Phase 1, randomized, rater and participant blinded placebo-controlled study of the safety, reactogenicity, tolerability and immunogenicity of H1N1 influenza vaccine delivered by VX-103 (a MIMIX microneedle patch [MAP] system) in healthy adults.

BACKGROUND: The MIMIX platform is a novel microneedle array patch (MAP) characterized by slowly dissolving microneedle tips that deploy into the dermis following patch application. We describe safety, reactogenicity, tolerability and immunogenicity for MIMIX MAP vaccination against influenza. METHODOLOGY: The trial was a Phase 1, exploratory, first-in-human, parallel randomized, rater, participant, study analyst-blinded, placebo-controlled study in Canada. Forty-five healthy participants (18 to 39 years of age, inclusive) were randomized in a 1:1:1 ratio to receive either 15 µg or 7.5 µg of an H1N1 influenza vaccine, or placebo delivered via MIMIX MAP to the volar forearm. A statistician used a computer program to create a randomization scheme with a block size of 3. Post-treatment follow-up was approximately 180 days. Primary safety outcomes included the incidence of study product related serious adverse events and unsolicited events within 180 days, solicited application site and systemic reactogenicity through 7 days after administration and solicited application site erythema and/or pigmentation 14, 28, 56 and 180 days after administration. Immunogenicity outcomes included antibody titers and percentage of seroconversion (SCR) and seroprotection (SPR) rates determined by the hemagglutination inhibition (HAI) assay. Exploratory outcomes included virus microneutralization (MN) titers, durability and breadth of the immune response. The trial was registered with ClinicalTrials.gov, number NCT06125717. FINDINGS: Between July 7, 2022 and March 13, 2023 45 participants were randomized to a treatment group. One participant was lost to follow up in the 15 µg group and 1 participant withdrew from the 7.5 µg dose group. Safety analyses included n = 15 per group, immunogenicity analyses included n = 14 for the 15 µg and 7.5 µg treatment groups and n = 15 for the placebo group. No SAEs were reported in any of the treatment groups. All treatment groups reported solicited local events within 7 days after vaccination, with mild (Grade 1) erythema being the most frequent symptom reported. Other local symptoms reported included mostly mild (Grade 1) induration/swelling, itching, pigmentation, skin flaking, and tenderness. Within 7 days after vaccination, 2 participants (4.4%) reported moderate (Grade 2) erythema, 1 participant (2.2%) reported moderate (Grade 2) induration/swelling, and 1 participant (2.2%) reported moderate (Grade 2) itching. There was an overall reduction in erythema and pigmentation reported on Days 15, 29, 57, and 180 among all treatment groups. Systemic symptoms reported within 7 days after vaccination, included mild (Grade 1) fatigue reported among all treatment groups, and mild (Grade 1) headache reported by 1 participant in the 7.5 µg treatment group. No study drug related severe symptoms were reported in the study. Group mean fold rises in HAI titers ranged between 8.7 and 12-fold, SCRs were >76% and SPRs were >92% for both VX-103 dose groups thereby fulfilling serological criteria established by the EMA and FDA for seasonal influenza vaccines. Longitudinal assessments demonstrate persistence of the immune response through at least Day 180. CONCLUSIONS: The MIMIX MAP platform is safe, well tolerated and elicits robust antibody responses.

Does high dose statin pretreatment affect global strains in patients undergoing valve replacement.

Purpose: To study the effect of rosuvastatin 40 mg (initiated 7 days prior to surgery) in patients undergoing valve replacement (VR) for rheumatic mitral valve disease on left ventricular (LV) strain and biomarker release kinetics. Methods: In this randomized study, cardiac biomarkers viz. troponin I (TnI), Creatine kinase MB (CK-MB), N-terminal pro B-type natriuretic peptide (NTPBNP) were measured before surgery; and 8, 24 and 48 h postoperatively. Global LV (circumferential, global circumferential strain (GCS); longitudinal, GLS; radial, global radial strain (GRS)) strains were measured preoperatively; and 48 h and 30 days postoperatively. Results: Following VR, Global Longitudinal Strain (GLS), Global Circumferential Strain (GCS) and Global Radial Strain (GRS) declined at 48 h in both statin loaded (SL) and non loaded (NL) groups. The %decline in strain was significantly lower in SL group (% change in GLS 35.8% vs 38.8%, GCS 34% vs 44.1%, GRS 45.7% vs 52.6%; p < 0.001).All strain values improved at 30 days with higher improvement in SL group (GLS -15.92 ± 2.00% vs -12.6 ± 1.66%, GCS -15.12 ± 2.93% vs -13.04 ± 2.44%; GRS 22.12 ± 6.85% vs 19.32 ± 6.48%). While TnI, CKMB, NTPBNP increased following surgery, values at 8, 24 and 48 h were lower in the SL vs. NL group. Mean change (baseline to peak biomarker value) was also significantly lower in SL group.The SL group had shorter hospital and Intensive Care Unit (ICU) stay. On Receiver Operating Characteristic Curve (ROC) analysis, baseline GCS ≤ 14% best predicted postoperative 30 day Left Ventricular Ejection Fraction (LVEF) ≤ 50%. Conclusion: Pre-operative high dose rosuvastatin was "cardioprotective" with favorable effect on LV global strain and release kinetics of biomarkers. These cut-offs (described for the first time for rheumatic VR) can be used as prognostic predictors.

Automated Spontaneous Echo Contrast Detection Using a Multisequence Attention Convolutional Neural Network.

OBJECTIVE: Spontaneous echo contrast (SEC) is a vascular ultrasound finding associated with increased thromboembolism risk. However, identification requires expert determination and clinician time to report. We developed a deep learning model that can automatically identify SEC. Our model can be applied retrospectively without deviating from routine clinical practice. The retrospective nature of our model means future works could scan archival data to opportunistically correlate SEC findings with documented clinical outcomes. METHODS: We curated a data set of 801 archival acquisitions along the femoral vein from 201 patients. We used a multisequence convolutional neural network (CNN) with ResNetv2 backbone and visualized keyframe importance using soft attention. We evaluated SEC prediction performance using an 80/20 train/test split. We report receiver operating characteristic area under the curve (ROC-AUC), along with the Youden threshold-associated sensitivity, specificity, F1 score, true negative, false negative, false positive and true positive. RESULTS: Using soft attention, we can identify SEC with an AUC of 0.74, sensitivity of 0.73 and specificity of 0.68. Without soft attention, our model achieves an AUC of 0.69, sensitivity of 0.71 and specificity of 0.60. Additionally, we provide attention visualizations and note that our model assigns higher attention score to ultrasound frames containing more vessel lumen. CONCLUSION: Our multisequence CNN model can identify the presence of SEC from ultrasound keyframes with an AUC of 0.74, which could enable screening applications and enable more SEC data discovery. The model does not require the expert intervention or additional clinician reporting time that are currently significant barriers to SEC adoption. Model and processed data sets are publicly available at https://github.com/Ouwen/automatic-spontaneous-echo-contrast.

A pilot study evaluating the role of ivabradine for rate control in patients with rheumatic atrial fibrillation.

OBJECTIVES: Ivabradine may have a role in rate control of atrial fibrillation (AF) due to effects on HCN channels in AV node. We studied role of Ivabradine in rate control of rheumatic AF. METHODS: 80 patients, rheumatic AF, HR > 100 bpm (age 47 ± 11 yrs, AF duration 6.8 ± 2.9 years, rate 131 ± 16 bpm) on maximally tolerated ßß or CCB's, randomized to Ivabradine or escalated ßß/CCB. Ivabradine started @ 2.5 mg BD; increased to 5 mg BD if inadequate response at 1 week (failure to decrease HR < 10% vs baseline). After Holter at 1 month, dose escalated to 7.5 mg BD if needed. RESULTS: Ivabradine resulted in significantly lower HR (81 ± 10 vs 99 ± 9) at 3 months and 6 months (79 ± 8 vs 94 ± 8, p < 0.001). Absolute reduction in HR: 56 ± 15 vs 31 ± 14 bpm and % change in HR: 41 ± 7 vs 24 ± 9%, both p < 0.00001). At 6 months, Ivabradine group had. 1Significantly lower NT Pro BNP (1168 vs 1314 pg/ml), higher 6 min walk distance (410 ± 47 vs 349 ± 54 m, all p < 0.001) 2Better symptom class (EHRA score 1: asymptomatic 84% vs 40%), improvement >1 EHRA class; baseline 60% vs 17% 3Better LA Strain (22.8 ± 2.8% vs 20.6 ± 2.5%) Ivabradine was well tolerated and there was no drug withdrawal. CONCLUSION: Our data suggest that Ivabradine can be an option for rate control in rheumatic AF.

Flecainide for conversion and maintenance of sinus rhythm after mitral valve replacement in rheumatic atrial fibrillation.

BACKGROUND: Despite successful mitral valve replacement (MVR), many patients remain in AF. Flecainide can be useful in these patients but has not been used because of underlying structural heart disease. METHODS: We assessed oral flecainide for conversion and maintenance of SR in 25 patients of chronic rheumatic AF following MVR (age 34.4 yrs, mean AF duration: 3.6 yrs). Non-converters underwent DC cardioversion at 24 h and 4 weeks. Patients received flecainide and bb/diltiazem at discharge. RESULTS: Single oral dose of Flecainide achieved SR in 6/25 (24%) while 19/25 achieved SR after DCC; at24 h 21/25 (84%) were in SR. With mean flecainide dose (93.10 ± 9.40 mg), successful maintenance of SR at 6 months was seen in 16/23 (69.5%). No significant changes in PR interval, QRS duration or QTc were noted; flecainide was well tolerated. Patients in SR had significantly better functional status, QOL scores and higher LA strain at 6 months (25.25 vs 17.43%, p < .0001). Baseline LA diameter ≤ 61 mm predicted SR at 6 months (sensitivity/specificity 93.7% and 85.71%) while the values for AF duration ≤ 4 years and LA strain > 21% for predicting SR were 87.5/71.43% and 100/85.71% respectively. CONCLUSION: Oral flecainide was safe and effective in post MVR rheumatic AF patients; maintenance of SR was achieved in 76% of initial converters and 64% of overall population, with better LA strain values. More studies are needed to validate these results.

Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD.

Patients receiving ibrutinib for CLL rarely achieve undetectable measurable residual disease (U-MRD), necessitating indefinite therapy, with cumulative risks of treatment discontinuation due to progression or adverse events. This study added venetoclax to ibrutinib for up to 2 years, in patients who had received ibrutinib for ≥12 months (mo) and had ≥1 high risk feature (TP53 mutation and/or deletion, ATM deletion, complex karyotype or persistently elevated ß2-microglobulin). The primary endpoint was U-MRD with 10-4 sensitivity (U-MRD4) in bone marrow (BM) at 12mo. Forty-five patients were treated. On intention-to-treat analysis, 23/42 (55%) patients improved their response to CR (2 pts were in MRD + CR at venetoclax initiation). U-MRD4 at 12mo was 57%. 32/45 (71%) had U-MRD at the completion of venetoclax: 22/32 stopped ibrutinib; 10 continued ibrutinib. At a median of 41 months from venetoclax initiation, 5/45 patients have progressed; none have died from CLL or Richter Transformation. In 32 patients with BM U-MRD4, peripheral blood (PB) MRD4 was analyzed every 6 months; 10/32 have had PB MRD re-emergence at a median of 13 months post-venetoclax. In summary, the addition of venetoclax in patients treated with ≥12mo of ibrutinib achieved high rate of BM U-MRD4 and may achieve durable treatment-free remission.

Effects of a Pragmatic Home-based Exercise Program Concurrent With Neoadjuvant Therapy on Physical Function of Patients With Pancreatic Cancer: The PancFit Randomized Clinical Trial.

OBJECTIVE: To determine the effects of a preoperative, home-based exercise program on fitness and physical function in patients with pancreatic cancer. BACKGROUND: We previously established a well-tolerated preoperative exercise program after finding a high frequency of sarcopenia and frailty in patients with pancreatic cancer. METHODS: In this randomized, controlled trial (NCT03187951), patients with pancreatic cancer were randomized to Arm A: enhanced usual care or Arm B: prescribed aerobic and resistance exercise during neoadjuvant therapy. Patients received nutrition counseling and activity trackers. The primary endpoint was a 6-minute walk distance (6MWD; ≥14 meters improvement was clinically meaningful). Secondary endpoints included additional physical function tests, health-related quality of life, and clinical outcomes. RESULTS: One hundred fifty-one patients were randomized. Objectively measured weekly activity (153.2±135.6 and 159.8±122.8 min in Arm A and B, respectively, P =0.62) and self-reported weekly moderate-to-strenuous physical activity (107.4±160.4 and 129.6±161.6 min in Arm A and Arm B, respectively, P =0.49) were similar, but weekly strength training sessions increased more in Arm B (by 1.8±1.8 vs 0.1±2.4 sessions, P <0.001). 6MWD improved in both Arm A (mean change 18.6±56.8 m, P =0.01) and Arm B (27.3±68.1 m, P =0.002). Quality of life and clinical outcomes did not significantly differ between arms. Pooling patients in both study groups, exercise, and physical activity was favorably associated with physical performance and clinical outcomes. CONCLUSIONS: In this randomized trial of prescribed exercise versus enhanced usual care during neoadjuvant therapy for pancreatic cancer, a high volume of physical activity and increased exercise capacity were observed in both arms, highlighting the importance of activity among patients preparing for surgery.

Isolated Cardiac Paraganglioma Encasing Right Coronary Artery With Evidence of Succinyl Dehydrogenase Gene Mutation: Successful Management Using Multimodality Imaging.

This report involves a young woman with isolated cardiac paraganglioma that was diagnosed using 68Gallium-labeled [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI3-octreotide positron emission tomographic scintigraphy. For the preoperative evaluation, multimodality imaging accurately described the anatomic location of the tumor and its relationship with the surrounding tissues. The patient underwent successful surgical resection of the tumor along with right coronary artery bypass grafting. The 2-month follow-up scintigraphy was normal. Next-generation sequencing evaluation revealed a novel germline mutation for the succinate dehydrogenase subunit B gene.

Comparison of non-invasive assessment for pulmonary vascular indices by two-dimensional echocardiography and cardiac computed tomography angiography with conventional catheter angiocardiography in unrepaired Tetralogy of Fallot physiology patients weighing more than 10 kg: a retrospective analysis.

AIMS: Assessment of pulmonary vascular dimensions (PVDs) in Tetralogy of Fallot (TOF) is an integral part of planning transcatheter and surgical interventions. We sought to examine the reliability and correlation of echocardiography (ECHO) and computed tomography angiography (CTA) measurements with those obtained by cardiac catheterization and angiography (CCA). METHODS AND RESULTS: Tetralogy of Fallot physiology patients undergoing ECHO, CTA, and CCA within a month prior to surgical correction during 2018-2020 were retrospectively enrolled. Indexed diameter of pulmonary annulus (iPAnn), indexed right pulmonary artery (iRPA), indexed left pulmonary artery (iLPA) and indexed descending aorta (iDA) were measured using ECHO and CTA followed by derivation of Nakata index (NI), McGoon's ratio (MGR), ratio of predicted peak right ventricular (RV) and left ventricular (LV) pressures (pRV/pLV) and Z-scores. Comparison with CCA-derived measurements was made and correlational equations were subsequently deduced. Pulmonary vascular dimensions for 54 patients with mean age of 15.5 ± 9.3 years (range: 3-34 years) were analysed. Computed tomography angiography and CCA measurements for iPAnn, iRPA, NI, MGR, pRV/pLV, and Z-score were comparable with each other while ECHO parameters were significantly lower than CCA. However, iLPA diameter was significantly underestimated by ECHO and overestimated by CTA. Correlational analysis showed stronger correlation between CTA- and CCA-derived PVD as against ECHO measurements except for iDA, pRV/pLV, and Z-score. CONCLUSIONS: For unrepaired TOF physiology patients weighing more than 10 kg, CTA-acquired PVD are reliable and comparable with CCA except for DA for which ECHO is non-inferior. Non-invasive modalities though are inferior to CCA for LPA sizing. Utilizing derived equations, precise estimation of PVD can be carried out using non-invasive tools.

A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL.

Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized that combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing. We conducted an investigator-initiated phase 2 clinical trial to assess the efficacy of combined nivolumab and ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL) RT and CLL. Patients included were ≥18 years of age with adequate hepatic and renal function. Patients received nivolumab every 2 weeks of a 4-week cycle for a maximum of 24 cycles. A standard dose ibrutinib was initiated from cycle 2 onward and continued daily until progression. For patients who were already on ibrutinib at the time of study entry, the same was continued while nivolumab was initiated. A total of 24 patients with RT with a median age of 64.5 years (range, 47-88) were enrolled. Ten patients (42%) had received prior treatment for RT and 13 patients (54%) had received a prior BTKi. A total of 10 patients (42%) responded with a median duration of response of 15 months. The median overall survival was 13 months. Four of 24 (17%) patients had checkpoint inhibition-related immunological toxicities. In the CLL cohort, 10 patients were enrolled, of whom 3 patients converted from partial to complete remission; 1 patient had a grade 2 immunological toxicity. Combined nivolumab and ibrutinib is an active regimen for patients with DLBCL RT with an overall response rate of 42%. Given the limited treatment options for patients with RT, checkpoint inhibition provides a potential therapeutic option. This trial is registered at www.clinicaltrials.gov as #NCT02420912.

Serum Gamma Glutamyltransferase (GGT) in coronary artery disease: Exploring the Asian Indian Connection.

Background: There is a need to identify novel markers for CAD, independent of traditional CV risk factors. One of these is gamma-glutamyl transferase (GGT), a marker of increased oxidative stress. Given the high prevalence of CAD in Asian Indians, the link of GGT and CAD in them needs to be studied. Aim: To assess GGT in patients with angiographically documented CAD. Methods and Results: Two hundred patients aged 58.1 ± 9.95 years, 73% males, hypertension 56%, diabetes 40% were included. Mean GGT was 63.6 ± 44.33 (10-269 U/L). The levels of GGT progressively increased in those with single/double or triple-vessel CAD (36.5, 61.5, and 87 U/L, respectively, P < 0.001). Using objective criteria of CAD burden (SYNTAX and Gensini scores), we reaffirmed these findings. GGT in patients with SYNTAX tertiles 0-22, 23-32, and ≥ 33 was 33, 62, and 97 U/L, respectively and in Gensini tertiles 0-17.65, 17.66-56.65, ≥56.66 was 32, 52, and 88 U/L, respectively, all P < 0.001. SYNTAX score ≥ 23 was present in only 23% patients in GGT tertile 1 (<41 U/L), whereas60% and 94% in GGT tertiles 2 and 3 had SYNTAX ≥ 23. Significant positive correlation was seen between GGT and SYNTAX (r = 0.634) and Gensini score (r = 0.772). Conclusions: In this study, GGT had an independent correlation with angiographic severity of CAD and SYNTAX and Gensini scores. Although the existing evidence seems biologically plausible, more studies are needed to explore the potential role of this inexpensive marker for predicting disease burden in patients with CAD.

A phase two study of high dose blinatumomab in Richter's syndrome.

Richter's Syndrome (RS) is an aggressive transformation of CLL, usually clonally-related diffuse large B-cell lymphoma (DLBCL), characterized by frequent TP53 mutations, intrinsic chemoresistance and poor survival. TP53-independent treatments are needed. We conducted a single center, phase 2, investigator-initiated study of high dose blinatumomab (maximum 112 mcg/d after initial, weekly dose escalation), NCT03121534, given for an 8-week induction and 4-week consolidation cycle. Responses were assessed by Lugano 2014 criteria. Serial multi-parameter flow cytometry from blood was performed to identify patient-specific biomarkers for response. Nine patients were treated. Patients had received a median of 4 and 2 prior therapies for CLL and RS, respectively. Five of 9 had del(17p) and 100% had complex karyotype. Four patients had reduction in nodal disease, including one durable complete response lasting >1 y. Treatment was well tolerated, with no grade >3 cytokine release syndrome and 1 case of grade 3, reversible neurotoxicity. Immunophenotyping demonstrated the majority of patients expressed multiple immune checkpoints, especially PD1, TIM3 and TIGIT. The patient who achieved CR had the lowest levels of immune checkpoint expression. Simultaneous targeting with immune checkpoint blockade, especially PD1 inhibition, which has already demonstrated single-agent efficacy in RS, could achieve synergistic killing and enhance outcomes.

Neutrophil Gelatinase-Associated Lipocalin as a Marker for Contrast-Induced Nephropathy in Patients Undergoing Percutaneous Coronary Intervention: A Prospective Observational Analysis.

Introduction: Incidence of contrast-induced nephropathy (CIN) post percutaneous coronary intervention (PCI) varies between 5% and 20%. Neutrophil gelatinase-associated lipocalin (NGAL) is a sensitive marker for acute kidney injury. Data regarding the predictive accuracy of NGAL in Indian patients undergoing PCI is sparse. Methods: A total of 212 consecutive "all-comer" patients, undergoing PCI from March 2015 to April 2016 were recruited in this single-center observational study. Plasma NGAL levels were measured at 4 hours post PCI using commercially available enzyme-linked immunosorbent assay (Triage® Alere™, San Diego, CA, USA). Results: Twenty-five (11.8%) patients developed CIN. The 4-hour post-PCI plasma NGAL levels were significantly higher in patients with CIN than without (400.6 ± 269.3 ng/mL vs. 109.8 ± 68.0 ng/mL, P < 0.0001). Patients developing CIN had higher age, low estimated glomerular filtration rate (eGFR), and higher contrast volume usage during PCI. After adjusting for confounding factors, diabetes mellitus (adjusted odds ratio [AOR] 3.04; P = 0.039; 95% confidence interval [CI]: 1.06-8.73), hypotension at presentation (AOR 24.84; P < 0.0001; 95% CI: 4.65-132.83), and multi-staged PCI (AOR 13.45; P < 0.0001; 95% CI: 4.54-39.79) were found to independently predict the development of CIN. NGAL levels significantly correlated with age (r = 0.149, P = 0.031), eGFR (r = -0.385, P < 0.0001), hemoglobin (r = -0.214, P = 0.002), contrast volume (r = 0.185, P = 0.007), and 48-hour post-PCI serum creatinine levels (r = 0.334, P < 0.0001). At a cutoff of 256.5 ng/mL, plasma NGAL had a sensitivity of 68% and a specificity of 95.2% (area under the curve = 0.878; P < 0.0001; 95% CI: 0.801-0.955) to predict the occurrence of CIN. Conclusions: Plasma NGAL is an early and highly predictive biomarker of CIN in patients undergoing PCI. Patients having diabetes, hypotension at presentation and those undergoing second-stage procedures are at a high risk of developing CIN after PCI.

Association of Flame-Retardant Clothing With Mycosis Fungoides: A Retrospective Analysis.

Introduction: Mycosis fungoides (MF), the most prevalent form of cutaneous T-cell lymphoma (CTCL), has been associated with a variety of environmental and occupational exposures. Flame-retardant clothing (FRC), in contrast to flame-resistant clothing, is chemically treated and may constitute a previously unrecognized occupational hazard. Objectives: To report an association between FRC and MF. Methods: After encountering several young male patients whose onset of MF coincided with the occupational use of FRC and occupation as fire fighters, we did a retrospective search. Additional biopsy proven MF patients with use of FRC were identified by the EPIC electronic medical record using the search terms "CTCL, mycosis fungoides, flame, and flame-retardant." Results: Eight MF patients, all males, ranging in age from 31 years to 64 years (median age, 35 years) with exposure to FRC were identified. MF remission was noted in three patients who discontinued FRC use and in one patient who used a cotton undershirt barrier, while disease persistence was noted in one patient who continued to use FRC. Conclusions: FRC appears to be associated with development of MF through chronic antigen stimulation. Use of FRC is an occupational hazard for fire fighters. Any patient whose MF coincides with use of FRC should avoid further exposure through avoidance or switching to clothing made from inherently flame-resistant fibers.

Clinical and pathologic features correlated with rare favorable survival in patients with BRAFV600E mutated colorectal cancer.

Background: BRAFV600E mutations occur in fewer than 10% of all patients with metastatic colorectal cancer (CRC) and arise from sessile serrated adenomas. Despite efficacy with targeted therapies against MAPK signaling and with immunotherapies in this population, survival outcomes for patients with BRAFV600E mutated metastatic CRC in general are poor. Characteristics distinguishing patients with BRAFV600E mutated metastatic CRC with favorable versus unfavorable outcomes have not been well annotated. Methods: Records of 187 patients with BRAFV600E mutated metastatic CRC evaluated at MD Anderson Cancer Center between 2005-2020 were reviewed. Patients with the shortest and longest metastatic survival (N=25 for each group) were compared. Associations between prognostic group and clinical/pathologic features were measured by odds ratio and for median survival by log-rank testing. Results: Median metastatic survival differed between the 2 BRAFV600E mutated metastatic CRC populations (8.6 vs. 83.9 months, hazard ratio 32; P<0.0001). Patients with poor survival more commonly had hepatic involvement [75% vs. 28%, odds ratio (OR) 8.1, 95% confidence interval (CI): 2.3-29; P=0.001]. Patients with favorable survival were more likely to develop metachronous metastases (52% vs. 16%, OR 5.7, 95% CI: 1.5-21; P=0.01) and undergo definitive locoregional therapy to metastatic disease (40% vs. 0%, OR 34.5, 95% CI: 1.9-630; P=0.01). Microsatellite instability (36% vs. 4%, OR 19.8, 95% CI: 2.2-180; P=0.008) and prior tobacco exposure (44% vs. 16%, OR 4.1, 95% CI: 1.1-15.6, P=0.04) were associated with a favorable prognosis. Durable responses to MAPK-targeted therapies and immunotherapy were noted in the favorable group. Conclusions: A small fraction of patients with BRAFV600E mutated metastatic CRC can achieve excellent long-term survival which belies conventional context and is driven by either surgical metastectomy or by systemic treatment options. While poor overall prognosis remains the recognized outcome for most patients with BRAFV600E mutated metastatic CRC, it is possible that few may achieve exceptionally favorable survival.

Is Indexed Left Atrial Volume (LAVi) in Indian Patients with Acute Coronary Syndrome (ACS) undergoing revascularization a predictor of cardiovascular outcomes?

BACKGROUND: Left atrial volume indexed to body surface area (LAVi) is the recommended method for LA size quantification. Assessing LAVi in Indian patients undergoing coronary interventions for acute coronary syndrome (STEMI, NSTEMI, and UA) is clinically relevant. METHODS AND RESULTS: Amongst 190 patients (66.4 yrs, 68.4% males), 29.5%, 40.5%, and 30% respectively had STEMI, NSTEMI and UA. Mean LAVi was 32.29 ± 12.06 ml/m2 and 111 (58.4%) had LAVi ≥32 while 79 (41.6%) had LAVi <32. Patients were divided into 2 groups (group 1 LAVi >32 and group 2 LAVi <32). Group 1 patients had higher prevalence of TVD [n = 49 vs n = 5, p = <0.001] and higher mean Syntax score (24.47 vs 14.64, p = <0.001). Despite similar LVEF, those with higher LAVi had had higher incidence of mild MR (50.4 vs 27.8, P = 0.0002) and moderate/severe MR was present only in Group 1 patients (27.9% and 5.4%). Grade I, II, and III diastolic dysfunction was present in 71.2, 17.1, and 9.9% patients in Group 1 vs 45.6%, 0%, and 0% in group 2. Diastolic parameters like septal E/e' and lateral E/e'ratio were also higher in Group 1. Major adverse cardiovascular events (MACE) at 30 days was significantly higher in group 1 (20.7 vs 6.3%, P = 0.006). On multivariate analysis, triple vessel disease and LAVi were the only predictors of MACE while LVEF was not. ROC curve analysis for LAVi demonstrated that a cut-off 33.35 ml/m2, predicted 30 day MACE with Area under curve (AUC) 0.775 (95% CI 0.700-0.850); sensitivity and specificity of 86.7% and 61.4%. Inter-quartile analysis of LAVi (<26.3, 26.3-33.35, 33.36-36.3, and >36.3 ml/m2) demonstrated that 30 day MACE increased across quartiles (4.16%, 4.25%, 22.44%, and 28.26%, respectively, P < 0.001). CONCLUSION: Amongst patients with ACS undergoing revascularization, those with higher LAVi had more severe CAD, diastolic dysfunction and higher 30 day MACE. LAVi provides superior prognostic information as compared to conventional LV systolic and diastolic parameters in patients with ACS and should be incorporated in routine echocardiographic analysis. More studies with larger numbers and longer follow up are required to further elucidate on this.

Exploring the association of fibrinogen and CRP with the clinical spectrum of CAD and periprocedural outcomes in patients undergoing percutaneous coronary interventions.

BACKGROUND: The pathophysiology of an atherosclerotic plaque is mediated by the mechanisms involving thrombus formation and systemic inflammation. While C-reactive protein (CRP) levels are useful in predicting a cardiovascular event in intermediate risk population, the usefulness of routinely measuring fibrinogen in patients with acute coronary syndrome (ACS) is debatable. Also, data on the association of these markers with periprocedural outcomes in patients undergoing percutaneous coronary interventions (PCI) is scarce. AIMS: The study aimed to determine whether the levels of fibrinogen and CRP vary across the different spectra of CAD and whether they have any correlation with cardiac Troponin I levels. MATERIALS AND METHODS: A total of 284 patients with coronary artery disease undergoing percutaneous coronary intervention were included in the study. Complete blood count, serum lipid profile, serum CRP, fibrinogen, and troponin I were measured for all patients. RESULTS: Patients with STEMI had significantly higher levels of CRP as compared to those with unstable angina (USA) and chronic stable angina (CSA). Patients presenting with ACS had significantly higher baseline fibrinogen as compared to those with CSA. A significant positive correlation between CRP and admission Troponin I (r = 0.50; P < 0.05) as well as fibrinogen and admission troponin I (r = 0.30; P < 0.05) was observed. The CRP levels were significantly higher in 15 patients with periprocedural MI as compared to those who did not develop periprocedural MI. CONCLUSIONS: : The levels of the markers of inflammation and atherothrombosis vary with presentation across varied spectra of CAD with generally higher levels in acute presentation and in those who develop periprocedural MI.

Risk factors associated with patient-reported fatigue among long-term oropharyngeal carcinoma survivors.

BACKGROUND: The study objective is to identify risk factors associated with fatigue among long-term OPC survivors. METHODS: This cross-sectional study included disease-free OPC survivors treated curatively between 2000 and 2013 who were surveyed from September 2015 to July 2016. The outcome variable was patient-reported fatigue. Multivariable logistic regression was used to identify factors associated with moderate to severe fatigue. RESULTS: Among 863 OPC survivors, 17.4% reported moderate to severe fatigue. Self-reported thyroid problems (OR: 2.01; p = 0.003), current cigarette smoking at time of survey (OR: 3.85; p = 0.001), late lower cranial neuropathy (OR: 3.44; p = 0.002), and female sex (OR: 1.91; p = 0.010) were concurrent risk factors of reporting moderate to severe fatigue. Ipsilateral intensity-modulated radiotherapy (OR: 0.18; p = 0.014) was associated with lower risk of reporting moderate to severe fatigue. CONCLUSIONS: Our study identified thyroid problems, smoking, and late lower cranial neuropathy as associated with moderate to severe fatigue. These findings should be further validated in prospective studies to address fatigue among OPC survivors.

Vascular dysfunction and its recovery after transradial coronary angioplasty- A serial observational study.

OBJECTIVE: To serially evaluate the effect of trans-radial coronary angioplasty (TRA) on the vascular function of radial artery (RA) and upstream brachial artery (BA) and to find out the relative contribution of endothelial dependent flow-mediated vasodilatation (FMD) and endothelial independent nitrate mediated dilatation (NMD). METHODS: Forty patients of chronic stable angina with successful TRA were studied. FMD and NMD of bilateral RA and BA were measured with high-resolution ultrasound, before and at 24 h and at 3 months, after catheterization. RESULTS: FMD as well as NMD were significantly decreased in right RA (16.3 ± 3.6% to 5.7 ± 1.8%; p = 0.001, and 24.1 ± 5.3% to 9.7 ± 2.8%; p = 0.001, respectively) as well as in upstream BA (17.0 ± 1.6% to 9.4 ± 0.5%; p = 0.001,and 26.5 ± 6.8% to 20.5 ± 3.7%; p = 0.001, respectively) at 24 h. FMD/NMD ratio was also decreased in RA (70 ± 10% to 60 ± 10%; p = 0.04) and as well as in BA (70 ± 20% to 50 ± 10%; p = 0.03). The endothelial dysfunctions returned to normal at 3 months. Control arm did not show any change in vascular function at any point of time. Radial artery diameter/sheath ratio <1 and catheter exchanges >2 were the independent predictors for >50% decrease in FMD. CONCLUSIONS: TRA results in reversible depression in FMD as well as NMD in the radial artery as well as upstream brachial artery. These vascular dysfunctions are limited to the catheterized arm only and return to normal after 3 months.

Acromegaly: Cardiovascular risk factors, cardiovascular manifestations and early vascular alterations in relation to disease activity.

Acromegaly is associated with increased cardiovascular morbidity and mortality. 49 acromegaly patients were evaluated for presence of cardiovascular risk factors and manifestations using 2D-Echocardiography, strain, strain-rate, carotid intima media thickness (CIMT) and flow mediated dilatation (FMD) and correlated with disease activity. 32 patients with growth hormone (GH) level >1 ng/ml were considered active. Patients with active disease have more LV dysfunction as assessed by strain(p-0.031) and strain rate(p-0.001); trend towards lower ejection fraction(p-0.11) with significant correlation to GH(cc -0.252,p-0.05). Patient with active disease have reduced FMD(p- 0.042); with no difference in prevalence of cardiovascular risk factors and CIMT inrelation to disease activity.