Lineage and ecology define liver tumor evolution in response to treatment.

A tumor ecosystem constantly evolves over time in the face of immune predation or therapeutic intervention, resulting in treatment failure and tumor progression. Here, we present a single-cell transcriptome-based strategy to determine the evolution of longitudinal tumor biopsies from liver cancer patients by measuring cellular lineage and ecology. We construct a lineage and ecological score as joint dynamics of tumor cells and their microenvironments. Tumors may be classified into four main states in the lineage-ecological space, which are associated with clinical outcomes. Analysis of longitudinal samples reveals the evolutionary trajectory of tumors in response to treatment. We validate the lineage-ecology-based scoring system in predicting clinical outcomes using bulk transcriptomic data of additional cohorts of 716 liver cancer patients. Our study provides a framework for monitoring tumor evolution in response to therapeutic intervention.

Combined immune checkpoint inhibition with durvalumab and tremelimumab with and without radiofrequency ablation in patients with advanced biliary tract carcinoma.

BACKGROUND: Current standard of care for advanced biliary tract cancer (BTC) is gemcitabine, cisplatin plus anti-PD1/PD-L1, but response rates are modest. The purpose of this study was to explore the efficacy and safety of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4), with and without an interventional radiology (IR) procedure in advanced BTC. METHODS: Eligible patients with advanced BTC who had received or refused at least one prior line of systemic therapy were treated with tremelimumab and durvalumab for four combined doses followed by monthly durvalumab alone with and without an IR procedure until the progression of disease or unacceptable toxicity. Objective response was assessed through CT or MRI by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: Twenty-three patients with advanced BTC were enrolled; 17 patients were assigned to treatment with durvalumab and tremelimumab (Durva/Treme); and 6 patients were treated with the combination of durvalumab, tremelimumab plus IR procedure (Durva/Treme + IR). The best clinical responses in the Durva/Treme arm were partial response (n = 1), stable disease (n = 5), progressive disease (n = 5), and in the Durva/Treme + IR arm: partial response (n = 0), stable disease (n = 3), progressive disease (n = 3). The median PFS was 2.2 months (95% CI: 1.3-3.1 months) in the Durva/Treme arm and 2.9 months (95% CI: 1.9-4.7 months) in the Durva/Treme + IR arm (p = 0.27). The median OS was 5.1 months (95% CI: 2.5-6.9 months) in the Durva/Treme arm and 5.8 months (95% CI: 2.9-40.1 months) in the Durva/Treme + IR arm (p = 0.31). The majority of AEs were grades 1-2. CONCLUSION: Durva/Treme and Durva/Treme + IR showed similar efficacy. With a manageable safety profile. Larger studies are needed to fully characterize the efficacy of Durva/Treme ± IR in advanced BTC.

VB-111 (ofranergene obadenovec) in combination with nivolumab in patients with microsatellite stable colorectal liver metastases: a single center, single arm, phase II trial.

BACKGROUND: Microsatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 (ofranergene obadenovec) is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces an immune response and disrupts neovascularization. Checkpoint inhibition may synergize the immune response induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine the safety and antitumor activity of VB-111 and nivolumab in patients with refractory MSS CLM and to characterize immunological treatment-response. METHODS: This was a phase II study of adult patients with histologically-confirmed MSS CLM who progressed on prior therapy. A priming dose of VB-111 1×1013 viral particles was given intravenously 2 weeks prior to starting biweekly nivolumab 240 mg and continued every 6 weeks. The combination continued until disease progression or unacceptable toxicity. The primary objectives were overall response rate and safety/tolerability. Secondary objectives included median overall survival and progression-free survival. Correlative studies were performed on paired tumor biopsies and blood. RESULTS: Between August 2020 and December 2021, 14 patients were enrolled with median age 50.5 years (40-75), and 14% were women. Median follow-up was 5.5 months. Of the 10 evaluable patients, the combination of VB-111 and nivolumab failed to demonstrate radiographic responses; at best, 2 patients had stable disease. Median overall survival was 5.5 months (95% CI: 2.3 to 10.8), and median progression-free survival was 1.8 months (95% CI: 1.4 to 1.9). The most common grade 3-4 treatment-related adverse events were fever/chills, influenza-like symptoms, and lymphopenia. No treatment-related deaths were reported. Qualitative analysis of immunohistochemical staining of paired tumor biopsies did not demonstrate significant immune infiltration after treatment, except for one patient who had exceptional survival (26.0 months). Immune analysis of peripheral blood mononuclear cells showed an increase of PD-1highKi67highCD8+ T cells and HLA-DRhigh T cells after VB-111 priming dose. Plasma cytokines interleukin-10 and tumor necrosis factor-α increased after treatment with both drugs. CONCLUSION: In patients with MSS CLM, VB-111 and nivolumab did not improve overall response rate or survival but were tolerated with minimal toxicities. While challenging to distinguish between antiviral or antitumor, correlative studies demonstrated an immune response with activation and proliferation of CD8+ T cells systemically that was poorly sustained. TRIAL REGISTRATION NUMBER: NCT04166383.

Underrepresentation of Hispanics in clinical trials for liver cancer in the United States over the past 20 years.

IMPORTANCE: Accurate representation of racial and ethnic population subgroups in clinical trials is fundamental to ensure universal effectiveness of new therapies as well as to decrease disparities in oncology care. OBJECTIVE: To determine whether Hispanic people are underrepresented in Phase I and II clinical trials for liver cancer in the United States. PARTICIPANTS: A database search was performed in clinicaltrials.gov for interventional liver cancer studies based only in the US with reported results from September 1, 2002, to February 1, 2023. A total of 37 trials with 963 total patients met inclusion criteria and were included for further analysis. Proportion of total patients by race/ethnicity was calculated for non-Hispanic white, non-Hispanic black, Asian, Hispanic, and American Indian/Alaska Native subpopulations. The age-adjusted incidence rates of liver and intrahepatic bile duct were acquired from the National Cancer Institute, Surveillance, Epidemiology, and End Results Program. RESULTS: Liver cancer incidence rates (per 100,000 people) were highest in Indians/Alaska Native people (18.8 cases) followed by Hispanic people (15.1 cases), then Asian people (12.5 cases), then non-Hispanic black people (11 cases), and non-Hispanic white people (7.5 cases). From a total of 91 phase I or II clinical trials for liver cancer in the US, 41% reported race/ethnicity enrollment data; among these, 62.8% of patients were non-Hispanic White, 15.9% were non-Hispanic black, 8.8% were Hispanic, 12.7% Asian, and 0.5% American Indian/Alaska Native. CONCLUSIONS AND RELEVANCE: Less than half of phase I or II clinical trials for liver cancer in the US in the last 20 years reported race/ethnicity data to clinicaltrials.gov. Compared to the relative incidence rate of liver cancer, non-Hispanic black people and Hispanic people are underrepresented in these clinical trials.

Hispanic Individuals are Underrepresented in Phase III Clinical Trials for Advanced Liver Cancer in the United States.

Background: Hispanic individuals comprise the second-largest subpopulation after non-Hispanic White (NHW) individuals in the United States (US). We compared the relative contribution of Hispanic individuals to the ten most common causes of cancer-related deaths and studied enrollment of Hispanic patients in multinational phase III advanced liver cancer trials with the aim to investigate whether racial subpopulations are adequately represented in liver cancer trials. Methods: Relative cancer incidence rates in Hispanic individuals, NHW individuals, non-Hispanic black (NHB) individuals, and Asian individuals were obtained from both the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results Program and the Center for Disease Control and Prevention (CDC), United States Cancer Statistics (USCS) database. Searching PubMed, Embase, and Web of Science, we identified phase III clinical trials studying advanced liver cancer in the last ten years and collected enrollment for each race and ethnicity. Incidence rates of liver cancer and enrollment rates in phase III trials were compared by race and ethnicity. Results: The cancer type with the relatively highest contribution of Hispanic individuals was liver cancer. From 2015 to 2019, 15.1% of liver cancer cases occurred in Hispanic individuals compared to 12.5% in Asian individuals, 11% in NHB individuals, and 7.5% in NHW individuals. In the last ten years, Hispanic individuals made up 1.6% of patients and NHB individuals 1.3% of patients included in phase III multinational liver cancer trials, compared to 31% NHW individuals and 47% Asian individuals. Conclusion: Hispanic individuals are disproportionately underrepresented in multinational phase III clinical trials for liver cancer despite having the highest relative incidence rates among the four major racial or ethnic groups in the US.

The current landscape of therapies for hepatocellular carcinoma.

Globally, primary liver cancer is the third leading cause of cancer-related deaths, with approximately 830 000 deaths worldwide in 2020, accounting for 8.3% of total deaths from all cancer types (1). This disease disproportionately affects those in countries with low or medium Human Development Index scores in Eastern Asia, South-Eastern Asia, and Northern and Western Africa (2). Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, often develops in the background of chronic liver disease, caused by hepatitis B or C virus, non-alcoholic steatohepatitis (NASH), or other diseases that cause cirrhosis. Prognosis can vary dramatically based on number, size, and location of tumors. Hepatic synthetic dysfunction and performance status (PS) also impact survival. The Barcelona Clinic Liver Cancer (BCLC) staging system best accounts for these variations, providing a reliable prognostic stratification. Therapeutic considerations of this complex disease necessitate a multidisciplinary approach and can range from curative-intent surgical resection, liver transplantation or image-guided ablation to more complex liver-directed therapies like transarterial chemoembolization (TACE) and systemic therapy. Recent advances in the understanding of the tumor biology and microenvironment have brought new advances and approvals for systemic therapeutic agents, often utilizing immunotherapy or VEGF-targeted agents to modulate the immune response. This review will discuss the current landscape in the treatments available for early, intermediate, and advanced stage HCC.

Tumor biology and immune infiltration define primary liver cancer subsets linked to overall survival after immunotherapy.

Primary liver cancer is a rising cause of cancer deaths in the US. Although immunotherapy with immune checkpoint inhibitors induces a potent response in a subset of patients, response rates vary among individuals. Predicting which patients will respond to immune checkpoint inhibitors is of great interest in the field. In a retrospective arm of the National Cancer Institute Cancers of the Liver: Accelerating Research of Immunotherapy by a Transdisciplinary Network (NCI-CLARITY) study, we use archived formalin-fixed, paraffin-embedded samples to profile the transcriptome and genomic alterations among 86 hepatocellular carcinoma and cholangiocarcinoma patients prior to and following immune checkpoint inhibitor treatment. Using supervised and unsupervised approaches, we identify stable molecular subtypes linked to overall survival and distinguished by two axes of aggressive tumor biology and microenvironmental features. Moreover, molecular responses to immune checkpoint inhibitor treatment differ between subtypes. Thus, patients with heterogeneous liver cancer may be stratified by molecular status indicative of treatment response to immune checkpoint inhibitors.

Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer.

BACKGROUND: Oncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with and without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients with standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) in a phase I/II trial. METHODS: Adult patients with histologically confirmed advanced pMMR mCRC, who had progressed on at least two prior lines of systemic chemotherapy were studied in four cohorts. Patients received four doses of PexaVec IV at a dose of 3×108 plaque forming units (pfu) (dose level 1) or 1×109 pfu (dose level 2) every 2 weeks. Twelve days after the first PexaVec administration, patients received either 1500 mg of durvalumab every 28 days alone or an additional single dose of 300 mg tremelimumab on day 1. Responses were assessed every 8 weeks by CT or MRI. AEs were recorded. The primary endpoints were safety and feasibility. Secondary endpoints included progression-free survival (PFS) and overall survival. Paired tumor samples and peripheral blood were collected to perform immune monitoring. RESULTS: Thirty-four patients with mCRC enrolled on to the study: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities observed were fever and chills after PexaVec infusion. Two cases of grade 3 colitis, one case of a grade 2 myositis and one case of grade 3 hypotension resulted in discontinuation of immune checkpoint inhibitor and PexaVec treatment, respectively. The median PFS in the PexaVec/durvalumab/tremelimumab cohorts was 2.3 months (95% CI: 2.2 to 3.2 months) vs 2.1 months (95% CI: 1.7 to 2.8 months; p=0.57) in the PexaVec/durvalumab cohorts. Flow cytometry analysis of peripheral blood mononuclear cells revealed an increase in Ki67+CD8+ T cells on treatment. CONCLUSION: PexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers. TRIAL REGISTRATION NUMBER: NCT03206073.

Reciprocity heightens academic performance in elementary school students.

Social relationships are pivotal for human beings. Yet, we still lack a complete understanding of the types and conditions of social relationships that facilitate learning among children. Here, we present the results of a study involving 855 elementary school children from 14 different public schools in Chile designed to understand their social learning strategies in classrooms. We mapped students' social relationships using a behavioral experiment-a non-anonymous social dilemma-that allows us to measure cooperation and infer reciprocal and asymmetrical relationships between peers. We implemented the experiment synchronously in each classroom using networked tablets and a friendly user interface to mitigate cognitive barriers and boost students' engagement. Using regression models, we found a positive and significant association between reciprocity and academic performance. This result holds after controlling for class attendance, sex, parents' education, social status, individual cooperative dispositions, and fixed effects per class group. Finally, using a difference-in-difference framework, we found robust evidence that reciprocity heightens academic performance by comparing two consecutive academic semesters. This effect is heterogeneous and is considerably more prominent for the top 20% students experiencing higher levels of reciprocity in their social relationships. We expect these results to inform cooperative learning interventions in elementary education.

Functional Imaging of Liver Cancer (FLIC): Study protocol of a phase 2 trial of 18F-DCFPyL PET/CT imaging for patients with hepatocellular carcinoma.

BACKGROUND: While prostate specific membrane antigen (PSMA) is overexpressed in high-grade prostate cancers, it is also expressed in tumor neovasculature and other malignancies, including hepatocellular carcinoma (HCC). Importantly, no functional imaging for HCC is clinically available, making diagnosis and surveillance following local therapies particularly challenging. 18F-DCFPyL binds with high affinity to PSMA yet clears rapidly from the blood pool. PET imaging with 18F-DCFPyL may represent a new tool for staging, surveillance and assessment of treatment response in HCC. The purpose of this Functional Imaging Liver Cancer (FLIC) trial is to assess the ability of 18F-DCFPyL-PET/CT to detect sites of HCC. METHODS: This is a phase II multi-site prospective imaging trial with a plan to enroll 50 subjects with suspected HCC on standard of care CT or MRI and eligible for standard local treatment. Participants will undergo a baseline 18F-DCFPyL-PET/CT, prior to therapy. Subjects will also be scanned with 18F-FDG-PET/CT within 2 weeks of 18F-DCFPyL-PET/CT. Participants will undergo histopathologic assessment and standard of care local treatment for HCC within a multidisciplinary team context. Participants with histopathologic confirmation of HCC and a positive baseline 18F-DCFPyL-PET/CT will undergo a post-treatment 18F-DCFPyL-PET/CT during the first routine follow-up, typically within 4-8 weeks. Subjects with negative baseline 18F-DCFPyL-PET/CT will not be re-scanned after treatment but will remain in follow-up. Participants will be followed for 5-years to assess for progression-free-survival. The primary endpoint is the positive predictive value of 18F-DCFPyL-PET for HCC as confirmed by histopathology. Secondary endpoints include comparison of 18F-DCFPyL-PET/CT with CT, MRI, and 18F-FDG-PET/CT, and evaluation of the value of 18F-DCFPyL-PET/CT in assessing treatment response following local treatment. Exploratory endpoints include next generation sequencing of tumors, and analysis of extracellular vesicles to identify biomarkers associated with response to therapy. DISCUSSION: This is a prospective imaging trial designed to evaluate whether PSMA-PET/CT imaging with 18F-DCFPyL can detect tumor sites, assess local treatment response in HCC patients, and to eventually determine whether PSMA-PET/CT could improve outcomes of patients with HCC receiving standard of care local therapy. Importantly, this trial may help determine whether PSMA-selective radiopharmaceutical therapies may be beneficial for patients with HCC. CLINICAL TRIAL REGISTRATION: NIH IND#133631. Submission date: 04-07-2021. Safe-to-proceed letter issued by FDA: 05.07.2021. NIH IRB #00080. ClinicalTrials.gov Identifier NCT05009979. Date of Registry: 08-18-2021. Protocol version date: 01-07-2022.

A Phase II Study of Pembrolizumab in Combination with Capecitabine and Oxaliplatin with Molecular Profiling in Patients with Advanced Biliary Tract Carcinoma.

BACKGROUND: We conducted a phase II study of the combination of pembrolizumab with capecitabine and oxaliplatin (CAPOX) in patients with advanced biliary tract carcinoma (BTC) to assess response rate and clinical efficacy. Exploratory objectives included correlative studies of immune marker expression, tumor evolution, and immune infiltration in response to treatment. PATIENTS AND METHODS: Adult patients with histologically confirmed BTC were enrolled and received oxaliplatin and pembrolizumab on day 1 of cycles 1-6. Capecitabine was administered orally twice daily as intermittent treatment, with the first dose on day 1 and the last dose on day 14 of cycles 1-6. Starting on cycle 7, pembrolizumab monotherapy was continued until disease progression. The primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, tolerability, feasibility, and response rate. Immunohistochemistry (IHC) for PD-L1 and immune infiltrates was analyzed in paired tumor biopsies, as well as bulk transcriptome and exome profiling for five patients and single-cell RNA sequencing for one partial responder. RESULTS: Eleven patients enrolled, three of whom had received no prior systemic therapy. Treatment was well tolerated, and the most common treatment-related grade 3 or 4 adverse events were lymphocytopenia, anemia, and decreased platelet count. Three patients (27.3%) achieved a partial response, and six (54%) had stable disease. The disease control rate was 81.8%. The median PFS was 4.1 months with a 6-month PFS rate of 45.5%. Molecular profiling suggests qualitative differences in immune infiltration and clonal evolution based on response. CONCLUSION: Capecitabine and oxaliplatin in combination with pembrolizumab is tolerable and a potentially effective treatment for refractory advanced BTC. This study highlights a design framework for the precise characterization of individual BTC tumors. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (NCT03111732).

Two Milestone Studies in Liver Cancer Immunotherapy.

Immunotherapy has changed the playing field for multiple cancers, and prime time for unresectable liver cancers may be here now. This issue of NEJM Evidence includes two trials describing novel immunotherapy options for patients with biliary tract cancer and hepatocellular carcinoma. Oh et al.1 describe the results of the TOPAZ-1 trial, which resulted in improved overall survival for patients with biliary tract cancer in the frontline setting - the first real advance in more than a decade.2 Abou-Alfa et al.3 present results from the HIMALAYA study.

Clinical Indicators for Long-Term Survival with Immune Checkpoint Therapy in Advanced Hepatocellular Carcinoma.

INTRODUCTION: Patients with advanced hepatocellular carcinoma have a dismal prognosis; only a subset of patients with advanced HCC will benefit from treatment with immunotherapy. We searched for clinical characteristics predicting exceptional long-term survival in HCC patients treated with immune checkpoint inhibitors. METHODS: We compared clinical characteristics of 59 patients with advanced hepatocellular carcinoma treated with immunotherapy with and without locoregional therapy between 2013-2019. We compared patients who lived less than 12 months with patients who lived more than 3 years. Traits of short-term (31 patients) and long-term (5 patients) survivors were compared. Patients who died between 12 months and 3 years of starting treatment on protocol were not included in the analysis. RESULTS: Two out of five patients (40%) in the long-term survival group had a partial response (PR) or a complete response (CR) per the modified Response Evaluation Criteria in Solid Tumors (mRECIST), while, of the 31 patients in the short-term survival group, only 2 (6.5%) had a CR or PR. Two of the 5 patients with a long-term survival had immune-related adverse events grade 3 or 4 (IrAEs-3/4). None of the patients in the short-term survival group had IrAEs-3/4. The patients, who presented with IrAEs-3/4, which included colitis and adrenal insufficiency, continued to have a response off treatment. The median overall survival (OS) was 11.8 months (95% CI: 7.8-15.4 months), with a 12-month OS of 46.6% (95% CI: 33.4-58.8%) and a 3-year OS of 12.5% (95% CI: 5.0-23.7%). CONCLUSION: We found a possible association between immune-related adverse events grade 3 and 4 and long-term survival in patients with advanced HCC. The cases in our analysis represent extraordinary defiance of the usual predicted dismal course of advanced HCC.

Targeting signalling pathways and the immune microenvironment of cancer stem cells - a clinical update.

Cancer stem cells (CSCs) have important roles in tumour development, relapse and metastasis; the intrinsic self-renewal characteristics and tumorigenic properties of these cells provide them with unique capabilities to resist diverse forms of anticancer therapy, seed recurrent tumours, and disseminate to and colonize distant tissues. The findings of several studies indicate that CSCs originate from non-malignant stem or progenitor cells. Accordingly, inhibition of developmental signalling pathways that are crucial for stem and progenitor cell homeostasis and function, such as the Notch, WNT, Hedgehog and Hippo signalling cascades, continues to be pursued across multiple cancer types as a strategy for targeting the CSCs hypothesized to drive cancer progression - with some success in certain malignancies. In addition, with the renaissance of anticancer immunotherapy, a better understanding of the interplay between CSCs and the tumour immune microenvironment might be the key to unlocking a new era of oncological treatments associated with a reduced propensity for the development of resistance and with enhanced antimetastatic activity, thus ultimately resulting in improved patient outcomes. Herein, we provide an update on the progress to date in the clinical development of therapeutics targeting the Notch, WNT, Hedgehog and Hippo pathways. We also discuss the interactions between CSCs and the immune system, including the potential immunological effects of agents targeting CSC-associated developmental signalling pathways, and provide an overview of the emerging approaches to CSC-targeted immunotherapy.

Myocarditis in a patient treated with Nivolumab and PROSTVAC: a case report.

BACKGROUND: Immune checkpoint inhibitors have revolutionized treatment and improved survival in many cancers. However, since immune-related adverse events (irAEs) are potentially fatal, early recognition and prompt treatment are warranted. One of the rarest but most dramatic irAE is myocarditis, which has significant morbidity and mortality if not recognized and treated early. OBJECTIVE: To report the first case of myocarditis in a patient with metastatic castration-resistant prostate cancer (mCRPC) treated with a combination of nivolumab, an anti-programmed cell death protein 1 antibody, and PROSTVAC, a vector-based therapeutic prostate cancer vaccine. CASE REPORT: A 79-year-old man with mCRPC metastatic to bone and lymph nodes and a history of atrial fibrillation presented with blurred vision and pain and stiffness in the upper back after 8 weeks on a clinical trial with nivolumab (1 mg/kg) and PROSTVAC, both given every 2 weeks. Eye exam was within normal limits, while musculoskeletal exam revealed tenderness in trapezius muscles and decreased motor strength in arms (III/V) and neck (IV/V). The rest of the physical exam was within normal limits, with the exception of an irregular heart rhythm. Laboratory tests were as follows: creatinine kinase (CK) 3200 U/L (normal: 39-308 U/L), CK-MB 65.7 mcg/L (normal: 0-7.6 mcg/L), troponin I 0.209 ng/mL (normal: 0-0.056 ng/mL). Electrocardiogram (ECG) revealed atrial fibrillation with QT prolongation (QTc 514 msec) and left anterior fascicular block, unchanged from baseline. 2D-echocardiogram showed a left ventricular ejection fraction of 65% with an enlarged left atrium, dilated right ventricle, and increased pulmonary artery pressure (45 mmHg). ProBNP was elevated at 1463 pg/mL and peaked at 3066 pg/mL one day after hydration. With a presumed diagnosis of autoimmune myositis and possible myocarditis, the patient was admitted and started on methylprednisolone 1 mg/kg/day. Cardiac MRI showed elevated native myocardial T1 values consistent with myocarditis (Fig. 1). The patient was discharged on a prednisone taper after normalization of cardiac enzymes on day 4. Treatment with PROSTVAC continued for three more months; nivolumab was discontinued. Six months later, patient is doing well, with no residual cardiac damage. DISCUSSION: Cardiovascular irAEs are relatively rare (< 1%) and have a variety of clinical presentations. Myocarditis is potentially life-threatening and can range from subclinical to fulminant. Therefore, clinical suspicion, early detection, and prompt treatment are imperative (1). The initial diagnostic workup should include cardiac enzymes, ECG, and 2D-echocardiogram. The most commonly observed ECG changes are generalized repolarization abnormalities, prolonged QT interval, and conduction abnormalities (2). An elevated troponin I in the absence of overt coronary artery disease is suggestive of myocarditis and should be evaluated further. Myocardial biopsy is the standard diagnostic procedure; however, a cardiac MRI can achieve a diagnosis when biopsy is not feasible (3). Advancements in parametric mapping techniques have allowed the use of native myocardial T1 in the detection of myocarditis, as it has superior diagnostic performance and higher sensitivity than older parameters (3). Our patient had been treated with an immune checkpoint inhibitor and a therapeutic cancer vaccine to induce effective antitumor activity through immunogenic intensification and presented with muscle stiffness and elevated CK. Although he had no new cardiovascular symptoms, cardiac enzymes were tested to rule out myocardial involvement. MRI with gadolinium confirmed the diagnosis of myocarditis. To date, none of the 1360 patients treated with PROSTVAC as a single agent have developed myocarditis, while myocarditis has been rarely reported in patients treated with nivolumab (< 1%) (1). Whether the combination of PROSTVAC and nivolumab presents an additional risk of myocarditis is unclear. To our knowledge, this is the first case of myocarditis in a patient with mCRPC receiving simultaneous treatment with an immune checkpoint inhibitor and a prostate cancer vaccine. Our experience highlights the importance of suspicion and early intervention in patients who present with cardiac abnormalities after receiving cancer immunotherapy. We propose following protocol: baseline troponin, ECG, and 2D-echocardiogram prior to treatment, then repeated troponin at 2, 4, and 12 weeks post-treatment, then monthly. If troponin becomes positive without alternative explanation, myocarditis should be ruled out with cardiac MRI or myocardial biopsy, and patient should be admitted for treatment with high-dose steroids as early intervention may minimize myocardial injury.

Patients with end-stage renal disease and acute myocardial infarction have poor short-term outcomes despite modern cardiac intensive care.

OBJECTIVE: Cardiovascular disease has a tremendous impact on patients with end-stage renal disease (ESRD). We sought to describe the outcomes of patients with ESRD and acute myocardial infarction (AMI). METHODS: We analyzed consecutive AMI patients admitted to a single coronary care unit, according to the presence or absence of ESRD. Multivariate modeling was used to determine the independent relationship between ESRD and in-hospital mortality. RESULTS: Data were available for 2025 AMI patients. ESRD was present in 82 patients (4%). Coronary angiography and revascularization were used aggressively in patients with ESRD, although less than among patients without ESRD (78 vs. 91%, P<0.001; and 60 vs. 79%, P<0.001, respectively). Length of stay was longer among patients with ESRD (9.5 vs. 5.0 days, P<0.001). In-hospital death occurred in 23.2% of the patients with ESRD compared with 9.0% of patients without ESRD (P<0.001). On multivariate analysis, the presence of ESRD was independently associated with the risk of in-hospital death (odds ratio 2.6, 95% confidence intervals, 1.3-4.9, P=0.005), even after controlling for the use of revascularization. CONCLUSION: Patients with ESRD and AMI are at tremendous risk for short-term mortality despite the aggressive use of coronary revascularization and modern coronary intensive care.

Autoimmune thyroid disease and chronic urticaria.

We report six cases of autoimmune thyroid disease associated with chronic urticaria and briefly review the literature, including the histopathological nature of such lesions, and their aetiology and pathogenesis. In view of the prevalence of thyroid disease in patients with chronic urticaria, screening measurements of thyrotropin and anti-thyroperoxidase antibodies are recommended, although negative antibodies do not exclude a relationship between urticaria and thyroid autoimmunity. After failure of conventional therapy for urticaria, patients who are apparently clinically euthyroid may be considered for a trial with levothyroxine. Improvement of urticaria was seen with levothyroxine treatment in three of four patients with only marginal abnormalities in thyroid function.

[Frequency of antibodies against rubella virus in puerperium women]. / Frecuencia de anticuerpos frente al virus de la rubéola en mujeres en posparto inmediato.

BACKGROUND: The significance of clinical and epidemiological rubella lies in its teratogenic effects on fetus; thus, rubella and congenital rubella represent great public health problems. OBJECTIVES: To determine the frequency of antibodies against rubella virus in early puerperium women, and to identify factors related to the absence of immunity against it. MATERIAL AND METHODS: During the period 2000-2002, a cross-sectional study was conducted. Women in puerperium period, residents of urban and rural areas of Delicias, Chihuahua, Mexico, were included. Women were interviewed and asked about factors that have been associated with the absence of immunity against rubella virus such as age, schooling, number of gestations, and residence area. We collected a blood sample between 1 and 6 hours after delivery, and anti-rubella IgG was determined. RESULTS: 396 patients aged 24 +/- 6 years were studied. The frequency of antibodies against rubella virus was of 87% (CI 95% 84-90). The factors related to the absence of antibodies against rubella were: number of gestations and schooling; patients whose pregnancy was the first or second gestation had a smaller frequency of antibodies against rubella virus (84%) compared to those with two previous gestations (95%, p = 0.03). CONCLUSION: The observed frequency of antibodies of rubella virus in this population is smaller than the informed one in industrialized countries. It is recommended to reinforce procedures of vaccination for susceptible women and after delivery, in order to prevent the infection consequences, as well as routinely carry out tests for detection of antibodies against rubella like protocol of premarital study.