Unselected Cohort Of Patients Research Articles

Molecular profiling of 888 pediatric tumors informs future precision trials and data-sharing initiatives in pediatric cancer

To inform clinical trial design and real-world precision pediatric oncology practice, we classified diagnoses, assessed the landscape of mutations, and identified genomic variants matching trials in a large unselected institutional cohort of solid tumors patients sequenced at Dana-Farber / Boston Children’s Cancer and Blood Disorders Center. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel. Diagnoses were classified according to the International Classification of Diseases for Oncology (ICD-O-3.2). Over 6.5 years, 888 pediatric cancer patients with 95 distinct diagnoses had successful tumor sequencing. Overall, 33% (n = 289/888) of patients had at least 1 variant matching a precision oncology trial protocol, and 14% (41/289) were treated with molecularly targeted therapy. This study highlights opportunities to use genomic data from hospital-based sequencing performed either for research or clinical care to inform ongoing and future precision oncology clinical trials. Furthermore, the study results emphasize the importance of data sharing to define the genomic landscape and targeted treatment opportunities for the large group of rare pediatric cancers we encounter in clinical practice.

Effectiveness and safety of an innovative silicone extender in suture reinforcement or dermatotraction: a retrospective study.

Multiple techniques are available for closing skin defects, such as skin grafts, flaps and tissue expansion. The tissue extender MID SEW (MID, France) was developed to achieve dermatotraction or suture reinforcement. The aim of this study was to evaluate the effectiveness and safety of this innovative silicone extender for large surgical wounds. A single-centre retrospective and observational study on an unselected consecutive cohort of patients treated with a tissue extender was conducted. Indications, initial and final wound surfaces, and adverse events (AEs) were retrieved from electronic medical records. The main outcome measure was the time to complete wound closure. We identified 50 patients from July 2017 to December 2018. Patients underwent cutaneous tumour-wide excision (n=44), or pilonidal disease surgical treatment (n=6). The average initial wound area was 53.3±42.4cm2. Healing was complete, without secondary dehiscence, within the first seven days after device withdrawal for 41 patients (82%). At least one AE was experienced by eight patients (16%) during the study period: five inflammation; five wound dehiscence; two skin necrosis; and one pain. This case series suggests that the tissue extender may be effective and safe in its dermatotraction and suture reinforcement indications in the treatment of large wounds after wide excision of skin cancer or treatment of pilonidal disease. This work was supported in part by the Hospices Civils de Lyon, France and in part by the University Claude Bernard Lyon 1, France. OB co-owns the patent on the MID SEW system. The authors have no other conflicts of interest to declare.

Germline Pathogenic Variants of Cancer Predisposition Genes in a multicentre Italian cohort of Pancreatic Cancer patients

Background and aimGermline BRCA1-2 test is routinely recommended in Pancreatic Cancer (PC) patients, due to its clinical-epidemiological relevance. Data on the prevalence of germline pathogenic variants (gPV) in other cancer predisposition and DNA Damage Repair (DDR) system-related genes in unselected PC cases are sparce in Italy. We assessed this prevalence in a multicentre cohort, to derive recommendations for PC patients. MethodsClinical data of 1200 consecutive PC patients, of any age and stage, tested with a multigene germline panel were collected. A descriptive analysis of gPV frequency and clinical variables was performed both in 1092 patients tested for an 18 genes core-panel (CP-18 cohort) and in 869 patients screened only for CDKN2A. Results11.5% (126/1092) of CP-18 cohort patients harbored a gPV in ≥1 gene. Highest gPV frequencies were detected in ATM (3.1%), BRCA2 (2.9%), BRCA1 (1.6%), CHEK2 (1.1%). Patients harboring any CP-18 gene and BRCA1-2 gPV were younger and with a higher rate of personal (PH) or family history (FH) of cancer when compared to no gPV patients. The risk of having a gPV was ≥7% in all subgroups of patients, including those aged >73, with tumor stage I-III and negative FH/PH. CDKN2A gPV were detected in 2.6% (23/869) of patients. ConclusionsA remarkable prevalence of gPV in cancer predisposition and DDR genes is reported in this large multicentre cohort of consecutive and unselected PC patients. Therefore, we recommend multigene germline testing (at least including BRCA1-2, ATM, CDKN2A, PALB2) for all PC patients, irrespective of age, stage, PH/FH.

Percutaneous left atrial appendage closure using a novel occlusion device for thromboembolic prevention: 3-year procedural experience

Abstract Background Stroke due to atrial fibrillation has been associated with a high risk of disability and mortality. Percutaneous left atrial appendage (LAA) closure has been established as a treatment strategy for stroke prevention in patients not eligible for oral anticoagulation as well as in patients after electrical isolation of the LAA and subsequent increased risk of thrombus formation. The aim of this study was to evaluate the feasibility and initial experience of LAA closure using a novel nitinol-based, self-expanding system in an unselected patient cohort. Methods and Results One hundred and two patients (39% female, median age 75 [71;80], median CHA2DS2-VASc score 5 [4;6]) underwent LAA closure with the novel system between October 2020 and October 2023. 61/102 (61%) patients underwent previous electrical LAA isolation, 30/102 (29%) patients had high bleeding risk as an indication for LAA closure. Median procedure time was 45 [38;59] minutes and median fluoroscopy time was 10 [7;12] minutes. Successful LAA closure was achieved in all patients, despite different LAA anatomies. Median umbrella and cover disc diameter were 22 [20;24] millimeter and 28 [20;24] millimeter, respectively. Procedure-related adverse events occurred in 2/111 (1.8%) patients. One patient had a vascular complication at the puncture site and another patient had non-hemodynamically significant pericardial effusion. Overall, the patients stayed for a median of 2 [1;4] days in hospital. Conclusion Left atrial appendage closure with a novel nitinol-based, self-expanding system is feasible and safe. LAA isolation was the most common indication for LAA closure at our institution. Further studies are needed, to identify differences and potential advantages of different LAA closure systems.

Incidental and anticipated arrhythmic diagnoses in patients with an implantable cardiac monitor.

In this study, we investigated a cohort of unselected patients with various indications for an implantable cardiac monitor (ICM). Our main objectives were to determine the incidence of arrhythmic diagnoses, both anticipated and incidental in relation to the ICM indication, and to assess their clinical relevance. We examined remote monitoring transmissions from patients with an ICM at four Italian sites to identify occurrences of cardiac arrhythmias. Concurrently, we collected data on medical actions taken in response to arrhythmic findings. The study included 119 patients, with a median follow-up period of 371 days. ICM indications were syncope/presyncope (46.2%), atrial fibrillation management (31.1%), and cryptogenic stroke (22.7%). In the atrial fibrillation management group, atrial fibrillation was the most common finding, with an incidence of 36% [95% confidence interval (CI) 22-55%] at 18 months. Rates of atrial fibrillation were not significantly different between patients with cryptogenic stroke and syncope/presyncope [17% (95% CI 7-40%) vs. 8% (95% CI 3-19%), P = 0.229].For patients with cryptogenic stroke, the incidence of asystole and bradyarrhythmias at 18 months was 23% (95% CI 11-45%) and 42% (95% CI 24-65%), respectively, similar to estimates obtained for patients implanted for syncope/presyncope ( P = 0.277 vs. P = 0.836).Overall, 30 patients (25.2%) required medical intervention following ICM-detected arrhythmias, predominantly involving atrial fibrillation ablation (10.9%) and medication therapy changes (10.1%). In a real-life population with heterogeneous insertion indications, approximately 25% of patients received ICM-guided medical interventions within a short timeframe, including treatments for incidental findings. Common incidental arrhythmic diagnoses were bradyarrhythmias in patients with cryptogenic stroke and atrial fibrillation in patients with unexplained syncope.

Sequelae Treatment Needs Following Peripheral Facial Palsy: Retrospective Analysis of 525 Patients.

This study uses retrospective longitudinal data from a large unselected cohort of patients with peripheral facial paralysis to determine the prevalence and patient characteristic predictors of sequelae receiving intervention. Retrospective case review. Karolinska University Hospital in Stockholm Sweden serves as the only tertiary facial palsy center in the region. Here, patients are diagnosed, are followed up, and undergo all major interventions. All adult patients presenting with peripheral facial palsy due to idiopathic, zoster, or Borrelia origin at Karolinska, January 1, 2010 to December 31, 2011 with follow-up until December 2022. Patient charts were studied to identify patient characteristics, etiology, initial treatment, severity of palsy, and treatments targeting sequelae. Types of initial and late treatments were noted. Sunnybrook and/or House-Brackmann scales were used for palsy grading. Five hundred twenty-five patients were included. Thirty-three patients (6.3%) received botulinum toxin injections and/or surgical treatment. In this subgroup, 67% received corticosteroids compared to 85% of all patients ( p = 0.005), cardiovascular disease prevalence was higher (23 and 42%, respectively, p = 0.009). For 81 patients (15%), follow-up was discontinued although the last measurement was Sunnybrook less than 70 or House-Brackmann 3 to 6. Of patients with peripheral facial palsy, 6.3% underwent injections and/or surgical treatment within 12 years. However, due to a rather large proportion not presenting for follow-up, this might be an underestimation. Patients receiving late injections and/or surgical treatment had more comorbidities and received corticosteroid treatment to a significantly lower extent in the acute phase of disease.

Nivolumab in pretreated pleural mesothelioma: Results from an observational real-world study of patients treated within the AIFA 5% Fund.

Pleural mesothelioma is a rare cancer with a dismal prognosis and few therapeutic options, especially in the pretreated setting. Immunotherapy with checkpoint inhibitors as single agents yielded interesting results in refractory pleural mesothelioma, achieving a response rate between 10-20%, median progression-free survival of 2-5 months and median overall survival of 7-13 months. A retrospective, multi-institutional study of pleural mesothelioma patients treated with nivolumab in second and further line was performed. The endpoints of the study are response rate, disease control rate, progression free survival and overall survival. Sixty-five patients with pleural mesothelioma treated with nivolumab in second and further line were enrolled at seven Italian institutions. The response rate was 8%, disease control rate was 37%, median progression free survival was 5.7 months (95% CI: 2.9-9.0) and median overall survival was 11.1 (95% CI 6.2-19.9) months. A higher neutrophils and neutrophils to lymphocytes ratio at baseline were associated with worse prognosis. Nivolumab as a single agent is fairly active in a cohort of unselected pretreated pleural mesothelioma patients. Further investigations on clinical and translational factors are needed to define which patient might benefit most from nivolumab treatment in pleural mesothelioma.

Clinical application of next generation sequencing for Mendelian disease diagnosis in the Iranian population

Next-generation sequencing (NGS) has been proven to be one of the most powerful diagnostic tools for rare Mendelian disorders. Several studies on the clinical application of NGS in unselected cohorts of Middle Eastern patients have reported a high diagnostic yield of up to 48%, correlated with a high level of consanguinity in these populations. We evaluated the diagnostic utility of NGS-based testing across different clinical indications in 1436 patients from Iran, representing the first study of its kind in this highly consanguineous population. A total of 1075 exome sequencing and 361 targeted gene panel sequencing were performed over 8 years at a single clinical genetics laboratory, with the majority of cases tested as proband-only (91.6%). The overall diagnostic rate was 46.7%, ranging from 24% in patients with an abnormality of prenatal development to over 67% in patients with an abnormality of the skin. We identified 660 pathogenic or likely pathogenic variants, including 241 novel variants, associated with over 342 known genetic conditions. The highly consanguineous nature of this cohort led to the diagnosis of autosomal recessive disorders in the majority of patients (79.1%) and allowed us to determine the shared carrier status of couples for suspected recessive phenotypes in their deceased child(ren) when direct testing was not possible. We also highlight the observations of recessive inheritance of genes previously associated only with dominant disorders and provide an expanded genotype–phenotype spectrum for multiple less-characterized genes. We present the largest mutational spectrum of known Mendelian disease, including possible founder variants, throughout the Iranian population, which can serve as a unique resource for clinical genomic studies locally and beyond.

Sidedness is not a prognostic factor in an unselected cohort of patients with colon cancer but prognosis for caecal carcinoma is worse – A multivariate analysis of a large single institution database

PurposeSidedness has emerged as a prognostic factor for metastatic colorectal cancer treated with modern systemic therapies. This study investigates whether it is also relevant for an unselected patient cohort including all stages.MethodsAll consecutive patients admitted with colon cancer between 1995 and 2018 were retrieved from an institution-held database. Patients were divided into two cohorts. The first cohort included patients without distant metastases who were able to undergo curative resection. The second cohort presented with distant metastases (stage IV). Potentially prognostic factors were subjected to multivariate Cox Regression analysis.ResultsOverall, 1,606 patients met the inclusion and exclusion criteria. An R0-resection was achieved in 1,222 patients without distant metastases. Five-year cause-specific survival rate was 89.3% for this group. There was no difference between right- and left-sided cancers (88.2% vs. 90.1%, p = 0.220). However, prognosis of caecal carcinoma was significantly worse than that of all other sites combined (83.5% vs. 90.2%, p = 0.007). In multivariate analysis, pT-category, pN-category, grading, vascular invasion, emergency operation, adjuvant chemotherapy, and caecal carcinoma remained as independent prognostic factors. In the 384 patients with stage IV-disease, 3-year overall survival for right- vs. left-sided cancers differed only in univariate analysis (17.7% vs. 28.6%, p = 0.013).ConclusionIn non-metastatic colon cancer, location in the caecum is an independent prognostic factor. In unselected patients with stage IV colon cancer, sidedness was not found to be a prognostic factor. Differentiation into right- and left-sided tumors may be simplistic, and further studies on the biological behavior of different colonic sites are warranted.

A Novel LDLC Equation is Superior to the NIH LDLC Equation and the Friedewald Equation.

LDLC equations have varying levels of underestimation for the calculated LDLC. Therefore, underestimating LDLC should be avoided as much as possible. We need to establish LDLC equations that underestimate LDLC as little as possible. We established the equations with a healthy cohort from Shuyang Hospital and validated the equations with an unselected patient cohort from The Second People's Hospital of Lianyungang. We established the novel LDLC equations by using the regression equation. The relationship between two markers was analysed using Pearson's approach. The 95% limits of measuring agreement within ±2 SD for the LDLC equations was performed using Bland‒Altman analysis. ROC curve analysis was used to predict LDLC levels and the accuracy of the LDLC equation for determining the direct LDLC levels at LDLC cut-offs was assessed. We obtained two novel LDLC equations (LDL_nonHDLC equation=-0.899+1.195*nonHDLC-0.00347*nonHDLC2 and LDL_TC(total cholesterol) equation=-2.775+1.29*TC -0.00990* TC 2). The correlation coefficient between the novel LDLC equation and the direct LDLC measurements is not lower than that between the LDL_NIH equation and the direct LDLC measurements. The AUCs of our novel LDLC equations were greater than those of the LDL_NIH equation and the LDL_F equation at the LDLC cut-offs for clinical decision-making. The measuring agreement in the methods of the LDL_nonHDL equation is superior to that of the LDL_NIH equation. LDLC calculated by the novel LDL_nonHDL equation exhibited superiority over the LDL_NIH equation. Combining the LDL_NIH equation and our novel LDLC equation may improve accuracy and avoid undertreatment of high LDLC levels.

Decreased percentages of plasmacytoid dendritic cells predict survival in critically ill patients.

Critically ill patients admitted to intensive care units (ICUs) experience a broad variety of life-threatening conditions. Irrespective of the initial cause of hospitalization, many experience systemic immune dysregulation. Dendritic cells (DCs) are the most potent antigen-presenting cells and play a pivotal role in regulating the immune response by linking the innate to the adaptive immune system. The aim of this study was to analyze whether DCs or their respective subsets are associated with 30-d mortality in an unselected patient cohort admitted to a medical ICU with a cardiovascular focus. A total of 231 patients were included in this single-center prospective observational study. Blood was drawn at admission and after 72 h. Subsequently, flow cytometry was utilized for the analysis of DCs and their respective subsets. In the total cohort, low percentages of DCs were significantly associated with sepsis, respiratory failure, and septic shock. In particular, a significantly lower percentage of circulating plasmacytoid DCs (pDCs) was found to be a strong and independent predictor of 30-d mortality after adjustment for demographic and clinical variables with an hazard ratio of 4.2 (95% confidence interval: 1.3-13.3, P = 0.015). Additionally, low percentages of pDCs were correlated with additional markers of inflammation and organ dysfunction. In conclusion, we observed low percentages of DCs in patients admitted to an ICU experiencing sepsis, respiratory failure, and cardiogenic shock, suggesting their depletion as a contributing mechanism for the development of immune paralysis. In our cohort, pDCs were identified as the most robust subset to predict 30-d mortality.

Development of an algorithm for identifying paraneoplastic ischemic stroke in association with lung, pancreatic, and colorectal cancer

Background: Paraneoplastic ischemic stroke has a poor prognosis. We have recently reported an algorithm based on the number of ischemic territories, C-reactive protein (CRP), lactate dehydrogenase (LDH), and granulocytosis to predict the underlying active cancer in a case-control setting. However, co-occurrence of cancer and stroke might also be merely incidental. Objective: To detect cancer-associated ischemic stroke in a large, unselected cohort of consecutive stroke patients by detailed analysis of ischemic stroke associated with specific cancer subtypes and comparison to patients with bacterial endocarditis. Methods: Retrospective single-center cohort study of consecutive 1612 ischemic strokes with magnetic resonance imaging, CRP, LDH, and relative granulocytosis data was performed, including identification of active cancers, history of now inactive cancers, and the diagnosis of endocarditis. The previously developed algorithm to detect paraneoplastic cancer was applied. Tumor types associated with paraneoplastic stroke were used to optimize the diagnostic algorithm. Results: Ischemic strokes associated with active cancer, but also endocarditis, were associated with more ischemic territories as well as higher CRP and LDH levels. Our previous algorithm identified active cancer-associated strokes with a specificity of 83% and sensitivity of 52%. Ischemic strokes associated with lung, pancreatic, and colorectal (LPC) cancers but not with breast and prostate cancers showed more frequent and prominent characteristics of paraneoplastic stroke. A multiple logistic regression model optimized to identify LPC cancers detected active cancer with a sensitivity of 77.8% and specificity of 81.4%. The positive predictive value (PPV) for all active cancers was 13.1%. Conclusion: Standard clinical examinations can be employed to identify suspect paraneoplastic stroke with an adequate sensitivity, specificity, and PPV when it is considered that the association of ischemic stroke with breast and prostate cancers in the stroke-prone elderly population might be largely incidental.

Real-world evaluation of Brainomix e-Stroke software.

Brainomix e-Stroke is an artificial intelligence-based decision support tool that aids the interpretation of CT imaging in the context of acute stroke. While e-Stroke has the potential to improve the speed and accuracy of diagnosis, real-world validation is essential. The aim of this study was to prospectively evaluate the performance of Brainomix e-Stroke in an unselected cohort of patients with suspected acute ischaemic stroke. The study cohort included all patients admitted to the University College London Hospital Hyperacute Stroke Unit between October 2021 and April 2022. For e-ASPECTS and e-CTA, the ground truth was determined by a neuroradiologist with access to all clinical and imaging data. For e-CTP, the values of the core infarct and ischaemic penumbra were compared with those derived from syngo.via, an alternate software used at our institution. 1163 studies were performed in 551 patients admitted during the study period. Of these, 1130 (97.2%) were successfully processed by e-Stroke in an average of 4 min. For identifying acute middle cerebral artery territory ischaemia, e-ASPECTS had an accuracy of 77.0% and was more specific (83.5%) than sensitive (58.6%). The accuracy for identifying hyperdense thrombus was lower (69.1%), which was mainly due to many false positives (positive predictive value of 22.9%). Identification of acute haemorrhage was highly accurate (97.8%) with a sensitivity of 100% and a specificity of 97.6%; false positives were typically caused by areas of calcification. The accuracy of e-CTA for large vessel occlusions was 91.5%. The core infarct and ischaemic penumbra volumes provided by e-CTP strongly correlated with those provided by syngo.via (ρ=0.804-0.979). Brainomix e-Stroke software provides rapid and reliable analysis of CT imaging in the acute stroke setting although, in line with the manufacturer's guidance, it should be used as an adjunct to expert interpretation rather than a standalone decision-making tool.

Low prevalence of germline TP53 and PALB2 mutations in unselected cohort of breast cancer patients from Brunei Darussalam

Background: Breast cancer is the most frequent malignancy affecting women worldwide. The majority of breast cancer occurs sporadically, with only 5-10% being caused by inheritance of susceptibility genes. In Brunei Darussalam, breast cancer is the leading cause of cancer in women. The prevalence and clinical relevance of breast cancer susceptibility genes in Brunei breast cancer patients is unknown. We investigated the prevalence and clinical relevance of germline TP53 and PALB2 genes, recognised to confer a high and moderate risk respectively, in the development of breast cancer in an unselected cohort of Brunei breast cancer patients. Methods: Genomic DNA was extracted from peripheral blood samples of 54 unselected Brunei breast cancer patients. The DNA samples were sequenced for germline BRCA1, BRCA2, TP53, and PALB2 variants using targeted panel sequencing on a Hi-Plex NGS platform. Identified variants were analysed for their pathogenicity classification based on clinical/population/mutation databases, in-silico data, and available functional data analysis. Chi-square test was used to determine the association between TP53 codon 72 and response to chemotherapy in Brunei breast cancer patients. Results: We identified two TP53 and five PALB2 missense variants in our study population. Five of the identified variants were classified as variants of uncertain significance (one in TP53 and four in PALB2) giving a prevalence of TP53 and PALB2 variant of uncertain significance carriers at 1.9% and 9.3%, respectively. No pathogenic TP53 and PALB2 mutation was identified in this study suggesting the rarity of these genes in breast cancer.TP53 codon 72 had no association with Brunei breast cancer patients’ response to chemotherapy supporting the benign characteristic of the variant P72R. Conclusions: Our current findings suggest that the contribution of germline TP53 and PALB2 genes in unselected Brunei breast cancer patients is rare, and a larger number of participants will be required to confirm this finding.

Analysis of an Unselected Patient Cohort With Advanced Colorectal Carcinoma from a Maximum Care Center.

Systemic treatment for metastatic colorectal cancer (CRC) includes chemotherapy in combination with a targeted antibody. Novel targeted therapies and immunotherapies are introduced for specific molecular subgroups. Prognostic relevant determinants are still under investigation. Systemic therapies of an unselected patient cohort with metastatic CRC were retrospectively analyzed. Treatment outcome was evaluated according to time-to-next-treatment (TTNT) and frequency of conversion surgery and compared between subgroups stratified by primary tumor side, molecular profile, sex and age, and metastases sites. More than 50% of patients with locally advanced or metastatic CRC underwent secondary resection after first-line systemic therapy. Rectum carcinoma had the best prognosis under anti-EGFR-antibody treatment. Female patients had a worse prognosis than male patients in late disease stage. Young patients demonstrated poor response to systemic therapy, but a high rate of conversion surgeries. Conversely, elderly patients benefited from systemic therapy but underwent surgery less frequently. Liver and lung metastases had a worse prognosis than other metastases sites, whereas lung metastases were more likely to be resected than liver metastases in early disease stage. Patient age, sex, primary tumor localization, and metastatic sites are prognostic factors that could guide future treatment decisions for the therapy of metastatic CRC.

Implementation of CMV-T-Track® in Clinical Routine to Guide Management of CMV Reactivation

Background: Despite Letermovir prophylaxis, reactivation of cytomegalovirus (CMV), requiring close monitoring and preemptive antiviral treatment, remains to be an issue after allogeneic hematopoietic stem cell transplantation (HSCT). Monitoring CMV-specific cellular immunity can help to identify patients at risk and may guide monitoring intervals and therapeutic decisions. CMV T-Track®, a standardized IFN-γ ELISpot assay, conducted after the end of treatment of a first CMV reactivation was shown to identify patients at risk of recurrent reactivation with a positive predictive value (patients with a negative test after the first CMV reactivation had a subsequent recurrent CMV reactivation) of 80%. As these results originate from a clinical trial with a distinct patient population, we analyzed its usefulness and value within the clinical routine. Here we describe the results within the clinical routine in an unselected patient cohort and the influence of different GvHD prophylaxis on T-Track® outcome, as well as factors promoting CMV reactivation despite positive test results. Methods: In total, 169 patients were monitored for CMV reactivation with CMV-PCR for 365 days after HSCT and CMV immunity was measured using CMV T-Track® at d+100. CMV T-Track® was repeated at d+200 and+ 300 in case of a negative first test result d+100. Patient characteristics: 125 patients received ATG, 24 Alemtuzumab i.v. and 12 ptCy. 8 patients were transplanted from an HLA-identical sibling and received no T cell depleting (TCD) agent. CMV-serostatus: Donor(D)+/recipient(R)+ in 123, D+/R- in 9, D-/R+ in 34 and D-/R- in 3 patients. All CMVpos recipients received Letermovir prophylaxis until d+100. Results: At d+100 164/169 tests produced a robust result, only 5 tests were invalid. 110 patients had a positive T-Track® at d+100, with a higher percentage in patients with a CMVpos donor (99/132 (75%) vs. (10/37 (27%)). After Alemtuzumab we observed the lowest rate of positive T-Track® 10/24 (42%) at d+100, followed by ATG 83/125 (66%), whereas pTCy showed a good response 11/12 (92%). Only 5/8 (63%) patients without TCD had a positive test result. 9/10 (90%) of patients with a positive T-Track® d+100 despite a CMVneg donor had a positive CMV-PCR before d+100, whereas only 3/27 (11%) CMVireamias were detected in those without CMV immunity. In patients with a CMVpos donor 59/108 (55%) had a documented reactivation leading to a positive T Track®, in contrast to 9/33 (27%) with a negative T-Track®. 18/20 (90%) patients developed a positive T-Track® at d+200 after CMViraemia between d+100 and d+200. 24 patients were persistently negative at d+300. Despite a positive T-Track® at d+100, 28/110 (25%) patients needed treatment for CMV reactivation. In most of them immunosuppressive treatment for GvHD was initiated after d+100: 20/28 (71%) high dose corticosteroids, 1/28 (4%) Ruxolitinib. Excluding patients, that received additional immunosuppression after d+100 only 7/89 (8%) developed a CMV reactivation despite a positive d+100 T-Track®. This yields a negative predictive value of 0,921 for the result of T-Track® at d+100. 25/59 (42%) patients with a negative T-Track® at d+100 subsequently developed a treatment requiring CMV reactivation. Discussion/Conclusion: CMV T-Track® is feasible in clinical routine and can help identify patients at risk for CMV reactivation. In our cohort 110/169 (65%) patients showed a cellular immune response against CMV at day +100. Excluding patients that received additional immunosuppression in the later course, only 7/89 (8%) developed a CMV reactivation after a positive d+100 T-Track®. With this T-Track® result at d+100 has a negative predictive value of 0,921. CMV negative donor was the strongest predictor for a negative test result. Alemtuzumab was the only TCD associated with a negative impact. CMVireamia increases CMV immune response and is mandatory in patients with a CMV negative donor to establish CMV-immunity. We therefore consider CMV T-Track® a useful tool in clinical routine to identify patients with sufficient CMV-immunity at d+100. This could help to guide monitoring intervals or therapeutic decisions such as prolonged prophylaxis or need for preemptive treatment.

Intensive Induction Chemotherapy (IC) Vs Hypomethylating Agents + Venetoclax (HMA/VEN) in IDH1- or IDH2-Mutant Newly Diagnosed Acute Myeloid Leukemia (AML) - a Multicenter Cohort Study

Introduction: Intensive induction chemotherapy (IC) remains the standard of care for younger and fit patients (pts) with acute myeloid leukemia (AML). Post-hoc analyses from clinical trials have associated IDH1 and IDH2 mutations with high rates of durable responses to venetoclax (VEN)-based therapies. However, these trials were conducted in pts ≥75 years of age or unfit for IC. As there are currently no trials comparing hypomethylating agents (HMA)+VEN and IC directly in IDH-mutant AML, we conducted a large multicenter retrospective cohort study of pts with newly diagnosed AML with IDH1 and IDH2 mutations to assess the impact of clinical and molecular characteristics on response and survival to IC versus HMA+VEN. Methods: We included pts with newly diagnosed IDH1- and IDH2-mutant AML who were treated at 4 large academic centers with IC (conventional 7+3 or liposomal cytarabine/daunorubicin) or HMA/VEN. Detection of IDH1 and IDH2 mutations was performed by next-generation sequencing per local standards at the participating sites. Responses were recorded according to European LeukemiaNet 2017 criteria. Composite complete response (cCR) was defined as complete response (CR) + CRi (CR with incomplete count recovery). Overall survival (OS) was compared between groups by log-rank test. Cox regression for OS was fitted to evaluate the effect of treatment, allogeneic stem cell transplantation (allo-SCT) as a time-varying covariate and additional covariates. All variables with p<0.1 in the univariate model were included in the multivariable stepwise backward selection model. Results: We reviewed 1132 pts with AML and included 98 and 131 pts with IDH1/2-mutant AML, respectively (9 pts had IDH1 and IDH2 co-mutations). As pts with IDH1-and IDH2-mutant AML had similar baseline demographic and disease characteristics, we combined both groups for further analyses. Of the 220 ptswith IDH1/2-mutant AML, 150 and 70 received IC and HMA+VEN, respectively ( Table 1). Twenty pts in the IC group received concurrent treatment with the IDH1 inhibitor ivosidenib. Compared to pts treated with IC, pts who received HMA+VEN were older (median age 75 years with HMA+Ven [Range: 60 - 88 years] vs 63 years [R: 24 -76] with IC; p<0.001) and had higher rates of molecular defined secondary AML (57% vs 41%; p<0.001), CEBPA mutations (10.0% vs 2.7%; p=0.040), and TP53 mutations (13% vs 2.7%; p=0.005) Despite these differences in baseline characteristics, rates of cCR were similar for IC and HMA+VEN-treated pts (68% vs 67%; p=0.90) with higher rates of CR seen with IC (64% vs 46%; p=0.010). The rate of allo-SCT was higher in pts treated with IC than with HMA+VEN (63% vs 23%; p<0.001). The median OS for the entire cohort was 32 months (95% CI: 24 months [mo] - not reached [NR]) with a significant difference in OS by treatment type favoring IC over HMA+VEN (52 mo [95% CI: 30 mo - NR] vs 14 mo [95% CI: 11 - 39 mo]; p=0.002). However, in pts > 60 years (n=168 pts), median OS was 21 mo (95% CI: 16 - 32 mo) and not statistically significant ( p=0.11) between IC (27 mo [95% CI: 20-57 mo]) and HMA+VEN (15 mo [95% CI: 11 mo - NR]). Comparable OS was seen among pts undergoing allo-SCT (n=111 pts; 24-mo OS 75% [95% CI: 66 - 84%] with IC vs 24-mo OS 79% [95% CI: 61 - 100% with HMA+VEN, p=0.71), as well as when censored at allo-SCT (IC 12 mo [95% CI: 7.7 - 25 mo]; HMA+VEN 12 mo [95% CI: 8.2 - 18 mo], p=0.58) Although treatment with HMA+VEN vs IC was found to be associated with worse OS in univariable analysis ( Table 2) it did not retain its prognostic value in the multivariable analysis (HR: 1.28; 95% CI: 0.74 - 2.19; p=0.37). Conversely, prior HMA, monosomal karyotype, JAK2 and FLT3-ITD mutations were associated with worse survival suggesting that these factors are more relevant for OS than the type of treatment. Conclusion: In pts with newly diagnosed IDH1/2-mutant AML, cCR rates were similar for pts treated with IC and HMA+VEN. While there was a difference in OS favoring treatment with IC over HMA+VEN in the unselected patient cohort, this difference was no longer present in subgroup analyses based on age >60 years and in pts who received an allo-SCT. Furthermore, treatment type did not impact OS in multivariable regression models suggesting that differences in OS between treatment groups are more likely to be explained by differences in patient and disease characteristics rather than treatment type. Due to the limitations of retrospective, real-world studies, a randomized clinical trial is needed.

Baseline Features, Treatment Choice and Early Frontline TKI Permanent Discontinuation in Younger Patients with Chronic Myeloid Leukemia: A “Campus CML” Study

Introduction Median age at diagnosis in patients with Chronic Myeloid Leukemia (CML) is about 60 years: only few data are available in younger subjects at present. Aim To analyze initial features, choice of frontline Tyrosine-Kinase Inhibitor (TKI) and early adverse events leading to permanent TKI discontinuation in the first 12 months from TKI start in newly diagnosed subjects aged ≤ 40 years in a large and unselected real-life cohort of CML patients. Methods We retrospectively evaluated 1963 patients newly diagnosed from 1/2012 to 12/2019 at 38 Hematology Centers in Italy participating at the “Campus CML” project: according to age at diagnosis, 302 were ≤ 40 years [Younger Patients (YP)], 900 were > 45 < 65 years [Intermediate Aged Patients (IAP)] and 761 were ≥ 65 years [Elderly Patients (EP)]. Results Clinical features, frontline TKI and causes of early TKI discontinuation according to age at diagnosis are reported in the Table 1. As to baseline clinical features, YP had significantly higher WBC count, lower Hb levels and higher rate of spleen enlargement: moreover, as expected, low-risk Sokal score was more common and rate of concomitant diseases/number of concomitant drugs lower in YP. As to frontline TKI, 96 YP (31.1%) received imatinib (IM) and 206 (68.9%) a 2G-TKI [dasatinib (DAS) n=60, 19.9%; nilotinib (NIL) n=144, 47.6%]: choice of 2G-TKI as frontline treatment was significantly more common in YP compared to both IAP and EP (p < 0.001). Causes of permanent frontline TKI discontinuation during the first 12 months of treatment according to age at diagnosis are reported in the Table 1: among YP, 45 (14.9%) discontinued frontline TKI treatment due to hematologic toxicity (5 cases, 1.6%), extra-hematologic toxicity (11 cases, 3.7%), primary resistance (24 cases, 8.0%), secondary resistance (2 cases, 0.6%) or evolution in blastic phase (BP) (3 cases, 1.0%). Cumulative incidence of permanent discontinuation at 12 months was 14.6% (95%CI 10.7 - 18.5) in YP compared to 16.9% (95%CI 14.3 - 19.2) in IAP (p=0.388) and 24.0% (95%CI 20.9 - 27.1) in EP (p < 0.001) (Figure 1): considering only permanent TKI discontinuation due to treatment resistance (primary resistance + secondary resistance + evolution in BP), no difference was observed according to age at diagnosis [9.6% (95%CI 6.3 - 12.9) in YP versus 10.2% (95%CI 8.2 - 12.2) in IAP versus 11.8% (95%CI 9.6 - 14.0) in EP, p=0.589]. Conclusions Our data highlight the following peculiar clinical features at baseline and during the first year of treatment in YP with CML compared with IAP and EP: a delayed diagnosis, outlined by higher WBC count and rate of spleen enlargement; an expected choice of 2G-TKI as frontline treatment in the real-life, even if about one third of them was still treated with IM; a lower incidence of early frontline TKI permanent discontinuation compared to EP but not IAP, mainly due to toxic causes and not related to resistance. Data on early molecular response and further evaluations at 24 and 36 months are warranted to complete present analysis.

Prevalence of BRCA1 and BRCA2 germline variants in an unselected pancreatic cancer patient cohort in Pakistan

BackgroundBRCA1 and BRCA2 (BRCA1/2) are the most frequently investigated genes among Caucasian pancreatic cancer patients, whereas limited reports are available among Asians. We aimed to investigate the prevalence of BRCA1/2 germline variants in Pakistani pancreatic cancer patients.MethodsOne hundred and fifty unselected and prospectively enrolled pancreatic cancer patients were comprehensively screened for BRCA1/2 germline variants using denaturing high-performance liquid chromatography and high-resolution melting analyses, followed by DNA sequencing of the variant fragments. The novel variants were analyzed for their pathogenic effect using in-silico tools. Potentially functional variants were further screened in 200 cancer-free controls.ResultsProtein truncating variant was detected in BRCA2 only, with a prevalence of 0.7% (1/150). A frameshift BRCA2 variant (p.Asp946Ilefs*14) was identified in a 71-year-old male patient of Pathan ethnicity, with a family history of abdominal cancer. Additionally, we found a novel variant in BRCA2 (p.Glu2650Gln), two previously reported variants in BRCA1 (p.Thr293Ser) and BRCA2 (p.Ile2296Leu) and a recurrent nonsense variant in BRCA2 (p.Lys3326Ter). These variants were classified as variants of uncertain significance (VUS). It is noteworthy that none of these VUS carriers had a family history of pancreatic or other cancers.ConclusionsIn this first study, BRCA1/2 pathogenic variant is identified with a low frequency in pancreatic cancer patients from Pakistan. Comprehensive multigene panel testing is recommended in the Pakistani pancreatic cancer patients to enhance genetic understanding in this population.

Association between body mass index and outcomes in heart failure across the ejection fraction spectrum: data from the Swedish Heart Failure Registry

Abstract Background Despite overweight/obesity being a well-known cardiovascular (CV) risk factor, high body mass index (BMI) has been suggested to be associated with longer survival in patients with heart failure (HF). Data on large populations are lacking, as well as whether this advantage might be consistent across the ejection fraction (EF) spectrum, i.e. reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF, where obesity may have a greater causative role). Purpose To assess the association between BMI and outcomes in a large and unselected contemporary cohort of patients with HF across the EF spectrum. Methods Patients with HF registered in the Swedish HF Registry (SwedeHF) between May 2000 and December 2021, with no missing values for EF and BMI, were selected. Linkage with the Cause of Death Registry and the National Patient Registry provided data on mortality, hospitalizations and comorbidities. Patients were categorised according to BMI class (underweight <18.5 kg/m2; normal weight 18.5-24.9 kg/m2; overweight 25.0-29.9 kg/m2; obesity>30-34.9 kg/m2). The primary outcome was all-cause death, secondary outcomes were CV death and HF hospitalization (HHF). The associations between BMI categories and outcomes were analysed by univariable and multivariable Cox proportional hazards models, both in the whole cohort and according to EF classes; this association was also explored by modeling BMI as a continuous variable through restricted cubic splines. Missing data were handled by chained equation multiple imputation. Results 69,874 patients (mean age 74 years, 36% females) were included, of whom 3% underweight, 35% with normal weight, 35 % overweight, obese 27%. Figure 1 reports the proportions of the different BMI categories according to EF: obesity was significantly more common in HFpEF. Regardless of EF, obese patients were younger, with lower N-terminal B-type natriuretic peptide, higher New York Heart Association class, and with diabetes and hypertension as compared with the other three BMI classes. Compared with normal weight, both overweight and obesity were independently associated with lower mortality risk, while underweight with higher mortality, with consistent results in HFrEF, HFmrEF and HFpEF; the same associations were found for CV death or all three EF classes, while underweight only was associated with HHF in HFrEF. When BMI was modelled as restricted cubic splines, a reverse J-shaped adjusted association was found between BMI and risk of all-cause death (Figure 2). Conclusion HF patients with overweight and obesity had a lower mortality risk compared with patients with normal or underweight patients across all EF classes, at least up to BMI>40 kg/m2. Our results are consistent with the previously suggested potential survival benefit in overweight patients, calling for future research to understand this apparent paradox.Figure 1