studies were consistent with an exudative effusion, with negative cytology and no bacterial or fungal growth, pH 7.48, LDH 200, glucose 88, total protein 4.1. Immediate post-procedure chest x-ray showed significant improvement in right effusion, and dyspnea was alleviated. Within 24 hours, the effusion on the right re-accumulated to a size equivalent to prior to thoracentesis. She was once again dyspneic. Suspecting an underlying inflammatory process, the patient was started on ibuprofen 600 mg QID. Within 2 days, patient felt symptomatic improvement. Outpatient follow-up chest X-ray 10 days after NSAID initiation was revealing of near-complete resolution of right effusion and symptoms. NSAID taper was then initiated. Repeat chest-XR 1 month after first dose of NSAID’s showed total resolution of pleural effusions. DISCUSSION: Foreign body reaction (FBR), or an inflammatory response to non-native entities such as breast implants, has been described as a cause of systemic release of inflammatory factors [1]. One report describes the development of pleural effusion 6 weeks after silicone breast implants [2]. We postulate the SGAP flap procedure resulted in manipulation of her prior silicone implants, resulting in an FBR. Neither IV diuretics nor therapeutic thoracentesis resulted in lasting resolution of her effusion, making fluid overload less likely. Pleural fluid studies were negative for cancer cells. The marked improvement with NSAIDs suggests an underlying systemic inflammatory response, not unlike Dressler’s Syndrome. CONCLUSIONS: Clinicians should be aware of pleural effusions that are secondary to a foreign body reaction, and consideration of a course of non-steroidal anti-inflammatory drugs should be considered if other causes of effusion have been ruled out. Reference #1: Tralhão, António et al. “The return of a disappearing entity: Dressler's syndrome after transvenous pacemaker implantation.” BMJ case reports vol. 2014 bcr2013203401. 20 Mar. 2014, doi:10.1136/bcr-2013-203401 Reference #2: Silicone Breast Implants: A Rare Cause of Pleural Effusion Shaik, Imam et al. CHEST, Volume 148, Issue 4, 444A DISCLOSURES: no disclosure on file for Alexander Geyer; No relevant relationships by Saamia Hossain, source=Web Response

WÜNDERLICH SYNDROME: A CASE OF HYPOVOLEMIC HEMORRHAGIC SHOCK

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Wünderlich syndrome (WS) is a rare presentation of hypovolemic hemorrhagic shock. It is a fatal disease described as a syndrome of spontaneous non-traumatic subcapsular and retroperitoneal hemorrhage. The etiology of WS is varied, with renal causes including malignancy being the most common, followed by renal vasculature abnormalities, vasculitis, cystic rupture, pyelonephritis, and idiopathic. The appropriate treatment depends on the accuracy of diagnosis and precise determination of its cause. To our knowledge, this is the first case report of WS due to acute pyelonephritis in a patient with congenital solitary kidney and Jehovah's Witness religious beliefs which impacted his care. CASE PRESENTATION: A 77 year old male with a two day history of flank pain accentuated on the right side, fevers, and confusion presented as critically ill and requiring vasopressor support. His medical history comprises prostate cancer in remission and atrial fibrillation on aspirin. He was diagnosed clinically with pyelonephritis, and culture positive urinary tract infection and sepsis with Escherichia coli. The initial hemoglobin was of 10.3 g/dL. Computed tomography (CT) of the abdomen showed nonspecific stranding and a solitary right kidney. He clinically deteriorated prompting repeat CT imaging that showed a large right perirenal hematoma with retroperitoneal blood. He underwent emergent coil angioembolization of a hemorrhagic branch of the inferior pole renal artery. His hemoglobin of 4 g/dL recovered with erythropoietin and intravenous iron. He briefly required hemodialysis for his acute kidney injury. The patient survived and the function of his congenital solitary kidney was preserved. DISCUSSION: The classic signs of WS include Lenk’s triad of flank pain, abdominal mass, and hypovolemic shock. However, in only 20% of cases, all three symptoms present. Acute onset of flank pain is the most common symptom. Although pyelonephritis is a rare cause of WS, in our case we believe that bleeding diathesis and etiology of WS was driven by cytokine induced endothelial damage from pyelonephritis along with aspirin induced platelet dysfunction. CT is preferred for the initial imaging workup. Angioembolization is a minimally invasive treatment modality for acute hemorrhage. Exploratory laparotomy or nephrectomy is typically recommended if malignancy is suspected. CONCLUSIONS: WS requires prompt recognition to prevent death from exsanguination. Shock is relatively common with WS, however, surgical exploration is not absolutely necessary with the advent of angioembolization. The unconventional treatment method with erythropoietin instead of blood may be considered in patients with Jehovah’s Witness religious beliefs. Reference #1: Katabathina VS, Katre R, Prasad SR, Surabhi VR, Shanbhogue AK, Sunnapwar A. Wunderlich syndrome: cross-sectional imaging review. J Comput Assist Tomogr. 2011;35(4):425-33. Reference #2: Chen YC, Lin YC. Wunderlich syndrome. QJM. 2013;106(2):187-8. Reference #3: Chamarthi G, Koratala A. Wunderlich syndrome. Clin Case Rep. 2018;6(9):1901-1902. DISCLOSURES: No relevant relationships by Francois Kaleta, source=Web Response No relevant relationships by Mitra Sahebazamani, source=Web Response No relevant relationships by Pratyaksha Sankhyan, source=Web Response

Zika virus-based immunotherapy enhances long-term survival of rodents with brain tumors through upregulation of memory T-cells.

Zika virus (ZIKV) exhibits a tropism for brain tumor cells and has been used as an oncolytic virus to target brain tumors in mice with modest effects on extending median survival. Recent studies have highlighted the potential for combining virotherapy and immunotherapy to target cancer. We postulated that ZIKV could be used as an adjuvant to enhance the long-term survival of mice with malignant glioblastoma and generate memory T-cells capable of providing long-term immunity against cancer remission. To test this hypothesis mice bearing malignant intracranial GL261 tumors were subcutaneously vaccinated with irradiated GL261 cells previously infected with the ZIKV. Mice also received intracranial injections of live ZIKV, irradiation attenuated ZIKV, or irradiated GL261 cells previously infected with ZIKV. Long-term survivors were rechallenged with a second intracranial tumor to examine their immune response and look for the establishment of protective memory T-cells. Mice with subcutaneous vaccination plus intracranial irradiation attenuated ZIKV or intracranial irradiated GL261 cells previously infected with ZIKV exhibited the greatest extensions to overall survival. Flow cytometry analysis of immune cells within the brains of long-term surviving mice after tumor rechallenge revealed an increase in the number of T-cells, including CD4+ and tissue-resident effector/ effector memory CD4+ T-cells, in comparison to long-term survivors that were mock-rechallenged, and in comparison to naïve untreated mice challenged with intracranial gliomas. These results suggest that ZIKV can serve as an adjuvant to subcutaneous tumor vaccines that enhance long-term survival and generate protective tissue-resident memory CD4+ T-cells.

Association between history of cancer and major adverse cardiovascular events in patients with chest pain presenting to the emergency department: a secondary analysis of a prospective cohort study.

Cancer survivorship status among patients evaluated for chest pain at the emergency department (ED) warrants high degree of suspicion. However, it remains unclear whether cancer survivorship is associated with different risk of major adverse cardiac events (MACE) compared to those with no history of cancer. Furthermore, while HEART score is widely used in ED evaluation, it is unclear whether it can adequately triage chest pain events in cancer survivors. We sought to compare the rate of MACE in patients with a recent history of cancer in remission evaluated for acute chest pain at the ED to those with no history of cancer, and compare the performance of a common chest pain risk stratification score (HEART) between the two groups. We performed a secondary analysis of a prospective observational cohort study of chest pain patients presenting to the EDs of three tertiary care hospitals in the USA. Cancer survivorship status, HEART scores, and the presence of MACE within 30 days of admission were retrospectively adjudicated from the charts. We defined patients with recent history of cancer in remission as those with a past history of cancer of less than 10 years, and currently cured or in remission. The sample included 750 patients (age: 59 ± 17; 42% females, 40% Black), while 69 patients (9.1%) had recent history of cancer in remission. A cancer in remission status was associated with a higher comorbidity burden, older age, and female sex. There was no difference in risk of MACE between those with a cancer in remission and their counterparts in both univariate [17.4 vs. 19.5%, odds ratio (OR) = 0.87 (95% confidence interval (CI), 0.45-1.66], P = 0.67] and multivariable analysis adjusting for demographics and comorbidities [OR = 0.62 (95% CI, 0.31-1.25), P = 0.18]. Patients with cancer in remission had higher HEART score (4.6 ± 1.8 vs. 3.9 ± 2.0, P = 0.006), and a higher proportion triaged as intermediate risk [68 vs. 56%, OR = 1.67 (95% CI, 1.00-2.84), P = 0.05]; however, no difference in the performance of HEART score existed between the groups (area under the curve = 0.86 vs. 0.84, P = 0.76). There was no difference in rate of MACE between those with recent history of cancer in remission compared to their counterparts. A higher proportion of patients with cancer in remission was triaged as intermediate risk by the HEART score, but we found no difference in the performance of the HEART score between the groups.

Printed Electrodes in Microfluidic Arrays for Cancer Biomarker Protein Detection.

Medical diagnostics is trending towards a more personalized future approach in which multiple tests can be digitized into patient records. In cancer diagnostics, patients can be tested for individual protein and genomic biomarkers that detect cancers at very early stages and also be used to monitor cancer progression or remission during therapy. These data can then be incorporated into patient records that could be easily accessed on a cell phone by a health care professional or the patients themselves on demand. Data on protein biomarkers have a large potential to be measured in point-of-care devices, particularly diagnostic panels that could provide a continually updated, personalized record of a disease like cancer. Electrochemical immunoassays have been popular among protein detection methods due to their inherent high sensitivity and ease of coupling with screen-printed and inkjet-printed electrodes. Integrated chips featuring these kinds of electrodes can be built at low cost and designed for ease of automation. Enzyme-linked immunosorbent assay (ELISA) features are adopted in most of these ultrasensitive detection systems, with microfluidics allowing easy manipulation and good fluid dynamics to deliver reagents and detect the desired proteins. Several of these ultrasensitive systems have detected biomarker panels ranging from four to eight proteins, which in many cases when a specific cancer is suspected may be sufficient. However, a grand challenge lies in engineering microfluidic-printed electrode devices for the simultaneous detection of larger protein panels (e.g., 50–100) that could be used to test for many types of cancers, as well as other diseases for truly personalized care.

A novel machine learning strategy for model selections - Stepwise Support Vector Machine (StepSVM).

An essential aspect of medical research is the prediction for a health outcome and the scientific identification of important factors. As a result, numerous methods were developed for model selections in recent years. In the era of big data, machine learning has been broadly adopted for data analysis. In particular, the Support Vector Machine (SVM) has an excellent performance in classifications and predictions with the high-dimensional data. In this research, a novel model selection strategy is carried out, named as the Stepwise Support Vector Machine (StepSVM). The new strategy is based on the SVM to conduct a modified stepwise selection, where the tuning parameter could be determined by 10-fold cross-validation that minimizes the mean squared error. Two popular methods, the conventional stepwise logistic regression model and the SVM Recursive Feature Elimination (SVM-RFE), were compared to the StepSVM. The Stability and accuracy of the three strategies were evaluated by simulation studies with a complex hierarchical structure. Up to five variables were selected to predict the dichotomous cancer remission of a lung cancer patient. Regarding the stepwise logistic regression, the mean of the C-statistic was 69.19%. The overall accuracy of the SVM-RFE was estimated at 70.62%. In contrast, the StepSVM provided the highest prediction accuracy of 80.57%. Although the StepSVM is more time consuming, it is more consistent and outperforms the other two methods.

Palmoplantar hyperkeratotic projections

Palmoplantar hyperkeratotic projections

Abstract LB-386: Novel multimodal precision immunotherapy by co-targeting the HER3 oncogenic signaling circuitry and PD-1 for head and neck squamous cell carcinoma

Abstract In prior studies, we have shown that persistent activation of the PI3K/mTOR signaling circuitry is the most frequently dysregulated signaling pathway in HNSCC (&amp;gt;80% of all HPV- and HPV+ cases), and that mTOR inhibitors (mTORi) exert potent antitumor activity in multiple experimental HNSCC model systems and in a recent Phase 2 clinical trial. In this regard, the overreliance on PI3K/mTOR signaling for tumor growth may in turn expose a cancer vulnerability that can be exploited therapeutically. However, the immunosuppressive effects of mTORi limit the potential benefits of their combination with new immune oncology (IO) agents. These include immune check point blockade with pembrolizumab and nivolumab (anti-PD-1), which have recently demonstrated anti-tumor activity in HNSCC, albeit only &amp;lt;20% of the patients show durable responses. There is urgent need to search for alternative approaches for HNSCC treatment. We conducted a kinome-wide siRNA screen to identify new therapeutic targets for HNSCC. This revealed that the ERBB3 gene, encoding HER3, is among the top 20 kinases whose knockdown (KD) decreases HNSCC cell proliferation. A counter screen analysis revealed that ERBB3 was the gene whose KD results in the highest reduction of mTOR pathway activation (indicated by pS6). Remarkably, HER3 KD specifically reduced activation of mTOR but not ERK in cells that do not harbor PIK3CA mutations, and immunoprecipitation of HER3 showed direct binding between HER3 and PI3K. Furthermore, a blocking antibody targeting HER3 (CDX-3379) potently inhibited the tumor growth of PIK3CA wild type but not PIK3CA mutant HNSCC cells. CDX-3379 also showed anti-tumor activity in 4MOSC1, our recently reported tobacco-associated syngeneic HNSCC model. Of importance, we found that HER3 is not expressed in immune cells, but CDX-3379 treatment led to a rapid increase in the accumulation of pro-immunogenic IL-2 and IL-7, concomitant with a reduction in multiple pro-tumorigenic and immune suppressive cytokines (e.g., IL-10, VEGF, G-CSF, GM-CSF, IL-6). This provided a rationale to combine HER3i with IO agents. Indeed, the combination of HER3 and PD-1 blockade elicited a remarkable beneficial effect, with an increase of tumor-infiltrating CD8+ T cells and ~70% of the mice exhibiting complete and durable (&amp;gt;6 months) responses and consequently a significant increase in overall survival. Overall, our findings suggest that persistent tyrosine phosphorylation of HER3 underlies aberrant PI3K/mTOR signaling in HNSCC harboring wild type PIK3CA, and that targeting HER3 may exert its anti-tumor effect by both reducing cancer-driving mTOR activity and reversing an immune evasive tumor microenvironment. These findings also support that co-targeting the HER3 signaling circuitry combined with PD-1 blockade may represent a novel multimodal precision therapeutic approach for HNSCC aimed at achieving durable responses and cancer remission. Citation Format: Zhiyong Wang, Yusuke Goto, Mara Gilardi, Michael Allevato, Victoria Wu, Robert Saddawi-konefka, Diego Alvarado, Alfredo Molinolo, J. Silvio Gutkind. Novel multimodal precision immunotherapy by co-targeting the HER3 oncogenic signaling circuitry and PD-1 for head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-386.