Heparin-induced thrombocytopaenia complicating cardiogenic shock requiring durable mechanical circulatory support: a case report.

Background: Heparin-induced thrombocytopaenia (HIT) is an immune-mediated reaction to heparin therapy that may lead to life-threatening thrombotic events. This disorder complicates intraoperative heparin use during left ventricular assist device (LVAD) implantation. Case summary: A 52-year-old man presented in acute decompensated heart failure. His admission laboratory studies were consistent with cardiogenic shock with a lactate of 6.1 mmol/L (ref range 0.50-1.99 mmol/L). Echocardiogram and CT scan demonstrated severe biventricular dysfunction and a left ventricular ejection fraction of 10%, as well as left upper lobe segmental pulmonary embolism. He was started on inotropes, diuretics, and a heparin infusion. Following heparin initiation, his platelets had decreased by 63% to a nadir of 39 000/µL (ref range 150 000-450 000/µL) and testing confirmed a diagnosis of HIT. His shock state worsened to INTERMACS 1 necessitating escalation of mechanical support. In preparation for HeartMate 3 LVAD implantation, he received 3 cycles of plasmapheresis with one session of IVIG perioperatively, resulting in a 60% reduction in the titre of heparin-dependent platelet antibodies. He underwent successful LVAD implantation including usage of intraoperative heparin, and was discharged home on post-operative Day 17, where he has remained stable on LVAD support. Discussion: Limited data exist on the perioperative management of patients with HIT undergoing LVAD implantation. Heparin is preferred to other antithrombin agents during surgery due to the availability of an immediate reversal agent. Plasmapheresis with IVIG is a potential management option to decrease heparin-dependent platelet antibodies in patients with HIT to allow for successful LVAD implantation.

Admission D-dimer levels, D-dimer trends, and outcomes in COVID-19.

Observational data suggest an acquired prothrombotic state may contribute to the pathophysiology of COVID-19. These data include elevated D-dimers observed among many COVID-19 patients. We present a retrospective analysis of admission D-dimer, and D-dimer trends, among 1065 adult hospitalized COVID-19 patients, across 6 New York Hospitals. The primary outcome was all-cause mortality. Secondary outcomes were intubation and venous thromboembolism (VTE). Three-hundred-thirteen patients (29.4%) died, 319 (30.0%) required intubation, and 30 (2.8%) had diagnosed VTE. Using Cox proportional-hazard modeling, each 1 µg/ml increase in admission D-dimer level was associated with a hazard ratio (HR) of 1.06 (95%CI 1.04-1.08, p < 0.0001) for death, 1.08 (95%CI 1.06-1.10, p < 0.0001) for intubation, and 1.08 (95%CI 1.03-1.13, p = 0.0087) for VTE. Time-dependent receiver-operator-curves for admission D-dimer as a predictor of death, intubation, and VTE yielded areas-under-the-curve of 0.694, 0.621, and 0.565 respectively. Joint-latent-class-modeling identified distinct groups of patients with respect to D-dimer trend. Patients with stable D-dimer trajectories had HRs of 0.29 (95%CI 0.17-0.49, p < 0.0001) and 0.22 (95%CI 0.10-0.45, p = 0.0001) relative to those with increasing D-dimer trajectories, for the outcomes death and intubation respectively. Patients with low-increasing D-dimer trajectories had a multivariable HR for VTE of 0.18 (95%CI 0.05-0.68, p = 0.0117) relative to those with high-decreasing D-dimer trajectories. Time-dependent receiver-operator-curves for D-dimer trend as a predictor of death, intubation, and VTE yielded areas-under-the-curve of 0.678, 0.699, and 0.722 respectively. Although admission D-dimer levels, and D-dimer trends, are associated with outcomes in COVID-19, they have limited performance characteristics as prognostic tests.

Globular C1q Receptor (gC1qR/p32/HABP1) Is Overexpressed in Malignant Pleural Mesothelioma and Is Associated With Increased Survival in Surgical Patients Treated With Chemotherapy.

Introduction: Globular C1q receptor (gC1qR/p32/HABP1) is overexpressed in a variety of cancers, particularly adenocarcinomas. This study investigated gC1qR expression in malignant pleural mesothelioma (MPM) and its pathophysiologic correlates in a surgical patient cohort. Methods: Tissue microarrays comprising 6 tumoral and 3 stromal cores from 265 patients with MPM (216 epithelioid, 26 biphasic, and 23 sarcomatoid; 1989-2010) were investigated by immunohistochemistry for gC1qR expression (intensity and distribution by H-score, range 0-300), and immune cell infiltration. Overall survival (OS) was analyzed by the Kaplan-Meier method (high vs. low gC1qR expression delineated by median score) in the whole cohort and by neoadjuvant chemotherapy (NAC) status. Multivariable Cox analysis included stage, chemotherapy, and immune cell infiltration. Results: gC1qR was overexpressed in all histological types of MPMs (263/265, 99.2%) compared to normal pleura. In epithelioid MPM, high gC1qR expression was associated with better OS (median 25 vs. 11 months; p = 0.020) among NAC patients, and among patients without NAC (No-NAC) but who received post-operative chemotherapy (median OS 38 vs. 19 months; p = 0.0007). In multivariable analysis, high gC1qR expression was an independent factor for improved OS in patients treated with NAC. In the No-NAC cohort, high gC1qR expression correlated with lower tumor stage. Moreover, the influence of Ki67 and CD4 T-cell infiltration on OS were more pronounced among patients with high gC1qR expression. Conclusion: This is the first description of gC1qR expression in MPM. The data identify gC1qR as a potential new prognostic factor in patients treated with surgery and chemotherapy.

Increased RNA Expression of von Willebrand Factor Gene Is Associated With Infiltrating Lobular Breast Cancer and Normal PAM50 Subtype.

BACKGROUND: Infiltrating lobular carcinoma (ILC) is the second most common histologicaI subtype of breast cancer, accounting for 10% of all cases. ILC has a characteristic genomic profile. ILC shows a high frequency of cadherin 1 (CDH1) mutations, along with loss of phosphatase and tensin homolog (PTEN), activation of alpha serine/threonine kinase (AKT), and mutations in T-box transcription factor (TBX3) and forkhead box protein A1 (FOXA1). We suspected that another gene, von Willebrand factor (VWF), might also be part of the profile, since coagulation tests reveal significant differences in patients with breast cancer. MATERIALS AND METHODS: For newly-diagnosed breast cancer, the association between VWF and histology in the GDC Breast Cancer dataset in The Cancer Genome Atlas (TCGA) was evaluated. The following were used to access and analyze the data: Genomic Data Commons Data Portal (https://portal.gdc.cancer.gov/); Xena browser (https://xenabrowser.net); cBioportal (http://cbioportal.org); Oncomine (https://oncomine.org); and Prediction Analysis of Microarray 50 (PAM50). RESULTS: Patients with ILC had higher VWF RNA expression than patients with infiltrating ductal carcinoma and other histology. The difference of expression was present to the same degree in both pre-menopausal and post-menopausal patients. Nine alterations in VWF and PTEN were significantly co-occurrent. Considering all histologies in 843 samples, Tukey's honest significant difference post hoc test showed that VWF RNA expression of the normal subtype was significantly greater than that of the other subtypes (p<0.001). CONCLUSION: Our finding of significantly higher VWF RNA expression in the PAM50 normal (non-basal-like) breast cancer subtype suggests that VWF protein measurement might complement or corroborate PAM50 results. VWF and PAM50 results both suggesting a low risk of recurrence might make the decision whether to give chemotherapy easier, especially if VWF protein were an independent predictor.

Surgical pathology of early stage non-small cell lung carcinoma.

The histologic classification of non-small cell lung carcinoma (NSCLC), particularly adenocarcinoma (ADC), has undergone extensive study in recent decades, ultimately resulting in an extensively updated classification system. The 2015 World Health Organization (WHO) classification of ADC provides greatly improved prognostic information in comparison to the 2004 WHO classification. Several issues still require further investigation: lepidic predominant ADC, prognostic significance of poor prognostic subtypes such as micropapillary carcinoma, the more recently described concept of spread of tumor through airspaces (STAS), and the utility of sublobar resections. While limited resection appears to be suitable for tumors with a ground glass radiographic appearance, which typically correspond to adenocarcinoma in situ (MIS) or minimally invasive adenocarcinoma (MIA) histologically, the role of sublobar resection in radiographic solid tumors is not as clear, and the impact of histologic subtypes with a poor prognosis needs further evaluation. Squamous cell carcinoma (SCC) has not been as extensively studied and the current classification lacks subclassification with significant prognostic information.

Soluble gC1qR in Blood and Body Fluids: Examination in a Pancreatic Cancer Patient Cohort.

BACKGROUND: gC1qR is a multifunctional cellular protein that has been linked to inflammation and cancer. gC1qR is highly upregulated in adenocarcinomas as compared to normal tissue counterparts, and soluble gC1qR (sgC1qR) has been detected in vitro in the pericellular milieu of proliferating malignant cells. AIM: The present study explored the tissue expression of gC1qR in pancreatic cancer by immunohistochemistry, and the presence of sgC1qR in vivo, by examining blood and malignant effusions from patients with metastatic pancreatic adenocarcinoma. METHODS: Tissue expression of gC1qR by pancreatic adenocarcinoma was visualized by immunohistochemistry. SgC1qR was quantified in serum from healthy volunteers (n=20) and pancreatic cancer patients (n=34), as well as in malignant pleural (n=23) and peritoneal effusions (n=27), using a newly developed, sensitive immunocapture sandwich ELISA. RESULTS: Overexpression of gC1qR was confirmed in pancreatic adenocarcinoma compared to nonmalignant pancreatic tissue. Moreover, increased serum levels of sgC1qR (0.29 ± 0.22 ng/ml) were noted in patients with metastatic pancreatic cancer compared to healthy controls (0.15 ± 0.10 ng/ml) (mean ± S.D.) (p=0.035). In 11 of 16 patients for whom sequential samples were available, serum sgC1qR levels rose with disease progression, and paralleled changes in tumor biomarkers, CEA and CA19.9. In addition to blood, sgC1qR was detected in malignant pleural (0.55 ± 0.47 ng/ml) and peritoneal effusions (0.57 ± 0.38 ng/ml). CONCLUSION: This study provides the first evidence for the presence of sgC1qR in vivo. The ability to detect sgC1qR in blood and body fluids will enable further studies to elucidate its pathophysiology in malignancy.

Impact of histologic subtyping on outcome in lobar vs sublobar resections for lung cancer: a pilot study.

OBJECTIVE: The 2011 International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification of pulmonary adenocarcinomas introduces adenocarcinoma in situ and minimally invasive carcinoma and categorizes adenocarcinoma with more extensive invasion by the predominant subtype. Data have shown that wedge or segmentectomy (W/S) may be appropriate for in situ and minimally invasive adenocarcinoma, but whether sublobar resection is appropriate for tumors with more extensive invasion is unclear. The aim of this pilot study is to evaluate whether there are any trends regarding the impact of invasion and subtypes of carcinoma regarding survival in lobectomy vs W/S procedures using a comprehensive histologic evaluation. METHODS: Eighty-five surgical specimens (59 lobectomies, 26 W/Ss) were reviewed. Histologic type, size, pleural, lymphovascular invasion, and necrosis were recorded. Adenocarcinomas were classified by 2011 IASLC/ATS/ERS guidelines with each histologic pattern recorded as a percentage of the total tumor. Statistical analysis was performed using SAS, version 9.2. Proportional hazards regression analysis was used to evaluate survival according to resection type (lobectomy or W/S) adjusting for tumor size and the predominant histology. RESULTS: Multivariate analysis did not show a statistically significant difference in survival between lobectomy and W/S specimens adjusting for tumor size, regardless of histologic subtype or other negative predictors of prognosis (P = .7704). CONCLUSIONS: Our findings corroborate the prognostic significance of the 2011 adenocarcinoma subtyping classification and additionally suggest that lobectomy does not offer an overall survival advantage over W/S regardless of histologic subtype. Therefore, this finding suggests that limited resection may be appropriate for small size tumors, particularly those ≤ 2 cm with invasive histology.

Atypical Chédiak-Higashi syndrome with attenuated phenotype: three adult siblings homozygous for a novel LYST deletion and with neurodegenerative disease.

BACKGROUND: Mutations in LYST, a gene encoding a putative lysosomal trafficking protein, cause Chédiak-Higashi syndrome (CHS), an autosomal recessive disorder typically characterized by infantile-onset hemophagocytic syndrome and immunodeficiency, and oculocutaneous albinism. A small number of reports of rare, attenuated forms of CHS exist, with affected individuals exhibiting progressive neurodegenerative disease beginning in early adulthood with cognitive decline, parkinsonism, features of spinocerebellar degeneration, and peripheral neuropathy, as well as subtle pigmentary abnormalities and subclinical or absent immune dysfunction. METHODS: In a consanguineous Pakistani kindred with clinical phenotypes consistent with attenuated CHS, we performed SNP array-based homozygosity mapping and whole gene sequencing of LYST. RESULTS: We identified three individuals homozygous for a novel six base pair in-frame deletion in LYST (c.9827_9832ATACAA), predicting the loss of asparagine and threonine residues from the LYST transcript (p.Asn3276_Thr3277del), and segregating with the phenotype in this family. CONCLUSIONS: We further characterize the neurologic features of the attenuated form of CHS, and discuss pathophysiologic mechanisms underlying the neurodegenerative components of CHS. Attenuated CHS is phenotypically heterogenous and should be considered when young adults develop neurodegenerative disease and have pigmentary abnormalities. We briefly discuss surveillance and management of patients with CHS-related neurodegeneration.

gC1qR expression in normal and pathologic human tissues: differential expression in tissues of epithelial and mesenchymal origin.

The gC1qR (i.e., gC1q receptor, gC1q binding protein, p32, p33) is a multifunctional cellular protein that interacts with components of the complement, kinin, and coagulation cascades and select microbial pathogens. Enhanced gC1qR expression has been reported in adenocarcinomas arising in a variety of organs. The present study compared gC1qR expression in normal, inflammatory, dysplastic, and malignant tissue of epithelial and mesenchymal origin. gC1qR expression was visualized in tissue sections by immunohistochemistry using the 60.11 monoclonal antibody (i.e., IgG(1) mouse monoclonal antibody directed against gC1qR) and the UltraVision LP Detection System. Sections were counterstained with hematoxylin and examined by light microscopy. Strongest gC1qR expression was noted in epithelial tumors of breast, prostate, liver, lung, and colon, as well as in squamous and basal cell carcinoma of the skin. However, increased gC1qR staining was appreciated also in inflammatory and proliferative lesions of the same cell types, as well as in normal continuously dividing cells. In contrast, tumors of mesenchymal origin generally stained weakly, with the exception of osteoblasts, which stained in both benign and malignant tissues. The data suggest that increased gC1qR expression may be a marker of benign and pathologic cell proliferation, particularly in cells of epithelial origin, with potential diagnostic and therapeutic applications.

Recommendations for appropriate activated partial thromboplastin time reagent selection and utilization.

The activated partial thromboplastin time (aPTT) is widely used as a screening coagulation test and for monitoring unfractionated heparin therapy. Various commercial reagents are available, with different performance characteristics, particularly responsiveness to the lupus anticoagulant (LA). Because aPTT reagent selection significantly affects the interpretation of results, we reviewed College of American Pathologists proficiency testing data involving approximately 4,000 coagulation laboratories, and conducted a survey of coagulation laboratories (n = 93) using The Fritsma Factor hemostasis Web site to determine the basis for aPTT reagent selection. The data demonstrate that for routine aPTT testing, most laboratories use reagents with high/moderate responsiveness to LA. Significant misunderstanding was apparent regarding the use of appropriate aPTT reagent for routine testing and LA identification. We recommend aPTT reagents with low LA responsiveness to screen for coagulation factor deficiencies and heparin monitoring, and suggest continued education of laboratory professionals and reagent manufacturers about appropriate aPTT reagent use.

Lupus anticoagulant testing: performance and practices by north american clinical laboratories.

Lupus anticoagulant (LAC) testing is important for evaluating patients with antiphospholipid syndromes and hypercoagulable states. We reviewed results of proficiency testing challenges (n = 5) distributed by the North American Specialized Coagulation Laboratory Association to examine LAC testing performed by participating laboratories. The activated partial thromboplastin time (APTT) and dilute Russell viper venom time (dRVVT) constituted major testing methods. In screening studies, LAC-sensitive APTT methods were more sensitive to weak LAC than dRVVT-based methods but less specific. In confirmatory testing, dRVVT methods performed better, but performance was LAC-dependent. The highest false-negative confirmatory test results were obtained for the platelet neutralization procedure. Noncompliance with recommendations for LAC testing by the International Society on Thrombosis and Haemostasis was high (8%-38%), with the majority of noncompliant laboratories failing to report results of mixing studies. These data provide new insights into LAC testing in North America and identify opportunities for standardization.

Screening coagulation testing using the APTT: which reagent to choose?

APTT testing is integral to hemostasis testing. A prolonged result, however, can be difficult to interpret, depending on the APTT reagent's sensitivity to the lupus anticoagulant. This often generates additional laboratory testing for both factor deficiencies and the presence of a lupus anticoagulant, and in so doing, delays patient management. We have found it useful to provide APTT testing with both a lupus anticoagulant sensitive and insensitive reagent, to facilitate the rapid exclusion of significant factor deficiencies. The following case report illustrates the utility of this approach and provides a backdrop for necessary discussions between laboratories and clinicians regarding which APTT reagent best meets their clinical need for screening hemostasis testing.

Thoracoscopic lobectomy: report on safety, discharge independence, pain, and chemotherapy tolerance.

OBJECTIVE: Controversies regarding the safety, morbidity, and mortality of thoracoscopic lobectomy have prevented the widespread acceptance of the procedure. This series analyzed the safety, pain, analgesic use, and discharge disposition in patients who underwent thoracoscopic lobectomy and segmentectomy at a single institution. METHODS: We collected data from 153 consecutive patients who underwent thoracoscopic (video-assisted thoracic surgery) lobectomy and assessed the perioperative outcomes, postoperative pain, and chemotherapy course. A total of 111 of 127 patients with lung cancer had stage I non-small cell lung cancer. The operative technique required 2 ports and an access incision (5-8 cm), individual hilar ligation, and lymph node dissection performed without rib-spreading devices. RESULTS: There were 9 major complications (6%), including 1 perioperative death (0.7%). Conversion to thoracotomy occurred in 14 patients (9.2%). Blood transfusion was required in 11 patients (7%). The median chest tube time was 3 days, and the length of hospital stay was 4 days; 94.4% of patients went home at the time of discharge, and 5.6% of patients required a rehabilitation facility. At a median postsurgical follow-up time of 2 weeks, the mean postoperative pain score was 0.6 (0-3), 73% of patients did not use narcotics for pain control, and 47% of patients did not use any pain medication. Of patients receiving chemotherapy (N = 26), 73% completed a full course on schedule and 85% received all intended cycles. CONCLUSION: Thoracoscopic (video-assisted thoracic surgery) lobectomy can be performed safely. Discharge independence and low pain estimates in the early postoperative period suggest that this approach may be beneficial. Furthermore, there is a trend toward improved tolerance of chemotherapy.

Video-assisted thoracoscopic lobectomy: state of the art and future directions.

BACKGROUND: Thoracoscopic lobectomy is performed with increasing frequency for early-stage lung cancer. Several published reports suggest thoracoscopic resection is safe, with the potential advantage of shorter hospital stay, quicker recovery, and comparable oncologic results. METHODS: Data on 180 video-assisted thoracoscopic surgery (VATS) patients who underwent thoracoscopic lobectomy or sublobar anatomic resection at our institution between January 2002 and December 2006 were reviewed. The conversion rate to thoracotomy, complications, length of stay, and duration of chest tube drainage were determined. Similar variables were evaluated for patients aged older than 80 years, those with a forced expiratory volume in 1 second (FEV1) that was less than 50% predicted, those who had undergone preoperative neoadjuvant therapy, and those who had undergone lung-sparing anatomic resections. RESULTS: Thoracoscopic anatomic lung resection was performed successfully in 166 patients. One of 180 patients (0.6%) died, and 14 patients (9.2%) underwent conversions. Overall median length of stay was 4 days (range, 1 to 98; interquartile range [IQR], 3), and median duration of chest tube drainage was 3 days (range, 0 to 35 days; IQR, 2). The median length of hospital stay and median chest tube duration for the group aged 80 years and older was 5 and 3 days; for the segmental resection group, 4 and 3 days; for the chemotherapy or radiotherapy induction group, 3.5 and 3 days; and for the FEV1 less than 50% group, 5.5 and 4 days, respectively. No patients died in any of these groups. CONCLUSIONS: Thoracoscopic lung resection can be performed safely in selected patients aged 80 years and older, in those with marginal pulmonary function, and in those with pathologic response to neoadjuvant therapy.

Monoclonal antibody specific for histone H1 phosphorylated by cyclin-dependent kinases: a novel immunohistochemical probe of proliferation and neoplasia.

Monoclonal antibody 12D11 (MAb 12D11) has been shown to bind histone H1 isolated from human placenta and other tissues but not histone H1 that has been digested with bacterial alkaline phosphatase. We show here that phosphorylation of phosphatase-treated histone H1 with cyclin dependent-kinase (CDK) restores binding by MAb 12D11. We conclude that MAb 12D11 selectively binds histone H1 that has been phosphorylated by CDKs, and we have investigated the use of MAb 12D11 as an immunohistochemical probe of CDK activity in situ. Previous immunofluorescence studies have revealed strong nuclear staining by MAb 12D11 in proliferating cultured cells and the absence of staining in terminally differentiated cells. Immunohistochemical staining of frozen and formalin-fixed, paraffin-embedded sections of benign tissues with MAb 12D11 was nuclear and confined to recognized foci of cell proliferation. In lymphoid germinal centers, MAb 12D11 preferentially stained large lymphoid cells with a relative lack of staining in small cleaved cells, contrasting with a lack of cell size discrimination observed with the monoclonal antibody proliferation probe, MIB-1. Tumor tissues displayed strong albeit heterogeneous staining of malignant cells by MAb 12D11, with little or no staining observed in surrounding nonneoplastic stromal cells. Differential staining by MAb 12D11 of invasive and in situ carcinoma suggest applications in prognostication. MAb 12D11 may also be useful in identification of tumors more likely to respond to therapeutic CDK inhibitors.

The adrenal gland in AIDS.

The adrenal gland has been known to be a common site of opportunistic infections and tumors that define the acquired immunodeficiency syndrome (AIDS) ever since the first autopsy data were published. We have examined the adrenal glands of 66 AIDS patients autopsied in New York City and tabulated and graded the findings in an attempt to estimate the likelihood of adrenal insufficiency developing on the basis of these lesions. AIDSdefining conditions were found in the adrenal glands of 56% of patients, primarily opportunistic infections (53%) and much less frequently neoplasms (3%). Cytomegaloviral (CMV) infection was by far the most common type (42%), followed by mycobacterial (8%) and fungal infections (3%). There was one case eachof Kaposi's sarcoma and lymphoma. Total necrosis of adrenal cortex was restricted to 2 cases of tuberculosis. CMV adrenalitis, although the most common infection and often associated with necrosis, never resulted in more than 30% destruction of the cortex. We conclude that although histopathological evidence of adrenal disease is common in AIDS, most such lesions are not sufficiently extensive to result in adrenal insufficiency. In contrast to previous reports stressing the importance of CMV adrenalitis as a possible cause of adrenocortical insufficiency, we now find tuberculosis the more likely cause of total cortical destruction.