Heart rate variability and haemodynamic factors associated with hypotension during spinal anaesthesia for caesarean delivery: A case-control study.

BACKGROUND: Hypotension frequently occurs during spinal anaesthesia for caesarean delivery, with potential adverse effects. OBJECTIVE: To investigate heart rate variability and haemodynamic factors associated with spinal anaesthesia-induced hypotension. DESIGN: Secondary case-control analysis of a randomised study. SETTING: Single obstetric centre. PATIENTS: Data were obtained from 230 healthy term singleton parturients who underwent elective caesarean delivery under spinal anaesthesia. INTERVENTION: With parturients at rest, continuous haemodynamic measurements were recorded using a Nexfin cardiac monitor. Baseline pre-operative values were defined as the average of five minutes of continuous measurements. After initiation of standardised spinal anaesthesia, vasopressors were administered to maintain SBP within 10% of pre-operative values. Hypotension was defined as any 10 seconds average SBP less than 80% of pre-operative values from initiation of spinal anaesthesia to foetal delivery. Parturients were classified into cases (hypotensive) or controls (normotensive), and both univariate and multivariable logistic regression models were used to identify independent factors associated with hypotension. MAIN OUTCOME MEASURES: Pre-operative standard deviation of the interbeat interval (SDNN), root mean square of successive interbeat difference, low-frequency to high-frequency ratio, SD1, SD2, approximate entropy, sample entropy, mean arterial pressure, SBP, stroke volume variation and systemic vascular resistance index were recorded, as were sensory block height, intravenous fluid volume and vasopressor use between spinal anaesthesia and foetal delivery. RESULTS: Of 230 parturients, 113 (49.1%) experienced hypotension. Pre-operative lower SDNN [odds ratio (OR) 0.87, 95% confidence interval (CI) 0.78 to 0.97], higher SD2 (OR 25.06, 95% CI 2.41 to 261.06), and lower SBP (OR 0.98, 95% CI 0.97 to 1.00) were independently associated with hypotension. Between spinal anaesthesia to foetal delivery, lower sensory block height (OR 0.76, 95% CI 0.65 to 0.90) and higher intravenous fluid volume (OR 0.98, 95% CI 0.96 to 0.99 per 15 ml change) were associated with a lower incidence of hypotension. Area under the receiver operating characteristic curve was 0.701. CONCLUSION: Pre-operative higher SD2, lower SDNN and lower SBP were associated with hypotension during spinal anaesthesia for caesarean delivery. TRIAL REGISTRATION: NCT02277730.

Checkpoint Inhibition in the Treatment of Unresectable, Advanced Lymphoepithelioma-like Hepatocellular Carcinoma.

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a very rare neoplasm, with distinct epidemiologic, morphologic and clinical characteristics. Molecular mechanistic insight into the pathogenesis of this carcinoma suggests a pivotal role for the host immune system in the proliferation and progression of this tumor. However, while detailed genomic profiling of these hepatic tumors have revealed an intra-tumoral inflammatory mutational signature that may predispose to immune checkpoint inhibitor efficacy, no published report has described their use in this tumor type. Unfortunately, with near 100 cases of LEL-HCC reported in the literature to date and the majority of cases confined to localized and resectable disease, current evidence-based practices in the unresectable setting are lacking, with unknown benefit of chemotherapy or immunotherapy. We report on the case of a 68 year-old man with unresectable, advanced LEL-HCC who had evidence of disease stability after starting on the immune checkpoint inhibitor nivolumab. His disease response persisted off therapy for over a year and was potentially augmented by radiotherapy at the site of local progression. For this extremely rare tumor subtype, this case highlights the potential efficacy and safety of immune checkpoint blockade in LEL-HCC and reinforces the need for more robust, large-scale analysis of patients with these rare tumors to better evaluate treatment strategies and outcomes.

Morphometry Confirms Fibrosis Regression From Sustained Virologic Response to Direct-Acting Antivirals for Hepatitis C.

Sustained virologic response (SVR) after direct-acting antiviral (DAA) therapy for chronic hepatitis C results in significant decreases in liver stiffness measured by transient elastography (TE). The aim of this study was to clarify if TE can guide post-SVR management in patients with advanced fibrosis or cirrhosis prior to treatment as current guidelines are unclear on the role of TE after SVR. In total, 84 patients with hepatitis C virus and advanced fibrosis or cirrhosis and from a single center underwent DAA treatment and achieved SVR. Overall, 62% had improved liver stiffness that was consistent with regression of at least one stage of fibrosis. In the cirrhosis group, 48% showed fibrosis regression by at least two stages by TE (<9.5 kPa). In the F3 fibrosis group, 39% regressed by at least two stages (<7 kPa). The median time from SVR to regression by TE was 1 year. Fifteen patients with liver biopsies prior to SVR underwent a biopsy after SVR; 13 of these patients had improved liver stiffness (to <9.5 kPa). The post-SVR liver biopsies of only 4 patients showed F1-F2 while 11 patients showed F3-F4; however, morphometry of the first 11 biopsied patients revealed that 10 patients had an average 46% decrease in collagen content. Conclusion: This is the first DAA study that also has paired liver biopsies showing fibrosis regression. After SVR is achieved, improvements in liver stiffness measured by TE are seen in a majority of patients with advanced fibrosis/cirrhosis within 2 years. TE improvements are overstated when compared to histologic staging but confirmed with morphometric analysis. It is unclear whether TE following SVR can reliably predict when patients no longer require advanced fibrosis/cirrhosis monitoring after SVR.

A rare localised nasal CD30+ primary cutaneous T-cell lymphoma following liver transplantation.

Cutaneous T-cell post-transplant lymphoproliferative disorder (PTLD) is a rare clinical presentation that can potentially turn aggressive in solid-organ transplant recipients if not detected and intervened on early. We encountered a rare case of rapidly worsening primary cutaneous CD30-positive, Epstein-Barr virus-negative anaplastic large cell lymphoma (ALCL) of T-cell origin, manifesting as an isolated nasal tip lesion in a 71-year-old man 4 years after orthotopic liver transplantation. Excisional biopsy with partial rhinectomy showed subepithelial diffuse infiltration of medium-to-large lymphoid cells having round-to-irregular nuclei, partially condensed chromatin and prominent nucleoli. Immunophenotypic studies revealed CD30-positive primary cutaneous ALCL. Positron emission tomography/CT imaging revealed a locally active disease, and radiation therapy was initiated with complete response. A high index of suspicion for PTLD when evaluating skin lesions in a post-transplant patient is paramount for its early recognition, prompt diagnosis and timely intervention while the window for curative therapy remains possible.

Epithelioid Glioblastomas and Anaplastic Epithelioid Pleomorphic Xanthoastrocytomas--Same Entity or First Cousins?

Epithelioid glioblastoma (eGBM) and pleomorphic xanthoastrocytoma (PXA) with anaplastically transformed foci (ePXA) show overlapping features. Eleven eGBMs and 5 ePXAs were reviewed and studied immunohistochemically. Fluorescence in situ hybridization for EGFR amplification, PTEN deletion and ODZ3 deletion was also performed, with Ilumina 450 methylome analysis obtained in five cases. The average age for eGBM was 30.9 (range 2-79) years, including five pediatric cases and a M : F ratio of 4.5. The ePXA patients had a M : F ratio of 4 and averaged 21.2 (range 10-38) years in age, including two pediatric cases. Six eGBMs and two ePXAs recurred (median recurrence interval of 12 and 3.3 months, respectively). All tumors were composed of solid sheets of loosely cohesive, "melanoma-like" cells with only limited infiltration. ePXAs showed lower grade foci with classic features of PXA. Both tumor types showed focal expression of epithelial and glial markers, retained INI1 and BRG1 expression, occasional CD34 positivity, and lack of mutant IDH1 (R132H) immunoreactivity. BRAF V600E mutation was present in four eGBMs and four ePXAs. ODZ3 deletion was detected in seven eGBMs and two ePXAs. EGFR amplification was absent. Methylome analysis showed that one ePXA and one eGBM clustered with PXAs, one eGBM clustered with low-grade gliomas, and two eGBMs clustered with pediatric-type glioblastomas. Common histologic, immunohistochemical, molecular and clinical features found in eGBM and ePXA suggest that they are closely related or the same entity. If the latter is true, the nomenclature and WHO grading remains to be resolved.

HER-2 fluorescence in situ hybridization: results from the survey program of the College of American Pathologists.

CONTEXT: Fluorescence in situ hybridization (FISH) is a common method used to determine HER-2 status in breast cancer. Limited information is available concerning reproducibility of FISH in determining HER-2 gene amplification. OBJECTIVE: To present proficiency testing results of FISH for HER-2 conducted by the Cytogenetics Resource Committee of the College of American Pathologists/American College of Medical Genetics. DESIGN: During the past 5 years, unstained sections from 9 invasive breast carcinomas were used for HER-2 FISH proficiency testing, allowing for comparison of FISH results among a large number of laboratories. Additional data were collected using an educational (ungraded) challenge and supplemental questions in the surveys. RESULTS: The number of laboratories participating in HER-2 FISH proficiency testing has increased steadily during the past 5 years (from 35 in 2000 to 139 in 2004). Reproducibility of test results among laboratories was excellent for breast tumors with low copy number (no HER-2 amplification) and for breast tumors with high copy number (HER-2 amplification). However, there was considerable variation in interpretation of results for a tumor with low-level HER-2 amplification that was tested on 2 separate occasions. Responses to supplemental questions indicated that there was a need for consensus on the use of a separate equivocal/borderline interpretative category and the need for standardization of cutoff values used to define interpretative categories. CONCLUSIONS: The College of American Pathologists proficiency survey programs provide useful information concerning the reproducibility of clinical testing for HER-2 by FISH and reflect clinical interpretation of HER-2 FISH analyses from laboratories across the country.

TTF-1 expression is specific for lung primary in typical and atypical carcinoids: TTF-1-positive carcinoids are predominantly in peripheral location.

Thyroid transcription factor (TTF)-1 expression in neuroendocrine tumors (NETs) has not been studied as widely as that in non-NETs, with the exception of small cell carcinomas, in which TTF-1 is highly sensitive but not specific for a primary lung tumor. The reported incidence of TTF-1 expression in pulmonary carcinoids has also been highly variable in the literature. To evaluate the expression of TTF-1 in NETs and potential value of TTF-1 in distinguishing pulmonary NETs from those of extrapulmonary origin, we performed an immunohistochemical study by using semiquantitative analysis on formalin-fixed, paraffin-embedded sections from 111 NETs, including 80 pulmonary (11 carcinoid tumorlets [TLs] or foci of neuroendocrine cell hyperplasia [NEH], 36 typical carcinoids [TCs], 17 atypical carcinoids [ACs], 16 large cell neuroendocrine carcinomas [LCNECs]), 13 thymic (3 TCs, 8 ACs, 2 LCNECs), 17 gastrointestinal or pancreatic (13 TCs, 4 ACs), and 1 ovarian (LCNEC). Pulmonary carcinoids were subdivided into those with central and those with peripheral location. TTF-1 positivity was seen exclusively in pulmonary NETs and was significantly higher in NEH or TLs (72.7%) than in TCs (27.8%), ACs (29.4%), and LCNECs (37.5%; P = 0.03). All extrapulmonary NETs were uniformly negative for TTF-1 staining. Interestingly, 12 of 14 TTF-1-positive pulmonary TCs and ACs had a peripheral location with spindle cell morphology, as did all cases of TL, a purported precursor of peripheral carcinoids. In conclusion, TTF-1 expression was 100% specific, though not so sensitive, for the lung primary in TCs and ACs and possibly also in LCNECs. Prevalent TTF-1 positivity in TLs and peripheral carcinoids suggest that they may be histogenetically distinct from the central carcinoids, which are typically composed of TTF-1-negative, more rounded cells.

Ampullary pancreatoblastoma in an elderly patient: a case report and review of the literature.

Pancreatoblastoma, generally regarded as a pediatric malignant tumor, is rarely found in the adult population. Only 13 adults with pancreatoblastoma, ranging in age from 19 to 68 years, have previously been reported in the world literature. A diagnosis of pancreatoblastoma relies on characteristic histologic features, including epithelial differentiation and, more importantly, squamoid differentiation. Despite aggressive therapy, adults with pancreatoblastoma have a poor outcome. We describe a 78-year-old woman who presented with painless jaundice and was found on abdominal computed tomographic scan to have a 2.7-cm ampullary mass. The patient underwent successful pancreaticoduodenectomy. Pathologic examination of the resected tumor revealed findings characteristic of pancreatoblastoma. The tumor formed acinar and glandular structures, solid areas, and contained many "squamoid corpuscles," a defining feature of pancreatoblastoma. The tumor cells also showed acinar and ductal phenotype by immunohistochemistry. To the best of our knowledge, this case represents the oldest patient with pancreatoblastoma to be described in the literature to date and the first to occur in the ampulla of Vater. We review previously published cases and discuss the clinical and histopathologic features of adult pancreatoblastoma.

Fine needle aspiration of splenic extramedullary hematopoiesis presenting as a solitary mass. A case report.

BACKGROUND: Extramedullary hematopoiesis (EMH) generally occurs in patients with deficient bone marrow hematopoiesis secondary to either peripheral red cell destruction or marrow replacement. EMH is most commonly seen in the liver and spleen as a diffuse lesion. Rarely EMH presents as a solitary mass, posing a diagnostic dilemma. In asymptomatic patients without obvious evidence of hematopathology, the differential diagnosis is even more complex. Despite the several articles detailing the radiographic findings in EMH, fewer promote the utility of fine needle aspiration (FNA) in making this diagnosis. CASE: EMH presented as a discrete, 6-cm, tumorlike splenic mass, first identified on computed tomography in a patient with a history of prostate carcinoma. FNA findings suggested a diagnosis of EMH, which was confirmed by splenectomy. In searching for the cause of EMH, no evidence of either metastatic or hematologic disease was identified. The cause of EMH in this patient remains unknown. To our knowledge, this is the first case of solitary splenic EMH reported to occur in an asymptomatic patient. CONCLUSION: FNA is a useful adjunct in the evaluation of isolated splenic masses, particularly in the diagnosis of EMH, where hematopoietic precursors are readily identified cytologically. We advocate the use of FNA in the management of splenic masses. In addition, our case also suggests that EMH be included in the differential diagnosis of isolated splenic lesions, even in patients without obvious hematologic disorders.

Transgenic expression of cholesterol-7-alpha-hydroxylase prevents atherosclerosis in C57BL/6J mice.

C57BL/6J mice are susceptible to atherosclerosis when fed a diet consisting of fat, cholesterol, and taurocholate. The susceptibility to diet-induced atherosclerosis is linked to a reduction in plasma high density lipoprotein (HDL). Diet-induced reduction of plasma HDL shows a physiological and a genetic correlation with repression of cholesterol-7-alpha-hydroxylase, the liver-specific enzyme that regulates the conversion of cholesterol into bile acids. To examine the hypothesis that the repression of cholesterol-7-alpha-hydroxylase is responsible for initiating the metabolic alterations leading to the formation of atherosclerosis and gallstones, we determined whether constitutive transgenic expression of cholesterol-7-alpha-hydroxylase in C57BL/6J mice would confer resistance to these 2 common human diseases. When fed the atherogenic diet, nontransgenic littermates, but not cholesterol-7-alpha-hydroxylase transgenic mice, accumulated cholesterol and cholesterol esters in their livers and plasma. Although the atherogenic diet caused a marked decrease in plasma HDL cholesterol in nontransgenic mice, HDL levels in transgenic mice remained relatively unchanged. Moreover, the ability of cholesterol-7-alpha-hydroxylase transgenic mice to maintain cholesterol and lipoprotein homeostasis completely prevented the formation of atherosclerosis and gallstones. These data establish the integral role that cholesterol-7-alpha-hydroxylase has in maintaining hepatic cholesterol homeostasis and, thus, in the susceptibility to the formation of gallstones and atherosclerosis.