Ball Memorial Hospital

Distinguishing follicular variant of papillary carcinoma (FVPC) from follicular adenoma and follicular carcinoma can be difficult if nuclear features of papillary carcinoma are not well developed or only focally present. We assessed interobserver and intraobserver agreement among 6 thyroid experts by using 15 cases in which original pathologists suspected FVPC. There was unanimous expert agreement in diagnosing FVPC in only 2 cases (13%) and majority agreement in 6 cases (40%). Unanimous agreement on benign and malignant diagnoses was seen in 4 cases (27%) and majority agreement on malignancy in 8 cases (53%). Intraobserver agreement ranged from 17% to 100%. Histologic features considered most helpful in diagnosing FVPC were nuclear clearing, nuclear grooves, nuclear overlapping and crowding, nuclear membrane irregularity, and nuclear enlargement. This considerable interobserver and intraobserver variability in the diagnosis of FVPC seems to result from lack of agreement on the minimal criteria needed to diagnose FVPC, even among experts.

The introduction of the activated partial thromboplastin time (APTT) as a screening test has resulted in increased recognition of circulating anticoagulants. The most frequently encountered inhibitor is the lupus-type anticoagulant. However, criteria for differentiation of this inhibitor are not well-established. We evaluated the ability of two procedures, tissue thromboplastin inhibition (TTI) and a new platelet neutralization procedure (PNP), to differentiate between various types of coagulation inhibitors. The TTI, widely used for the diagnosis of lupus anticoagulants, proved to be nonspecific. The PNP specifically separated lupus-type inhibitors from Factor VIII, X, and V inhibitors. The PNP may be a useful test for the diagnosis of lupus anticoagulants.

The relationship between lupus anticoagulants and antibodies directed against negatively charged phospholipids, as measured by an enzyme-linked immunosorbent assay, was explored in a series of plasma samples from 100 patients with well-characterized lupus anticoagulants. Only 73% of the patients had detectable IgG, IgM antibodies, or both, to one or more of four phospholipids. Of these patients, 29% had IgG-type antibodies only, 56% had both IgG and IgM antibodies, and 15% had IgM antibodies only. Of the 100 patients, 19% had a history of thrombosis, 8% had a history of spontaneous abortion, and 6% had a history of seizure disorder. These complications occurred in the presence (80%) and absence (20%) of detectable antiphospholipid antibodies. Drug-related antibodies were observed in 34 patients; of these, 71% had detectable anti-phospholipid antibodies and 24% had a history of thrombosis. There were ten patients with lupus anticoagulants associated with infections; none of these patients had a history of thrombosis. The results indicate that antiphospholipid antibodies are not present in all patients with lupus anticoagulants, that the presence of antiphospholipid antibodies in patients with lupus anticoagulants does not increase the risk of thrombosis in these patients, and that drug-related antibodies are associated with an increased risk of thrombosis. Lupus anticoagulants and antiphospholipid antibodies seem to define two distinct but related patient populations, each associated with an increased risk of thrombosis.

The National Cancer Institute (NCI) sponsored the NCI Thyroid fine-needle aspiration (FNA) State of the Science Conference on October 22-23, 2007 in Bethesda, MD. The 2-day meeting was accompanied by a permanent informational website and several on-line discussion periods between May 1 and December 15, 2007 (http://thyroidfna.cancer.gov). This document summarizes matters addressing manual and ultrasound guided FNA technique and related issues. Specific topics covered include details regarding aspiration needles, devices, and methods, including the use of core needle biopsy; the pros and cons of anesthesia; the influence of thyroid lesion location, size, and characteristics on technique; the role of ultrasound in the FNA of a palpable thyroid nodule; the advantages and disadvantages of various specialists performing a biopsy; the optimal number of passes and tissue preparation methods; sample adequacy criteria for solid and cystic nodules, and management of adverse reactions from the procedure. (http://thyroidfna.cancer.gov/pages/info/agenda/)

Lupus anticoagulants (LAs) are antibodies that interfere with phospholipid dependent coagulation reactions in vitro. This workshop was designed to provide the participants with an experience in identification of LAs, to evaluate different criteria for mixing studies, to assess the performance of recently introduced confirmatory studies and to assess the performance of two potential surrogate LA control plasmas. The results demonstrate that there continues to be significant variation in the sensitivity and responsiveness of APTT reagents to the presence of LAs, confirming the need for more than one screening assay before the presence of a LA can be ruled out. In this workshop, the best distinction between factor deficiency and inhibitors was obtained using a 1:1 mix of normal plasma with patient plasma and the criterion defining correction as shortening of the APTT to within 5 s of the APTT of pooled normal plasma. A 4:1 mix of patient to normal plasma did not work well in distinguishing factor deficiency from inhibitors. The platelet neutralization procedure, DVV confirm and StaClot LA all gave positive results with the LA samples. False positive platelet neutralization procedures were seen with the samples from patients on oral anticoagulants and a factor V inhibitor. False positive StaClot LA results were obtained with high titer factor VIII inhibitors. Both of the potential surrogate plasmas gave variable results with multiple assays; they can not be recommended for routine use at present.

Hemostasis is initiated by injury to the vascular wall, leading to the deposition of platelets adhering to components of the subendothelium. Platelet adhesion requires the presence of von Willebrand factor and platelet receptors (IIb/IIIa and Ib/IX). Additional platelets are recruited to the site of injury by release of platelet granular contents, including ADP. The "platelet plug" is stabilized by interaction with fibrinogen. In this review, I consider laboratory tests used to evaluate coagulation, including prothrombin time, activated partial thromboplastin time, thrombin time, and platelet count. I discuss hereditary disorders of platelets and/or coagulation proteins that lead to clinical bleeding as well as acquired disorders, including disseminated intravascular coagulation and acquired circulating anticoagulants.

Atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) diagnosed in core needle biopsy (CNB) are generally regarded as risk indicators for developing invasive ductal or lobular carcinoma in either breast. Currently, there are no well-established guidelines for management of these patients. The most common management options are careful observation and endocrine chemoprophylaxis for high-risk patients. Previous studies had contradicting recommendations regarding follow-up surgical excision (FSE) of CNB yielding ALH or LCIS. These studies, unfortunately, have been limited by their retrospective nature, small number of patients examined, and association with other high-risk lesions. Only CNB diagnosed as pure LCIS or ALH (not associated with other high-risk lesions such as ADH, radial scar, or papilloma) were included in the study. We reviewed 33 CNB (20 ALH and 13 LCIS) with subsequent FSE from 33 patients (age range, 30-83 years; mean, 58 years). Eighteen of these patients were prospectively analyzed, where FSE was performed in an unselected fashion. All CNBs were obtained by mammotome (11-gauge, 30 cases; and 14-gauge, 3 cases). Mammography identified calcifications in 29 cases (88%) and a mass in 4 cases (12%). FSE revealed infiltrating ductal and/or lobular carcinoma in 4 of 13 LCIS (31%). FSE of 20 ALH revealed cancer in 5 cases (25%), including 4 ductal carcinoma in situ (DCIS) and 1 invasive lobular carcinoma. Seven of these nine cancers were associated with calcifications, and two presented as masses. Sampling error and underestimation of cancer (DCIS or invasive carcinoma) was associated with CNB diagnosis of LCIS or ALH in 27% of all cases. Underestimation of cancer was seen in 28% of prospectively examined patients, including 20% of ALH and 38% of LCIS. CNB associated with mass lesions or that showed histologic features of pleomorphic LCIS or extensive classic LCIS had a higher rate of cancer underestimation. Despite removal of all abnormal mammographic calcifications by CNB in 6 patients, one cancer was detected on FSE. To the best of our knowledge, this is the largest study reported to date, and the only one to include prospectively examined patients with no pre-selection bias. Our data strongly suggests that subsequent FSE is warranted in all patients with CNB diagnoses of LCIS or ALH, to exclude the presence of cancer.

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) has provided a set of uniform diagnostic terminology including benign (B), atypia of undetermined significance (AUS), follicular neoplasm (FN), suspicious for malignancy (SM), malignancy (M), and nondiagnostic (ND) for the interpretation of thyroid fine-needle aspiration (FNA). We applied this terminology on our 1,382 thyroid aspirates in a community practice setting, which included 539 cases of B (39%), 376 cases of AUS (27.2%), 116 cases of FN (8.4%), 37 cases of malignant (2.7%), 36 cases of SM (2.6%), and 278 cases of ND (20.1%). Two hundred twenty-one cases (16%) of thyroid FNA had corresponding follow-up thyroidectomies. Each diagnostic category represented a unique association with risk of malignancy and risk of neoplasm. Based on histologic follow-up, the risk of neoplasm (including benign and malignant neoplasm) was B 14%, AUS 44%, FN 67%, SM 77%, and M 100% and the risk of malignancy was B 3%, AUS 6%, FN 22%, SM 56%, and M 100%. The classification and follow-up recommendation of TBSRTC are appropriate for each category. Both B and AUS are low-risk lesions with low probability of malignancy. FN predicts a higher rate for neoplasm but an intermediate rate for malignancy while SM carries a high risk for malignancy.

BACKGROUND: Five-year overall survival (OS) for patients with unresectable stage III non-small cell lung cancer (NSCLC) is poor. Until recently, a standard of care was concurrent chemoradiation alone. Patients with metastatic NSCLC treated with anti-programmed death 1 antibodies have demonstrated improved OS. This trial evaluated pembrolizumab as consolidation therapy after concurrent chemoradiation in patients with unresectable stage III disease. METHODS: Patients with unresectable stage III NSCLC received concurrent chemoradiation with cisplatin and etoposide, cisplatin and pemetrexed, or carboplatin and paclitaxel and 59.4 to 66.6 Gy of radiation. Patients with nonprogression of disease were enrolled and received pembrolizumab (200 mg intravenously every 3 weeks for up to 12 months). The primary endpoint was the time to metastatic disease or death (TMDD). Secondary endpoints included progression-free survival (PFS) and OS. RESULTS: The median follow-up for 93 patients (92 for efficacy) was 32.2 months (range, 1.2-46.6 months). The median TMDD was 30.7 months (95% confidence interval [CI], 18.7 months to not reached), which was significantly longer than the historical control of 12 months (P < .0001). The median PFS was 18.7 months (95% CI, 12.4-33.8 months), and the median OS was 35.8 months (95% CI, 24.2 months to not reached). The 1-, 2-, and 3-year OS estimates were 81.2%, 62.0%, and 48.5%, respectively. Forty patients (43.5%) completed 12 months of treatment (median number of cycles, 13.5). Symptomatic pneumonitis (grade 2 or higher) was noted in 16 patients (17.2%); these cases included 4 grade 3 events (4.3%), 1 grade 4 event (1.1%), and 1 grade 5 event (1.1%). CONCLUSIONS: Consolidation pembrolizumab after concurrent chemoradiation improves TMDD, PFS, and OS in comparison with historical controls of chemoradiation alone. Rates of grade 3 to 5 pneumonitis were similar to those reported with chemoradiation alone.

*Pathologists Associated, Ball Memorial Hospital, Muncie, IN; †Allegheny General Hospital, Pittsburgh, PA

BACKGROUND: Histoplasmosis may complicate tumor necrosis factor (TNF)-α blocker therapy. Published case series provide limited guidance on disease management. We sought to determine the need for long-term antifungal therapy and the safety of resuming TNF-α blocker therapy after successful treatment of histoplasmosis. METHODS: We conducted a multicenter retrospective review of 98 patients diagnosed with histoplasmosis between January 2000 and June 2011. Multivariate logistic regression was used to evaluate risk factors for severe disease. RESULTS: The most commonly used biologic agent was infliximab (67.3%). Concomitant corticosteroid use (odds ratio [OR], 3.94 [95% confidence interval {CI}, 1.06-14.60]) and higher urine Histoplasma antigen levels (OR, 1.14 [95% CI, 1.03-1.25]) were found to be independent predictors of severe disease. Forty-six (47.4%) patients were initially treated with an amphotericin B formulation for a median duration of 2 weeks. Azole treatment was given for a median of 12 months. TNF-α blocker therapy was initially discontinued in 95 of 98 (96.9%) patients and later resumed in 25 of 74 (33.8%) patients at a median of 12 months (range, 1-69 months). The recurrence rate was 3.2% at a median follow-up period of 32 months. Of the 3 patients with recurrence, 2 had restarted TNF-α blocker therapy, 1 of whom died. Mortality rate was 3.2%. CONCLUSIONS: In this study, disease outcomes were generally favorable. Discontinuation of antifungal treatment after clinical response and an appropriate duration of therapy, probably at least 12 months, appears safe if pharmacologic immunosuppression has been held. Resumption of TNF-α blocker therapy also appears safe, assuming that the initial antifungal therapy was administered for 12 months.

Lupus anticoagulants (LAs) are immunoglobulins (IgG, IgM, or both) which interfere with in vitro phospholipid (PL) dependent tests of coagulation (e. g. APTT, dilute PT, dilute Russell Viper Venom Time). These antibodies may be identified in a wide variety of clinical settings. With the exception of heparinized patient samples, the presence of LAs is often the most common cause of an unexplained APTT in a routine clinical laboratory. The diagnosis of LAs is difficult due to variable screening reagent sensitivity and intrinsic heterogeneity of LAs. Recently, Rauch and colleagues have shown human monoclonal hybridoma LAs were inhibited by hexagonal (II) phase PLs. In contrast, lamellar phase PLs had no effect. We have evaluated a new assay system, Staclot LA, which utilizes a hexagonal (II) phase PL (egg phosphatidylethanolamine [EPE]) as a confirmatory test for LAs. Plasma samples from the following patient populations were studied: LA positive, heparinized, oral anticoagulated, hemophilia A and B, and specific factor inhibitors (factors V, VIII, IX). Unlike previous studies, the LA positive patients were a mixed population including: autoimmune diseases, drug-induced, and post-infection. Our findings confirm the specificity of hexagonal (II) phase PL neutralization of LAs.

Phosphatidylethanolamine (PE) is an important membrane component for supporting activated protein C anticoagulant activity but has little influence on prothrombin activation. This difference constitutes a potential mechanism for selective inhibition of the protein C anticoagulant pathway by lupus anticoagulants and/or antiphospholipid antibodies. In this study, we demonstrate that the presence of PE augments lupus anticoagulant activity. In the plasma of some patients with lupus anticoagulants, activated protein C anticoagulant activity is more potently inhibited than prothrombin activation. As a result, in the presence of activated protein C and PE, these patient plasmas clot faster than normal plasma. Patients with minimal lupus anticoagulant activity are identified whose plasma potently inhibits activated protein C anticoagulant activity. This process is also PE dependent. In three patient plasmas, these phenomena are shown to be due to immunoglobulins. The PE requirement in the expression of activated protein C anticoagulant activity and the PE dependence of some antiphospholipid antibodies provide a mechanistic basis for the selective inhibition of the protein C pathway. Inhibition of activated protein C function may be a common mechanism contributing to increased thrombotic risk in certain patients with antiphospholipid antibodies.

BACKGROUND: Debate continues among nurses about the advantages and disadvantages of family presence during resuscitation. Knowledge development about such family presence is constrained by the lack of reliable and valid instruments to measure key variables. OBJECTIVES: To test 2 instruments used to measure nurses' perceptions of family presence during resuscitation, to explore demographic variables and perceptions of nurses' self-confidence and the risks and benefits related to such family presence in a broad sample of nurses from multiple hospital units, and to examine differences in perceptions of nurses who have and who have not invited family presence. METHODS: Nurses (n = 375) completed the Family Presence Risk-Benefit Scale and the Family Presence Self-confidence Scale. RESULTS: Nurses' perceptions of benefits, risks, and self-confidence were significantly and strongly interrelated. Nurses who invited family presence during resuscitation were significantly more self-confident in managing it and perceived more benefits and fewer risks (P < .001). Perceptions of more benefits and fewer risks were related to membership in professional organizations, professional certification, and working in an emergency department (P < .001). Data supported initial reliability and construct validity for the 2 scales. CONCLUSIONS: Nurses' perceptions of the risks and benefits of family presence during resuscitation vary widely and are associated with how often the nurses invite family presence. After further testing, the 2 new scales may be suitable for measuring interventional outcomes, serve as self-assessment tools, and add to conceptual knowledge about family presence.

This study was conducted to determine whether improvements in glucose tolerance could be observed after a single bout of resistance exercise in young (27.1 +/- 1.24 yr) control subjects, older (53.3 +/- 1.7 yr) patients with non-insulin-dependent diabetes mellitus (NIDDM), and older (50.7 +/- 1.9 yr) age-matched control subjects. Each subject was screened for fitness level and any contraindications to exercise before inclusion in the study. A 75-g oral glucose tolerance test was administered 2 wk after the subjects were screened, and the subjects were familiarized with the exercise equipment. The maximum weight that could be lifted with one repetition was determined on seven Nautilus machines that utilized the upper and lower body. After a 48-h rest period, a 3-set x 10-repetition protocol based on the subject's one repetition maximum was completed by each participant on each machine. Eighteen hours after the lifting protocol, a second oral glucose tolerance test was administered. There was no change in the pre- to post-exercise glucose levels in any of the treatment groups, but the total insulin responses (area under the curve) of the young control and NIDDM groups were significantly lower after exercise: from 6.93 +/- 0.8 x 10(3) to 5.38 +/- 0.65 x 10(3) pM in the young control group and from 9.83 +/- 1.95 x 10(3) to 7.77 +/- 1.50 x 10(3) pM in the NIDDM group. The postexercise C-peptide levels were unchanged in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Lupus anticoagulants (LA) are immunoglobulins (IgG, IgM, IgA or a mixture) which interfere with in vitro phospholipid (PL) dependent tests of coagulation (e.g. APTT, KCT, dilute Russell Viper Venom Time). LA are heterogeneous; consequently, the laboratory diagnosis is difficult and relies on multiple tests. We have developed a sensitive and relatively specific confirmatory test system based on fractions of two snake venoms. Textarin, a protein fraction of Pseudonaja textilis venom (Australian Eastern brown snake), activates prothrombin in the presence of PL, factor V and calcium ions. Ecarin, a protein fraction of Echis carinatus venom, will activate prothrombin in the absence of any cofactors. The activation of prothrombin by Textarin yields thrombin while Ecarin yields meizothrombin. In the presence of LA, the Textarin time is prolonged and the Ecarin time is unaffected. The test results are reported as a ratio of Textarin/Ecarin times (abnormal greater than 1.3). We have evaluated this test system in the following patient populations: LA positive, therapeutically heparinized, stable oral anticoagulated, liver disease, routine preoperative, anticardiolipin antibody positive LA negative, hemophilia A, various other hereditary factor deficiencies or dysfunctional proteins, and specific inhibitors of factor V and factor VIII. The LA positive patients represented a mixed population of autoimmune disease, drug-induced and post-infectious states. Our findings indicate the sensitivity of the Textarin/Ecarin system in the confirmation of LA. In order to use the test system most effectively, it is recommended to incorporate polybrene with Textarin when evaluating heparinized samples. Factor V deficiency and specific inhibitors of factor V yielded, in some instances, false positive results.

Epilepsy is a common disease found in 2% of the population, affecting both young and old. Unfortunately, epileptics have previously been discouraged from participation in physical activity and sports for fear of inducing seizures or increasing seizure frequency. Despite a shift in medical recommendations toward encouraging rather than restricting participation, the stigma remains and epileptics continue to be less active than the general population. This results in increased body mass index, decreased aerobic endurance, poorer self-esteem, and higher levels of anxiety and depression. Although there are rare cases of exercise-induced seizures, studies have shown that physical activity can decrease seizure frequency, as well as lead to improved cardiovascular and psychologic health. The majority of sports are safe for epileptics to participate in with special attention to adequate seizure control, close monitoring of medications, and preparation of family, coaches, or trainers. Contact sports including football, hockey, and soccer have not been shown to induce seizures, and epileptics should not be precluded from participation. Water sports and swimming are felt to be safe if seizures are well controlled and direct supervision is present. Additional care must be taken in sports involving heights such as gymnastics, harnessed rock climbing, or horseback riding. Sports such as hang-gliding, scuba diving, or free climbing are not recommended, given the risk of severe injury or death, if a seizure were to occur during the activity. This article reviews the risks and benefits of physical activity in epileptics, discusses sports in which epileptics may participate, and addresses how to decrease possible risks for injury.

Lupus anticoagulants (LA) were originally described in patients with systemic lupus erythematosus (SLE) and clinical bleeding. Following the original description, they were associated with numerous clinical conditions and it was soon appreciated that there was not an increased risk of hemorrhage. Hence the name is a misnomer which has resisted attempts at modification. The paradox of LA is the apparent increased risk of both arterial and venous thromboembolic events. Thus, a laboratory finding which was once associated with bleeding and subsequently was regarded as a nuisance has now acquired new respectability as a marker of a thrombotic predisposition. The riddle of the anticoagulant effect in vivo and the apparent procoagulant effect in vivo remains unsolved. Perhaps it is an epiphenomenon, but more importantly, it may open the door to greater understanding of the delicate regulatory systems which prevent thrombosis. LA exist in virtually every patient population. Therefore, they are no longer a topic of interest limited to hematologists, rather they have achieved multidisciplinary attention. Laboratories are now being asked to prospectively evaluate patients for the presence of LA or antiphospholipid antibodies (APA). The evaluation of LA, both in the research laboratory and clinic, should continue to provide important insights applicable to a variety of specialties.

We present our experience of fine-needle aspiration (FNA) cytology of the thyroid in a community hospital setting and discuss the cancer probability of the indeterminate FNA results. There were 1,621 FNAs, 401 of which have follow-up thyroidectomies during a 10-yr period. The initial FNA diagnoses of these 401 cases were benign non-neoplastic (BNN) 159, malignant 34, atypical 33, suspicious 19, follicular neoplasm (FN) 88, follicular lesion (FL) 51, and inadequate 17. There were no false-positive cases. Cancer was found in 11 cases diagnosed as BNN (7%), 6 cases were due to sampling errors (incidental microcarcinomas), and 5 cases were due to failure to identify focal atypia in the smears of a follicular variant of papillary carcinoma. The false-negative rate was 3%, with the exclusion of cases of incidental microcarcinomas. Among the indeterminate FNA results, the follow-up operations revealed malignant tumors in 16 of 33 (48%) cases of atypical, 13 of 19 (68%) cases of suspicious, 29 of 88 (33%) cases of FN, and 7 of 51 (14%) cases of FL. Malignant tumors were also found in 2 of 17 (12%) of inadequate specimens with follow-up. When compared to the cancer rate (3%) for FNA diagnosis of BNN, the likelihood of finding cancer in the thyroidectomy is 5 times more for a FL, 11 times more for a FN, 16 times more for atypical, and 23 times more for suspicious. The sensitivity and specificity are 87 and 100%, respectively.

Antiphospholipid antibodies (APAs) may be identified in the laboratory by using either coagulation studies or solid-phase immunologic assays (ELISA; RIA). These methodologies do not necessarily evaluate the same antibody; consequently, it is appropriate to screen a patient's plasma by utilizing both assays. APAs have been associated with a variety of obstetrical complications including recurrent spontaneous abortion, intrauterine fetal death, early onset preeclampsia, deep vein thrombosis, and postpartum serositis syndrome. The Kaolin Clotting Time appears to be the most sensitive coagulation test for identifying the lupus anticoagulant. However, preliminary studies would suggest the presence of anticardiolipin antibodies as detected by solid-phase assays are more sensitive and predictive of the clinical course. Although there are no prospective trials to analyze treatment of patients with APA, preliminary data suggest the use of prednisone in combination with aspirin significantly improves the probability of delivery of a viable infant. In addition, heparin, intravenous gammaglobulin, and exchange plasmaphoresis have all been tried with varying degrees of success in individual patients in small series.