Underlying causes of cryptogenic stroke and TIA in the nordic atrial fibrillation and stroke (NOR-FIB) study - the importance of comprehensive clinical evaluation.

BACKGROUND: Cryptogenic stroke is a heterogeneous condition, with a wide spectrum of possible underlying causes for which the optimal secondary prevention may differ substantially. Attempting a correct etiological diagnosis to reduce the stroke recurrence should be the fundamental goal of modern stroke management. METHODS: Prospective observational international multicenter study of cryptogenic stroke and cryptogenic transient ischemic attack (TIA) patients clinically monitored for 12 months to assign the underlying etiology. For atrial fibrillation (AF) detection continuous cardiac rhythm monitoring with insertable cardiac monitor (Reveal LINQ, Medtronic) was performed. The 12-month follow-up data for 250 of 259 initially included NOR-FIB patients were available for analysis. RESULTS: After 12 months follow-up probable stroke causes were revealed in 43% patients, while 57% still remained cryptogenic. AF and atrial flutter was most prevalent (29%). In 14% patients other possible causes were revealed (small vessel disease, large-artery atherosclerosis, hypercoagulable states, other cardioembolism). Patients remaining cryptogenic were younger (p < 0.001), had lower CHA2DS2-VASc score (p < 0.001) on admission, and lower NIHSS score (p = 0.031) and mRS (p = 0.016) at discharge. Smoking was more prevalent in patients that were still cryptogenic (p = 0.014), while dyslipidaemia was less prevalent (p = 0.044). Stroke recurrence rate was higher in the cryptogenic group compared to the group where the etiology was revealed, 7.7% vs. 2.8%, (p = 0.091). CONCLUSION: Cryptogenic stroke often indicates the inability to identify the cause in the acute phase and should be considered as a working diagnosis until efforts of diagnostic work up succeed in identifying a specific underlying etiology. Timeframe of 6-12-month follow-up may be considered as optimal. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02937077, EudraCT 2018-002298-23.

Prediction of underlying atrial fibrillation in patients with a cryptogenic stroke: results from the NOR-FIB Study.

BACKGROUND: Atrial fibrillation (AF) detection and treatment are key elements to reduce recurrence risk in cryptogenic stroke (CS) with underlying arrhythmia. The purpose of the present study was to assess the predictors of AF in CS and the utility of existing AF-predicting scores in The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study. METHOD: The NOR-FIB study was an international prospective observational multicenter study designed to detect and quantify AF in CS and cryptogenic transient ischaemic attack (TIA) patients monitored by the insertable cardiac monitor (ICM), and to identify AF-predicting biomarkers. The utility of the following AF-predicting scores was tested: AS5F, Brown ESUS-AF, CHA2DS2-VASc, CHASE-LESS, HATCH, HAVOC, STAF and SURF. RESULTS: In univariate analyses increasing age, hypertension, left ventricle hypertrophy, dyslipidaemia, antiarrhythmic drugs usage, valvular heart disease, and neuroimaging findings of stroke due to intracranial vessel occlusions and previous ischemic lesions were associated with a higher likelihood of detected AF. In multivariate analysis, age was the only independent predictor of AF. All the AF-predicting scores showed significantly higher score levels for AF than non-AF patients. The STAF and the SURF scores provided the highest sensitivity and negative predictive values, while the AS5F and SURF reached an area under the receiver operating curve (AUC) > 0.7. CONCLUSION: Clinical risk scores may guide a personalized evaluation approach in CS patients. Increasing awareness of the usage of available AF-predicting scores may optimize the arrhythmia detection pathway in stroke units.

Atrial fibrillation in cryptogenic stroke and TIA patients in The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study: Main results.

Introduction: Secondary stroke prevention depends on proper identification of the underlying etiology and initiation of optimal treatment after the index event. The aim of the NOR-FIB study was to detect and quantify underlying atrial fibrillation (AF) in patients with cryptogenic stroke (CS) or transient ischaemic attack (TIA) using insertable cardiac monitor (ICM), to optimise secondary prevention, and to test the feasibility of ICM usage for stroke physicians. Patients and methods: Prospective observational international multicenter real-life study of CS and TIA patients monitored for 12 months with ICM (Reveal LINQ) for AF detection. Results: ICM insertion was performed in 91.5% by stroke physicians, within median 9 days after index event. Paroxysmal AF was diagnosed in 74 out of 259 patients (28.6%), detected early after ICM insertion (mean 48 ± 52 days) in 86.5% of patients. AF patients were older (72.6 vs 62.2; p < 0.001), had higher pre-stroke CHA2DS2-VASc score (median 3 vs 2; p < 0.001) and admission NIHSS (median 2 vs 1; p = 0.001); and more often hypertension (p = 0.045) and dyslipidaemia (p = 0.005) than non-AF patients. The arrhythmia was recurrent in 91.9% and asymptomatic in 93.2%. At 12-month follow-up anticoagulants usage was 97.3%. Discussion and conclusions: ICM was an effective tool for diagnosing underlying AF, capturing AF in 29% of the CS and TIA patients. AF was asymptomatic in most cases and would mainly have gone undiagnosed without ICM. The insertion and use of ICM was feasible for stroke physicians in stroke units.

Identification of immunogenic regions within the alternative reading frame protein of hepatitis C virus (genotype 3).

Hepatitis C virus (HCV) encodes ten classic proteins as well as a newly discovered alternative reading frame protein (ARFP) whose synthesis originates from the core region by a +1 frameshift. ARFP is produced by all HCV genotypes, but its function remains unknown. Although the immunogenicity of genotype 1- and 2-derived ARFP in infected hosts has been reported, no information is available for genotype 3-encoded ARFP. HCV genotype 3 core/ARFP region was PCR amplified, cloned, and sequenced. Recombinant ARFP and peptides were employed in ELISAs with patient serum samples. The effect of peptides on peripheral blood mononucleocytes (PBMCs) was also studied. DNA cloning and sequencing of HCV genotype 3 strain (PKHCV3) revealed it to encode 160 aa ARFP, which harbors a C-terminal extension of 36 aa. Serum from 74 of 88 patients (84%) contained rARFP-reactive antibodies. Peptide ELISAs showed that all regions of rARFP were immunogenic, with peptide F7 (DSLSPRRAGAKAGPGLSPGT) being the most immunodominant. When incubated with PBMCs from HCV-infected individuals, F7 stimulated the production of TNFα and IL10. PKHCV3-derived ARFP encodes a 160 aa protein and antibodies against its entire length are found in 84% of all genotype 3-infected subjects. Peptide ELISAs revealed F7 to be highly immunogenic and capable of eliciting impressive T-cell responses.

Phase I clinical and pharmacokinetic study of diethyldithiocarbamate as a chemoprotector from toxic effects of cisplatin.

Diethyldithiocarbamate (DDTC) has been shown to provide protection against most clinically significant toxic effects from cisplatin (DDP) without inhibiting tumor response in a variety of murine animal models. We conducted a phase I clinical and pharmacokinetic study of DDTC in combination with DDP to establish the types and severity of toxic effects and to determine whether protection of normal tissues and tumors occurs. Twenty-two courses of DDP plus DDTC were given to 10 patients. No nephrotoxic effects were seen at DDP doses of 50-120 mg/m2, and three patients had amelioration of nausea and vomiting. Objective antitumor responses were observed. Dose-limiting toxic effects from DDTC occurred at 150 mg/kg; these consisted of numbness in the infusion arm often accompanied by severe diaphoresis, chest discomfort, and agitation during DDTC infusion. These toxic effects resolved spontaneously, however, after termination of the infusion. The preliminary results suggest that plasma levels of DDTC that provide excellent protection in rodents were exceeded at the doses used in our clinical study without compromising antitumor response.

Estrogen receptors and the pattern of relapse in breast cancer.

To determine if the pattern of relapse in patients with breast cancer was influenced by the presence or absence of hormonal receptors, we examined 300 patients with breast cancer who had estrogen receptor (ER) assays performed on their primary tumors. A multivariate discriminant analysis of the initial site of recurrence was performed, and we included in the analysis such factors as ER status, menopausal status, axillary lymph node involvement, and the interaction between menopausal status and ER status. Estrogen receptor status was found to be the single most important independent variable associated with the pattern of recurrence. There was significantly higher likelihood of visceral metastasis with ER-negative tumors, 52.1% as opposed to 5.38% for ER-positive tumors. Conversely, there was a high frequency of osseous relapse with ER-positive tumors, 60.4%, as opposed to 13.4% for ER-negative tumors. We also found that postmenopausal women tended to be ER positive more often than premenopausal women, and progesterone receptor status appears to be a good indicator for five-year disease-free survival in patients without axillary node involvement. With the progression of disease, there was a loss of receptors, even without therapeutic intervention.

Predictors of mortality in the immunocompromised patient with pulmonary infiltrates.

To determine predictors of mortality in immunocompromised patients with pulmonary infiltrates, we reviewed the records of all such patients admitted to two community teaching hospitals who underwent a lung biopsy over a ten-year period. We examined the consequences of advancing age, primary disease, fever, neutropenia, immunosuppressive corticosteroid therapy, previous lung radiation, roentgenographic pattern, result of lung biopsy, room air arterial oxygen pressure (Pao2), early mechanical ventilation, and the presence of a comorbid disease on eventual outcome. We identified 104 episodes in 99 patients. Sixty-seven (64%) survived and 37 died. By both discriminant analysis and logistic regression statistical methods, mechanical ventilation, the initial room air Pao2, and corticosteroid therapy were the dominant independent variables, in that order, to significantly predict mortality. No patient survived who simultaneously had a room air Pao2 less than or equal to 50 mm Hg, was on corticosteroids, and was mechanically ventilated. Eighty-three percent of survivors had either none or, at most, one of these three variables present. We conclude that hypoxia, immunosuppression by corticosteroids, and the necessity for mechanical ventilation within 72 hours of hospitalization indicate a poor prognosis in the immunocompromised patient with pulmonary infiltrates who has undergone a lung biopsy.

Septicemia, rash, and pulmonary infiltrates secondary to Corynebacterium group JK infection.

This report describes a leukemic patient undergoing induction therapy in whom a Corynebacterium JK infection developed while he was leukopenic. The clinical triad of perirectal inflammation, skin lesions, and interstitial lung infiltrates, which has not previously been reported, is discussed. Characteristics of the organism and postulated routes of infection as well as treatment are explored.

Sensitivity, specificity, and predictive values of bronchoscopy in neoplasm metastatic to lung.

Bronchoscopic examination to diagnose lung metastases has not been as rewarding as in primary lung cancer. Despite a lower expected yield, we believe the procedure has value in certain patients, ie, those with clinical findings of endobronchial disease. To determine better the value of bronchoscopy in this population, we retrospectively reviewed records of patients at five community teaching hospitals over a 66-month period. These patients all underwent fiberoptic bronchoscopy. They had a history of prior nonpulmonary malignancy and an abnormal chest roentgenogram suspicious for recurrent malignant disease, or they presented with abnormal chest roentgenographic findings and further evaluation showed the lung disease to be metastatic. Bronchoscopy for metastatic lung disease was most likely diagnostic in patients with primary colorectal cancer (79 percent) and breast cancer (57 percent), and least likely in patients with genitourinary tract cancer (33 percent). Hemoptysis, signs of local airway obstruction, or a roentgenogram showing either atelectasis or diffuse lung disease especially favored a positive biopsy. Bronchoscopy is a valuable diagnostic procedure in selected patients with metastatic lung disease.

Phase II study of cisplatin for metastatic prostatic carcinoma. An Eastern Cooperative Oncology Group study.

In a phase ii trial 18 previously treated patients with metastatic prostatic carcinoma with measurable or evaluable disease were treated with cisplatin 50 mg/m2 every 3 weeks. Treatment was well tolerated in this elderly group of patients except for GI toxicity seen in 75% of the patients. There were no objective responses. Changes in serum acid phosphatase were often transient and not accompanied by clinical improvement. Cisplatin does not appear to be an effective agent in metastatic prostatic carcinoma in the dose schedule employed.

Combination chemotherapy for advanced colorectal cancer. A pilot study.

Twenty-three patients with advanced colorectal carcinoma, mostly with liver and lung metastases and measurable disease, were treated with mitomycin-C 20 mg/m2 I.V. and vincristine 1.2 mg/m2 I.V. every 6 weeks, and cisplatinum 50 mg/m2 I.V. and 5-fluorouracil 1,000 mg/m2/24 hours I.V. continuous infusion for 96 hours every 3 weeks based upon the hypothesis that cisplatinum may potentiate the antitumor activity of antimetabolites and alkylating agents. Five patients had received prior chemotherapy and six had received prior radiotherapy, with one of these patients receiving both. One complete and 10 partial responses were observed, with an overall response rate of 48% (90% confidence interval 30-70%). The toxicity was manageable. A possible potentiating effect of cisplatinum is suggested in this first attempt in the treatment of colorectal cancer, and warrants further exploration.

Survival of patient with pleural involvement by breast carcinoma.

To determine factors which affect survival in patients with pleural involvement by breast carcinoma, we reviewed records of all patients at two community teaching hospitals presenting with malignant pleural effusion over a 6-year period. Forty-five patients had had mastectomy for breast cancer, no history of other malignancy, and cytologic confirmation of subsequent pleural metastases. All had received conventional combination systemic chemo- or hormonal therapy. Ten patients (group 1) in whom effusion was the initial and only site of recurrent disease had a median survival of 48 months. The median survival was 12 months in 35 patients (group 2) who developed effusion in association with other metastatic disease. Half of the patients in group 1 had no axillary node involvement at mastectomy. Twenty-eight patients (80%) in group 2 had had more advanced disease at initial diagnosis. This, and behavior of the effusion as regional rather than systemic disease, suggested by the high incidence of effusion on the ipsilateral side of the mastectomy, probably accounts for the better outlook in patients with effusion alone.

A phase II study of carboplatin and CHIP in patients with metastatic colon carcinoma.

Fifty-six patients were treated in each arm of a study comparing CHIP and carboplatin for the therapy of previously untreated metastatic colorectal carcinoma. There were one partial response (2%) with CHIP and two partial responses (4%) with carboplatin. Side effects were significantly more severe with CHIP than with carboplatin. The most common side effect for both drugs was vomiting followed by hematologic side effects. Sixteen percent of the patients receiving CHIP and 9% of those receiving carboplatin had life-threatening side effects. Neither drug offers significant activity in metastatic colorectal carcinoma.

Snake bite experience at Pakistan Institute of Medical Sciences.

We reviewed 40 cases of snake bite seen from January, 1996 to December, 1996. Most of the cases survived uneventfully but many developed complications which were either haematologic, (23 patients) or neurological (5 patients). Appropriate treatment was offered in every case. Polyvalent antisnake venom was administered to 30 patients (75%). Premedication used was steroids and antihistamines to prevent anaphylactic reactions. Antifibrinolytic therapy (tranxemic acid) was given to every bleeding patient. The species of offending snake could be recognized in one patient while in all others, it was not possible due to night time incidence and poor description by the patient.

Peritoneovenous shunt for palliation of malignant ascites.

Forty patients with malignant ascites refractory to conventional medical management had peritoneovenous shunt for palliation. The shunt provided effective palliation in 28 with decrease in weight, abdominal girth, number of paracenteses required and increase in urine output. These patients also had improvement in strength, appetite and ambulation. Complications such as hemodilution, volume overload, and sepsis do not contraindicate surgery. In 12 patients with high ascitic fluid protein content (4.5 g/liter) and a large number of malignant cells, loculated ascites and prior severe renal and cardiac disease, the shunt did not provide palliation. Peritoneovenous shunt appears to provide effective palliation in carefully selected patients with refractory malignant ascites.

Spontaneous regression in non-Hodgkin's lymphoma: clinical and pathogenetic considerations.

The spontaneous regression (SR) of tumor has been noted in a variety of neoplastic conditions. In non-Hodgkin's lymphoma, this phenomenon has been reported in indolent histologic subtypes, with a frequency of 10-20% in selected series. Investigators evaluating new therapies for lymphomas with a favorable histology need to be cognizant of SR's impact. Mechanisms which have been proposed to explain SR have included the role of contemporaneous bacterial or viral infection, as well as an augmented host immune response which is able to mediate tumor regression via humoral and cellular effector mechanisms. The ability to recapture immunoregulatory control is aptly illustrated by lymphomas developing after organ transplantation where reduction of immunosuppression has, on occasion, resulted in tumor regression. The importance of immune regulation of B-cell lymphoma is also suggested by the tumor's responses to immunotherapy and interferons in vivo and by the biologic and pathologic characteristic of indolent lymphomas being analogous, in may respects, to benign neoplasms. Indolent lymphomas which differ from aggressive lymphomas in their clinical and biological behavior may be more responsive to these host immunoregulatory influences. Review of clinical experience as well as proposed mechanisms of spontaneous regression in non-Hodgkin's lymphoma will be explored in this report.