Prospective investigation of amino acid transport and PSMA-targeted positron emission tomography for metastatic lobular breast carcinoma.

PURPOSE: To explore the feasibility of imaging amino-acid transport and PSMA molecular pathways in the detection of metastatic breast invasive lobular carcinoma (ILC) and if there is superior detection compared to standard-of-care imaging [computed tomography (CT)/bone scan, or 18F-FDG positron-emission-tomography (PET)-CT]. METHODS: 20 women with de-novo or suspected metastatic ILC underwent two PET-CT scans with 18F-fluciclovine and 68Ga-PSMA-11 on separate days. Uptake per patient and in 3 regions per patient - ipsilateral axillary lymph node (LN), extra-axillary LN (ipsilateral supraclavicular or internal mammary), or distant sites of disease - was compared to standard-of-care imaging (CT/bone scan in 13 patients and 18F-FDG PET-CT in 7 patients). Results were correlated to a composite standard of truth. Confirmed detection rate (cDR) was compared using McNemar's test. Mean SUVmax of 18F-fluciclovine and 68Ga-PSMA-11 in the most avid lesion for each true positive metastatic region and intact primary lesion were compared by t-test. RESULTS: The cDR for standard-of-care imaging was 5/20 patients in 5/60 regions. 68Ga-PSMA-11 PET-CT detected metastasis in 7/20 patients in 7/60 regions. 18F-fluciclovine PET-CT detected metastasis in 9/20 patients in 12/60 regions. The cDR for 18F-fluciclovine PET-CT was significantly higher versus standard-of-care imaging on the patient and combined region levels, while there were no significant differences between 68Ga-PSMA-11 and standard-of care imaging. 18F-fluciclovine cDR was also significantly higher than 68Ga-PSMA-11 on the combined region level. Mean SUVmax for true positive metastatic and primary lesions with 18F-fluciclovine (n = 18) was significantly greater than for 68Ga-PSMA-11 (n = 11) [5.5 ± 1.8 versus 3.5 ± 2.7 respectively, p = 0.021]. CONCLUSION: In this exploratory trial, 18F-fluciclovine PET-CT has a significantly higher cDR for ILC metastases compared to standard-of-care imaging and to 68Ga-PSMA-11. Mean SUVmax for true positive malignancy was significantly higher with 18F-fluciclovine than for 68Ga-PSMA-11. Exploratory data from this trial suggests that molecular imaging of amino acid metabolism in patients with ILC deserves further study. CLINICAL TRIAL REGISTRATION: Early phase (I-II) clinical trial (NCT04750473) funded by the National Institutes of Health (R21CA256280).

Real-world use patterns, effectiveness, and tolerability of sacituzumab govitecan for second-line and later-line treatment of metastatic triple-negative breast cancer in the United States.

PURPOSE: Patients with metastatic triple-negative breast cancer (mTNBC) have poor prognosis and limited treatment options. Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is approved for patients with mTNBC who have received ≥ 2 systemic therapies (≥ 1 in the metastatic setting) based on the ASCENT study (NCT02574455). The current study describes real-world SG use and outcomes in patients with mTNBC in the United States. METHODS: This retrospective, observational study included adult patients with mTNBC from the ConcertAI Patient360™ database who received SG in the second line (2L) and later from April 2020 to May 2022. SG use patterns, effectiveness, and tolerability are described. RESULTS: This analysis included 230 patients (median age 60 years, 26% Black, 17% with ECOG performance status ≥ 2, 66% in community settings; median of 2 prior lines of treatment in the metastatic setting); median follow-up was 7.2 months. Median (95% CI) real-world overall survival was 10.0 (8.3-11.1) months for all patients and 13.9 (9.8-not estimable) months in the 2L subgroup (n = 77). Granulocyte-colony stimulating factor (G-CSF) was administered concomitantly with SG in 134 (58%) patients; 35 (15%) received G-CSF for the first time. Median (IQR) time from SG start to G-CSF use was 8.5 (8.0-29.0) days. Seventeen (7%) patients discontinued SG due to toxicity. CONCLUSIONS: Using a real-world, ethnically diverse population of patients with mTNBC presenting with poor prognosis, these data reinforced the findings from ASCENT. In routine clinical practice, SG is an effective treatment in the 2L setting, consistent with treatment guidelines.

Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) metastatic breast cancer: prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice.

BACKGROUND: The treatment landscape for HR(+)HER2(-) metastatic breast cancer (MBC) is evolving for patients with ESR1 mutations (mut) and PI3K/AKT pathway genomic alterations (GA). We sought to inform clinical utility for comprehensive genomic profiling (CGP) using tissue (TBx) and liquid biopsies (LBx) in HR(+)HER2(-) MBC. METHODS: Records from a de-identified breast cancer clinicogenomic database for patients who underwent TBx/LBx testing at Foundation Medicine during routine clinical care at ~ 280 US cancer clinics between 01/2011 and 09/2023 were assessed. GA prevalence [ESR1mut, PIK3CAmut, AKT1mut, PTENmut, and PTEN homozygous copy loss (PTENloss)] were calculated in TBx and LBx [stratified by ctDNA tumor fraction (TF)] during the first three lines of therapy. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared between groups by Cox models adjusted for prognostic factors. RESULTS: ~ 60% of cases harbored 1 + GA in 1st-line TBx (1266/2154) or LBx TF ≥ 1% (80/126) and 26.5% (43/162) in LBx TF < 1%. ESR1mut was found in 8.1% TBx, 17.5% LBx TF ≥ 1%, and 4.9% LBx TF < 1% in 1st line, increasing to 59% in 3rd line (LBx TF ≥ 1%). PTENloss was detected at higher rates in TBx (4.3%) than LBx (1% in TF ≥ 1%). Patients receiving 1st-line aromatase inhibitor + CDK4/6 inhibitor (n = 573) with ESR1mut had less favorable rwPFS and rwOS versus ESR1 wild-type; no differences were observed for fulvestrant + CDK4/6 inhibitor (n = 348). CONCLUSION: Our study suggests obtaining TBx for CGP at time of de novo/recurrent diagnosis, followed by LBx for detecting acquired GA in 2nd + lines. Reflex TBx should be considered when ctDNA TF < 1%.

Pharmacological suppression of the OTUD4/CD73 proteolytic axis revives antitumor immunity against immune-suppressive breast cancers.

Despite widespread utilization of immunotherapy, treating immune-cold tumors remains a challenge. Multiomic analyses and experimental validation identified the OTUD4/CD73 proteolytic axis as a promising target in treating immune-suppressive triple negative breast cancer (TNBC). Mechanistically, deubiquitylation of CD73 by OTUD4 counteracted its ubiquitylation by TRIM21, resulting in CD73 stabilization inhibiting tumor immune responses. We further demonstrated the importance of TGF-ß signaling for orchestrating the OTUD4/CD73 proteolytic axis within tumor cells. Spatial transcriptomics profiling discovered spatially resolved features of interacting malignant and immune cells pertaining to expression levels of OTUD4 and CD73. In addition, ST80, a newly developed inhibitor, specifically disrupted proteolytic interaction between CD73 and OTUD4, leading to reinvigoration of cytotoxic CD8+ T cell activities. In preclinical models of TNBC, ST80 treatment sensitized refractory tumors to anti-PD-L1 therapy. Collectively, our findings uncover what we believe to be a novel strategy for targeting the immunosuppressive OTUD4/CD73 proteolytic axis in treating immune-suppressive breast cancers with the inhibitor ST80.

Monitoring of Triple Negative Breast Cancer After Neoadjuvant Chemotherapy.

Triple negative breast cancer (TNBC) is an aggressive disease with a poor prognosis that disproportionately affects young women and African Americans, and represents a major unmet need in the field. TNBCs display a more aggressive growth pattern with an increased risk of advanced disease and high recurrence risk in patients with early stage TNBC. The addition of immunotherapy to chemotherapy for the treatment of patients with early stage TNBC in the (neo) adjuvant setting per the pivotal KEYNOTE 522 significantly improved pCR rates. Despite this advancement, however, approximately 35% of patients had residual disease at the time of surgery and reduced event free survival. Further techniques to assess for molecular residual disease after completion of neoadjuvant chemotherapy (NAC) may allow us to identify patients at high risk of relapse who may benefit from salvage adjuvant systemic therapy, while also potentially de-escalating treatment in those achieving a molecular complete response.

A Discordant Pattern of Uptake on 68 Ga-PSMA PET/CT Versus 18 F-Fluciclovine PET/CT in Radiation-Induced Hepatitis : Implications for Early Postradiotherapy Imaging-Based Response Assessment.

ABSTRACT: A 62-year-old woman with right-sided invasive lobular breast carcinoma completed external beam radiotherapy 6 weeks before undergoing a 68 Ga-PSMA PET/CT and 18 F-fluciclovine PET/CT scan as part of an ongoing clinical trial (NCT04750473) assessing the performance of these molecular imaging modalities in invasive lobular breast carcinoma. The 68 Ga-PSMA PET/CT demonstrated a band-like area of increased radiotracer uptake in the dome of the right lobe of the liver anteriorly, whereas 18 F-fluciclovine PET/CT done a day later revealed photopenia in the corresponding area of the liver. The external beam radiotherapy plan confirmed that the radiotherapy field overlaid the region of the hepatic discordant radiotracer uptake on the PET/CT scans.

A Tale of 3 Tracers: Contrasting Uptake Patterns of 18F-Fluciclovine, 68Ga-PSMA, and 18F-FDG in the Uterus and Adnexa.

ABSTRACT: A 41-year-old woman with invasive lobular carcinoma of the breast underwent sequential 68Ga-PSMA-11 PET/CT and 18F-fluciclovine PET/CT as part of an ongoing clinical trial (NCT04750473). 68Ga-PSMA PET/CT showed increased radiotracer uptake in the uterine endometrium and left adnexa. 18F-fluciclovine PET/CT showed increased radiotracer uptake in a leiomyomatous uterus. A clinical 18F-FDG PET/CT demonstrated radiotracer uptake in the endometrium and a circumferential area of uptake in the left adnexa, a pattern more similar to the 68Ga-PSMA uptake pattern. This case highlights the discordance in the uptake pattern of 2 radiotracers approved for prostate cancer imaging but increasingly used in non-prostate malignancies imaging.

Racial Disparities in Clinical Outcomes on Investigator-Initiated Breast Cancer Clinical Trials at an Urban Medical Center.

BACKGROUND: Black women are 40% more likely to die of breast cancer compared to White women. Inadequate representation of Black patients in clinical trials may contribute to health care inequity. We aimed to assess breast cancer clinical outcomes in Non-Hispanic Black (Black) versus Non-Hispanic White (White) women with metastatic breast cancer (MBC) enrolled on investigator-initiated clinical trials at Winship Cancer Institute at Emory University, given the significant number of patients from underrepresented minority groups seen at Winship. MATERIALS AND METHODS: Black and White women with MBC on investigator-initiated trials at Emory between 2009 and 2019 were retrospectively evaluated. Univariate analyses and multiple logistic regression models were used to assess clinical response and treatment toxicities. Differences in overall survival between groups was assessed using quantile analysis. RESULTS: Sixty-two women with MBC were included (66% White vs. 34% Black). Black patients had less clinical benefit from the trial therapy as only 57% had partial response or stable disease as best response compared to 78% of White women (P = .09). Quantile analysis showed significant difference in mean survival between Whites and Blacks by the end of follow up (64 vs. 38 months). There were no significant differences in toxicities between groups. CONCLUSION: Participation rates of Black women with MBC on investigator-initiated clinical trials at an urban cancer center were higher compared to key national trials. Black women had worse treatment response and survival. These results reinforce the need for assessment of tumor differences by ancestry and continued improvement in minority representation on clinical trials.

Spatially variant immune infiltration scoring in human cancer tissues.

The Immunoscore is a method to quantify the immune cell infiltration within cancers to predict the disease prognosis. Previous immune profiling approaches relied on limited immune markers to establish patients' tumor immunity. However, immune cells exhibit a higher-level complexity that is typically not obtained by the conventional immunohistochemistry methods. Herein, we present a spatially variant immune infiltration score, termed as SpatialVizScore, to quantify immune cells infiltration within lung tumor samples using multiplex protein imaging data. Imaging mass cytometry (IMC) was used to target 26 markers in tumors to identify stromal, immune, and cancer cell states within 26 human tissues from lung cancer patients. Unsupervised clustering methods dissected the spatial infiltration of cells in tissue using the high-dimensional analysis of 16 immune markers and other cancer and stroma enriched labels to profile alterations in the tumors' immune infiltration patterns. Spatially resolved maps of distinct tumors determined the spatial proximity and neighborhoods of immune-cancer cell pairs. These SpatialVizScore maps provided a ranking of patients' tumors consisting of immune inflamed, immune suppressed, and immune cold states, demonstrating the tumor's immune continuum assigned to three distinct infiltration score ranges. Several inflammatory and suppressive immune markers were used to establish the cell-based scoring schemes at the single-cell and pixel-level, depicting the cellular spectra in diverse lung tissues. Thus, SpatialVizScore is an emerging quantitative method to deeply study tumor immunology in cancer tissues.

Mass spectrometry-based serum proteomic signature as a potential biomarker for survival in patients with non-small cell lung cancer receiving immunotherapy.

BACKGROUND: VeriStrat test is a serum assay which uses a mass spectrometry (MS)-based proteomic signature derived from machine learning. It is currently used as a prognostic marker for patients with non-small cell lung cancer (NSCLC) receiving chemotherapy. However, little is known about its role for NSCLC patients receiving immune checkpoint inhibitors (ICIs). METHODS: This is a retrospective study that includes 47 patients with advanced stage NSCLC without an activating EGFR mutation, who underwent the VeriStrat test from 2016 to 2018. Spectra from blood samples were evaluated to assign patients into the VeriStrat 'Good' (VS-G) or VeriStrat 'Poor' (VS-P) risk group. The clinical outcomes of 32 patients who received programmed cell death 1 (PD-1) inhibitors nivolumab or pembrolizumab were analyzed by VeriStrat status. RESULTS: The VS-G group demonstrated significantly higher progression-free survival (PFS) and overall survival (OS) compared to the VS-P group among overall NSCLC patients regardless of treatment (median PFS of 7.1 vs. 4.2 months, P=0.013, and median OS, not reached vs. 17.2 months, P=0.012). Among NSCLC patients treated with ICIs, VS-G classification was associated with significantly increased PFS in comparison to VS-P classification (median PFS of 6.2 vs. 3.0 months, P=0.012), while the differences in OS trended towards significance (median OS, not reached vs. 16.5 months P=0.076). Multivariate analysis showed that the VeriStrat status was significantly correlated with PFS and OS in NSCLC patients treated with ICIs (P=0.017, P=0.034, respectively). CONCLUSIONS: MS-based serum proteomic signature has potential as a biomarker for survival outcome in NSCLC patients receiving immunotherapy.

Is Routine Recurrence Score Testing in Patients Older than 70 Years of Age Warranted? An Evaluation of the National Cancer Database After TAILORx.

BACKGROUND: Recurrence score (RS) testing in early-stage, ER-positive breast cancer is used to predict the benefit of adjuvant chemotherapy for disease recurrence and overall survival. TAILORx results decreased the ambiguity of "intermediate risk" RS by creating a binary classification system. We aimed to determine how women ≥ 70 years with intermediate RS were redistributed post-TAILORx and to identify predictors of low RS. METHODS: Patients ≥ 70 years with early-stage, node-negative, ER-positive breast cancers in the National Cancer Database(2006-2014) were included. "Pre-TAILORx" RS were classified as low (0-17), intermediate (18-30), and high (> 30). "Post-TAILORx" RS were classified as low (0-25) and high (> 25). RESULTS: In total, 14,925 women were included. Average age was 74 years. 60% (n = 9009) had low pre-TAILORx RS, 31% (n = 4635) intermediate, and 9% (n = 1281) high. Of 4635 patients with intermediate RS, 72% (n = 3660) were reclassified to low RS. Only 12% (n = 1783) of patients received chemotherapy. Of patients with pre-TAILORx intermediate RS who received chemotherapy, 55% (n = 417) would have been spared chemotherapy by being reclassified with low RS post-TAILORx. The strongest predictor of post-TAILORx low RS was tumor grade; 95% of well-differentiated had low RS, compared with 56% of poorly/undifferentiated tumors (p < 0.001). Smaller tumor size also was associated with low RS. Age was not associated with RS. CONCLUSIONS: With post-TAILORx RS criteria, the vast majority of patients ≥ 70 years can be classified as low-risk and unlikely to benefit from chemotherapy. Given that the elderly have greater rates of chemotherapy-associated complications, reconsideration of routine RS testing in patients ≥ 70 years is warranted. Tumor grade and size also may inform the decision to omit RS testing.

Systematic review and meta-analysis of selected toxicities of approved ALK inhibitors in metastatic non-small cell lung cancer.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) inhibitors are the mainstay treatment for patients with non-small cell lung carcinoma (NSCLC) harboring a rearrangement of the ALK gene or the ROS1 oncogenes. With the recent publication of pivotal trials leading to the approval of these compounds in different indications, their toxicity profile warrants an update. MATERIALS AND METHODS: A systematic literature search was performed in July 2017. Studies evaluating US FDA approved doses of one of the following ALK inhibitors: Crizotinib, Ceritinib, Alectinib or Brigatinib as monotherapy were included. Data were analyzed using random effects meta-analysis for absolute risks (AR), study heterogeneity, publication bias and differences among treatments. RESULTS: Fifteen trials with a total of 2,005 patients with evaluable toxicity data were included in this report. There was significant heterogeneity amongst different studies. The pooled AR of death and severe adverse events were 0.5% and 34.5%, respectively. Grade 3/4 nausea, vomiting, diarrhea, and constipation were uncommon: 2.6%, 2.5%, 2.7%, 1.2%, respectively. CONCLUSIONS: ALK inhibitors have an acceptable safety profile with a low risk of treatment-related deaths. Important differences in toxicity profile were detected amongst the different drugs.

Effect of Aromatase Inhibitor Therapy on Sleep and Activity Patterns in Early-stage Breast Cancer.

INTRODUCTION: Adherence to aromatase inhibitor (AI) therapy is poor, often because of treatment-emergent side effects, including musculoskeletal symptoms, fatigue, and insomnia. In the present analysis, we examined the sleep patterns and daytime function both objectively using actigraphy and subjectively using validated questionnaires in women initiating AI therapy. PATIENTS AND METHODS: Postmenopausal women with stage 0-III hormone receptor-positive breast cancer who were initiating AI therapy were eligible. The patients wore actigraphy devices for 10 consecutive days and completed questionnaires at baseline before the initiation of AI and after 3 months of AI therapy. Associations between the baseline demographics and symptoms, changes in patient-reported outcomes and actigraphy measures from baseline to 3 months of AI therapy and discontinuation of AI therapy were examined using sign tests, logistic regression models, Spearman's correlation, and linear mixed models. RESULTS: Forty-two patients (86%) completed the baseline assessments and 23 patients (47%) completed both the baseline and the 3-month assessments. Objectively measured daytime function as measured by total daytime activity decreased during the 3 months after starting AI (232,566 activity count vs. 204,205 activity count; P = .023), and the decrease was more evident in women with higher baseline physical function. Reduced daytime activity correlated with increased fatigue (ρ = -0.49; P = .017). CONCLUSION: Daytime function decreased after initiation of AI therapy and correlated moderately with increased fatigue, although no association was identified with changes in pain or sleep quality. Additional studies are required to understand why function is reduced, which could have implications for interventions to improve patient tolerance of, and persistence with, AI therapy.

Cancer immunotherapy in a neglected population: The current use and future of T-cell-mediated checkpoint inhibitors in organ transplant patients.

Although the indications for immune checkpoint inhibitors continue to grow, organ transplant recipients with advanced malignancies have been largely excluded from clinical trials testing the safety and efficacy of these therapies given their need for chronic immunosuppression and the risk of allograft rejection. With the rapid growth of transplant medicine and the increased risk of malignancy associated with chronic immunosuppression, it is critical that we systematically analyze the available data describing immune checkpoint blockade in the organ transplant population. Herein we provide a current and comprehensive review of cases in which immune checkpoint blockade was used on organ transplant recipients. Furthermore, we discuss the differences in efficacy and risk of allograft rejection between CTLA-4 and PD-1 inhibitors and make recommendations based on the limited available clinical data. We also discuss the future of immune checkpoint blockade in this subpopulation and explore the emerging data of promising combination therapies with mTOR, BRAF/MEK, and BTK/ITK inhibitors. Further clinical experience and larger clinical trials involving immune checkpoint inhibitors, whether as monotherapies or combinatorial therapies, will help develop regimens that optimize anti-tumor response and minimize the risk of allograft rejection in organ transplant patients.

Extended Endocrine Therapy: Is 5 Years Enough?

PURPOSE OF REVIEW: Women with hormone receptor (HR)-positive breast cancer remain at risk for cancer recurrence for decades. In this review, we address recent data regarding the benefits and risks of extended endocrine therapy. RECENT FINDINGS: Ten years of treatment with either tamoxifen or an aromatase inhibitor resulted in superior disease-free survival compared to 5 years of treatment. However, there are risks associated with extended therapy with either class of medication. Multiparameter genetic tests are in development to individualize the risk of late breast cancer recurrence and predict benefit from extended endocrine treatment. Extended endocrine therapy is a promising strategy to reduce breast cancer recurrence in women with HR-positive breast cancer. This approach should be considered based on individual risk of cancer recurrence compared to potential benefit, comorbidities, and tolerance of therapy.

An update on the risk prediction and prevention of anticancer therapy-induced cardiotoxicity.

PURPOSE OF REVIEW: Cardiotoxicity is a well established complication of anticancer therapy. As cancer survivorship and life expectancy for cancer patients improves, the morbidity and mortality of anticancer therapy-related cardiotoxicity has become more problematic. It is of utmost importance to identify patients at the highest risk for the development of cardiotoxicity and to determine strategies for prevention, early detection and treatment. RECENT FINDINGS: Clinical risk factors, biomarkers, advanced cardiac imaging and pharmacogenomics may be used to classify patients at risk for therapy-induced cardiotoxicity. A much broader armamentarium of imaging modalities for risk prediction, in addition to simple two-dimensional echocardiogram and radionucleotide angiography, has also shown clinical utility in identifying early-onset cardiotoxicity and areas of reversible myocardial injury. Exciting new research aimed at predicting cardiotoxicity and developing cardioprotective strategies may lead to changes in the administration of cardiotoxic chemotherapies. SUMMARY: Personalized assessments of the risks and benefits of therapy should be used as opposed to standardized dosing and schedules. Patients at higher risk for cardiotoxicity should receive closer monitoring, cardioprotective agents, dose adjustment or alternative regimens in an effort to reduce cardiovascular morbidity and mortality. Future research will hopefully define specific risk prediction tools and clinical protocols to prevent irreversible cardiotoxicity.

Cardiovascular toxicity of biologic agents for cancer therapy.

There has been significant progress in the development of new anticancer therapies over the last decade.Targeted therapies, including anti-human epidermal growth factor receptor 2 agents, vascular endothelial growth factor inhibitors, and tyrosine kinase inhibitors, have been important components of current treatment strategies. However, many of these therapies have been associated with chemotherapy-related cardiac dysfunction. While newer targeted agents provide "on-target" anticancer activity, their "off-target" drug effects encompass a wide range of cardiovascular toxicities. Many of these toxicities are reversible, but they may limit the use and length of treatment and compromise its efficacy. Oncologists are often the first to diagnose chemotherapy-related cardiac dysfunction, although patients with advanced cardiotoxicity are referred to cardiologists for further care. The field of cardio-oncology has emerged as a necessary discipline to address these disabling complications. In order to prevent late-stage cardiotoxicity, an early collaborative effort between oncologists and cardiologists is warranted to risk-stratify patients prior to therapy and to treat at the earliest signs of cardiotoxicity. It is therefore of utmost importance for oncologists to be aware of the cardiotoxicities of anticancer therapies, and to be familiar with modifiable risk factors and early interventions that can prevent long-term cardiac damage.

Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events.

UNLABELLED: Nonalcoholic steatohepatitis (NASH) is an independent predictor of coronary artery disease (CAD). Our aim was to compare the incidence of cardiovascular (CV) events between patients transplanted for NASH and alcohol (ETOH)-induced cirrhosis. This is a retrospective cohort study (August 1993 to March 2010) of 242 patients (115 NASH and 127 ETOH) with ≥12 months follow-up after liver transplantation (LT). Those with hepatocellular carcinoma or coexisting liver diseases were excluded. Kaplan-Meier's and Cox's proportional hazard analyses were conducted to compare survival. Logistic regression was used to calculate the likelihood of CV events, defined as death from any cardiac cause, myocardial infarction, acute heart failure, cardiac arrest, arrhythmia, complete heart block, and/or stroke requiring hospitalization <1 year after LT. Patients in the NASH group were older (58.4 versus 53.3 years) and were more likely to be female (45% versus 18%; P < 0.001). They were more likely to be morbidly obese (32% versus 9%), have dyslipidemia (25% versus 6%), or have hypertension (53% versus 38%; P < 0.01). On multivariate analysis, NASH patients were more likely to have a CV event <1 year after LT, compared to ETOH patients, even after controlling for recipient age, sex, smoking status, pretransplant diabetes, CV disease, and the presence of metabolic syndrome (26% versus 8%; odds ratio = 4.12; 95% confidence interval = 1.91-8.90). The majority (70%) of events occurred in the perioperative period, and the occurrence of a CV event was associated with a 50% overall mortality. However, there were no differences in patient, graft, or CV mortality between groups. CONCLUSIONS: CV complications are common after LT, and NASH patients are at increased risk independent of traditional cardiac risk factors, though this did not affect overall mortality.

Challenges of multiple mutations in individual patients with haemophilia.

Multiple mutations in the same gene within a haemophilia family are being increasingly reported and raise many issues with regard to the specificity of the mutations in causing the disease. In a proportion of families with multiple mutations, discordant phenotypic severity is often observed among the affected members. Understanding whether these mutations influence additively or non-additively the structure, stability and function of the protein will help in a better clinical evaluation of these patients. In case of haemophilia A, out of 2740 entries, ten are double mutants. Among the 2891 patient entries in the Haemophilia B mutation database, there are 34 double mutants and one triple mutant. The major challenge in patients with multiple mutations lies in genetic diagnosis and counselling especially in developing countries wherein the entire gene is not being sequenced and the screening is stopped as soon as the mutation is identified. As of now, the presence of multiple mutations stresses the importance of additional DNA testing in patients with known mutations who have unusual phenotypes or additional, unexplained clinical problems, until more cost-effective techniques for screening the entire gene are identified.