Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy.

BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage II colon cancer: the randomized phase III ACHIEVE-2 trial.

BACKGROUND: Oxaliplatin-based adjuvant chemotherapy may be associated with debilitating peripheral sensory neuropathy (PSN) in patients with high-risk stage II colon cancer. This open-label, multicenter, randomized phase III trial was conducted as a prospective pooled analysis to investigate the non-inferiority of 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy. PATIENTS AND METHODS: From 12 February 2014 to 31 January 2017, 525 Asian patients with high-risk stage II colon cancer were randomly assigned to 3- and 6-month treatment arms. The treatment consisted of either modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine combined with oxaliplatin (CAPOX). The primary end point was disease-free survival (DFS). The secondary end points were treatment compliance and safety. RESULTS: Of the 525 randomized patients, 11 were not treated. Among the 514 participating patients (255 in the 3-month arm; 259 in the 6-month arm), 432 (84%) received CAPOX, and 184 (36%) presented with T4 as a high-risk factor for recurrence. The 3-year DFS rate was 88.2% in the 3-month arm and 87.9% in the 6-month arm [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.67-1.87]. With CAPOX, the 3-year DFS rate was 88.2% in the 3-month arm and 88.4% in the 6-month arm (HR, 1.13; 95% CI, 0.65-1.96). The discontinuation rate in the 3- and 6-month arms was 10% and 31% for mFOLFOX6 (P = 0.0193), and 15% and 35% for CAPOX (P < 0.0001), respectively. The incidence of grade ≥2 PSN was significantly lower in the 3-month arm than in the 6-month arm (16% and 43%, respectively, P < 0.0001). CONCLUSIONS: Three months of combination therapy presented significantly less grade ≥2 PSN than the respective 6-month regimen. The shortened therapy duration did not affect the 3-year DFS rate, suggesting that a 3-month course of CAPOX can be an effective treatment option. CLINICAL TRIAL INFORMATION: UMIN Clinical Trials Registry, UMIN000013036 and Japan Registry of Clinical Trials, jRCTs031180128.

Large-scale prospective pharmacogenomics study of oxaliplatin-induced neuropathy in colon cancer patients enrolled in the JFMC41-1001-C2 (JOIN Trial).

BACKGROUND: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.

Ramucirumab plus FOLFIRI as second-line treatment for patients with RAS wild-type metastatic colorectal cancer previously treated with anti-EGFR antibody: JACCRO CC-16.

BACKGROUND: Chemotherapy in combination with anti-epidermal growth factor receptor (EGFR) antibody is considered a first-line treatment regimen for RAS wild-type and left-sided metastatic colorectal cancer (mCRC), whereas second-line treatment regimens have not yet been established. Few studies have prospectively evaluated second-line treatment with anti-vascular endothelial growth factor antibody after first-line anti-EGFR antibody therapy for RAS wild-type mCRC. PATIENTS AND METHODS: This non-randomized phase II trial investigated the clinical outcomes of second-line ramucirumab (RAM) plus fluorouracil, levofolinate, and irinotecan (FOLFIRI) after first-line anti-EGFR antibody in combination with doublet or triplet regimen in patients with RAS wild-type mCRC. The primary endpoint was the 6-month progression-free survival (PFS) rate. The secondary endpoints were PFS, overall survival (OS), objective response rate (ORR), rate of early tumor shrinkage (ETS), and safety. We hypothesized a threshold 6-month PFS rate of 30% and an expected 6-month PFS rate of 45%. Treatment was considered effective if the lower limit of the 90% confidence interval (CI) of the 6-month PFS rate was >0.30. RESULTS: Ninety-two patients were enrolled in the study. The primary tumor was located on the left side in 86 (95.6%) patients. Twenty (22.0%) patients had received triplet plus cetuximab as previous therapy. Six-month PFS rate was 58.2% (90% CI 49.3% to 66.2%) with a median PFS of 7.0 months (95% CI 5.7-7.6 months). Median OS was 23.6 months (95% CI 16.5-26.3 months). The ORR and ETS rate were 10.7% and 16.9%, respectively, in 83 patients with measurable lesions. The 6-month PFS rate was comparable between patients previously treated with doublet and triplet regimens; however, median PFS was longer for the doublet regimen (7.4 versus 6.4 months, P = 0.036). CONCLUSIONS: Our study demonstrated prospectively that RAM plus FOLFIRI is an effective second-line treatment after anti-EGFR antibody-containing first-line therapy in RAS wild-type and left-sided mCRC. Furthermore, the results were similar for patients who were previously treated with triplet regimen.

SAPPHIRE: a randomised phase II study of planned discontinuation or continuous treatment of oxaliplatin after six cycles of modified FOLFOX6 plus panitumumab in patients with colorectal cancer.

BACKGROUND: Fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) plus panitumumab therapy is a commonly used first-line chemotherapy for metastatic colorectal cancer (mCRC). However, the long-term administration of oxaliplatin is associated with peripheral neuropathy (PN). We investigated whether the planned discontinuation of oxaliplatin after FOLFOX plus panitumumab therapy can maintain efficacy and reduce PN incidence. PATIENTS AND METHODS: Chemotherapy-naive patients with RAS wild-type mCRC, aged ≥20 years, were enrolled and received six cycles of modified FOLFOX6 (mFOLFOX6) plus panitumumab as induction therapy. Patients who completed induction therapy without progression were randomised to mFOLFOX6 plus panitumumab (group A) or to 5-FU/LV plus panitumumab (group B). The primary end-point was the progression-free survival (PFS) rate at 9 months after randomisation. The secondary end-points were PFS, overall survival (OS), time to treatment failure (TTF), response rate (RR) and safety. RESULTS: In total, 164 patients were enrolled; of whom, 113 patients were then randomised (group A, n = 56; group B, n = 57). The median follow-up after randomisation was 19.6 months. The PFS rates at 9 months and median PFS were 46.4% (80% confidence interval [CI], 38.1-54.9) and 9.1 months (95% CI, 8.6-11.1) in group A, compared with 47.4% (80% CI, 39.1-55.8) and 9.3 months (95% CI, 6.0-13.0) in group B, respectively. RR, OS and TTF were also similar in both groups. Grade ≥2 PN incidence was lower in group B (9.3%) than in group A (35.7%). CONCLUSION: Planned discontinuation of oxaliplatin after six cycles of mFOLFOX6 plus panitumumab is a potential treatment option in patients with mCRC, achieving similar efficacy while reducing oxaliplatin-associated PN compared with mFOLFOX6 plus panitumumab. TRIAL REGISTRATION NUMBER: NCT02337946.

pH-sensing nano-crystals of carbonate apatite: effects on intracellular delivery and release of DNA for efficient expression into mammalian cells.

Two unique and fascinating properties of carbonate apatite which are well-known in hard tissue engineering, have been unveiled, for the first time, for the development of the simplest, but most efficient non-viral gene delivery device - ability of preventing the growth of crystals needed for high frequency DNA transfer across a plasma membrane and a fast dissolution rate for effective release of DNA during endosomal acidification, leading to a remarkably high transgene expression (5 to 100-fold) in mammalian cells compared to the widely used transfecting agents. Moreover, by modulating the crystal dissolution rate of carbonate apatite through incorporation of fluoride or strontium into it, transfection activity could be dramatically controlled, thus shedding light on a new barrier in the non-viral route, which was overlooked so far. Thus we have developed an innovative technology with significant insights, that would come as a promising tool for both basic research laboratories and clinical settings.

Characterization of a brain-specific nuclear LIM domain protein (FHL1B) which is an alternatively spliced variant of FHL1.

We have amplified and sequenced a novel, alternatively spliced variant of a human gene coding for the four-and-a-half LIM domain protein 1 (FHL1). This gene is located at chromosome Xq27 and the spliced variant is named FHL1B. The ORF of FHL1B cDNA codes for a LIM-only protein that possesses a zinc finger and three tandem repeats of LIM domains at the N-terminus with an active bipartite nuclear localization signal (NLS) motif and a possible RBP-J binding region at the C-terminus. FHL1B and FHL1 have the same N-terminal three-and-a-half LIM domains but different C-terminal protein sequences, due to the presence of an additional alternative exon 4b in FHL1B causing a frame-shift in the 3'coding region. RT-PCR results revealed that the expression of FHL1 is not restricted in skeletal muscle and heart, but is widely distributed in other tissues, including brain, placenta, lung, liver, kidney and pancreas, albeit as a low abundance transcript. In contrast, FHL1B is specifically expressed in brain. The C-terminal alternative region in FHL1B is sufficient to localize FHL1B in the nucleus of mammalian cell. FHL1B is probably related to neural differentiation and certain fragile X syndrome.

Cardiovascular effects of a newly synthesized cardiotonic agent (TA-064) on normal and diseased hearts.

A new inotropic agent, TA-064, (-)-alpha-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzylalcohol, was shown to have strong effects in experimental animals. Its effectiveness and associated adverse effects were tested in humans invasively (n = 6) and noninvasively (n = 17). Increasing doses of intravenous infusion (1, 2, and 4 micrograms/kg/min) increased plasma levels to 15, 35, and 82 ng/ml, respectively, resulting in marked increases in the peak rate of left ventricular pressure rise (dP/dt) (1,450 +/- 63 to 3,042 +/- 349 mm Hg/s) (mean +/- standard error of the mean [SEM], p less than 0.01) and the ratio of dP/dt to left ventricular pressure at a developed pressure of 40 mm Hg (25 +/- 3 to 39 +/- 2 s-1) (p less than 0.01), with a reduction in left ventricular end-diastolic pressure (12 +/- 2 to 4 +/- 1 mm Hg) (p less than 0.01). Minimal or no changes were seen in heart rate and left ventricular systolic pressure. After a single oral dose (10 mg), the plasma level reached its peak at 90 minutes (16 +/- 9 ng/ml, n = 17). A positive inotropic effect was confirmed echocardiographically in both healthy volunteers (n = 8) and patients with congestive heart failure (CHF) (n = 9) who were maximally treated with conventional regimens: increase in mean velocity of circumferential fiber shortening (healthy volunteers: 1.29 +/- 0.05 to 1.60 +/- 0.11 circ/s [p less than 0.05]; patients with CHF: 0.69 +/- 0.08 to 0.93 +/- 0.09 circ/s [p less than 0.01]), ejection fraction (healthy volunteers: 68 +/- 2 to 75 +/- 2% [p less than 0.05], patients with CHF: 37 +/- 4 to 45 +/- 5% [p less than 0.01]) without change in heart rate. The cardiac index was increased only in the CHF group (2.71 +/- 0.22 to 3.21 +/- 0.24 liters/min/m2) (p less than 0.05). No significant untoward effects were observed. Thus TA-064 is a potent inotropic agent and can be used either parenterally or orally. Salutary effects can be expected in patients with congestive heart failure who are treated with digitalis and diuretic agents.

[Clinical evaluation of the laryngeal mask airway using capnogram].

The laryngeal mask airway (LMA) was clinically evaluated using capnogram in patients who breathed spontaneously under the combination of general and spinal anesthesia. Using the LMA, the airway was maintained without jaw lift and no remarkable hemodynamic change was observed during its insertion and removal. Capnogram was useful to confirm the intact airway and to monitor the respiration. Respiratory depression was observed after thiopental administration and enflurane inhalation. The respiration recovered promptly following the increase of respiratory rate (RR) and tidal volume at first, and it made a further recovery following increase in RR. The use of the LMA under light inhalation anesthesia is hence a useful combination with regional anesthesia.

[Factorial structure of mutural cognition between parents and child].

Tsujioka's Children's Report of Parental Behavior Inventory (EICA) and its modification adapted to the parents were administered to the high school students (75 boys and 63 girls) and their parents. The results were analyzed by means of the Cliff's Procrustian factor analysis. In the first-order factor analysis, very congruent eight primary factors were obtained in two kinds of samples (boy-parents sample and girl-parents sample). These factors were 1. Acceptance in mother, 2. Autonomy in parents, 3. Identification in child, 4. Acceptance in father, 5. Autonomy in child, 6. Control in father, 7. Control in mother, and 8. Emotional support in child. Sex differences in children were examined in terms of the means and the standard deviations.

Experimental influenza A virus myocarditis in mice. Light and electron microscopic, virologic, and hemodynamic study.

To elucidate the heart involvement associated with influenza virus infection, the authors studied the hearts of influenza A/PR/8/34 virus-inoculated ICR mice by light and electron microscopy, cardiac catheterization, virus assay, and indirect immunofluorescence. Light microscopy showed small necrotic foci with inflammatory cell infiltration spreading in the myocardium on days 3 to 7 and evidence of healing by day 9 after inoculation. Electron microscopy demonstrated that necrotic cell debris was phagocytosed by macrophages, and that degenerating cardiocytes, macrophages, and lymphocytes were often in close contact, suggesting immunologic interactions, and that platelet thrombi were present in some capillaries on days 3 to 5. Both systolic and diastolic functions of the left ventricle (LV) were impaired on days 3 to 9 and recovered almost to normal by day 14. The virus could be isolated from the heart on days 3 to 7. Immunofluorescent preparations showed virus antigens in the vascular walls and cardiocytes until day 7. These results suggest that the acute cardiac injury was related to cytotoxic immunologic interactions, virus-induced cytolysis and, at least in part, to ischemia due to intracapillary thrombosis. Compared with coxsackie B3 myocarditis in mice, the influenza myocarditis was mild in degree and short in duration, but the influenza infection is a most common and repetitive disease in humans. The clinical implications of this animal model with myocarditis are discussed.

Cell-mediated immune cardiocyte injury in viral myocarditis of mice and patients.

The cellular immune mechanism of cardiocyte injury in viral myocarditis was investigated by observing and analyzing the interactions among cardiocytes, T cells, B cells, natural killer (NK) cells and macrophages in situ in the myocardium of our murine model (C3H/He mice) and of human patients. In murine coxsackie B3 virus myocarditis, lymphocyte subsets were identified by light and electron microscopic immunohistochemical techniques with antibodies against specific antigens of pan T (Thy 1.2), helper/inducer T (Th/i) (Lyt 1+), cytotoxic/suppressor T (Tc/s) (Lyt 2+), B (Ig+) and asialo GM1+ cells in the myocardium. In the acute phase of myocarditis, asialo GM1+ (mostly NK) cells predominated over pan T cells and peaked on day 9. Pan T cells then reached a peak on day 14. The T4/T8 (Lyt 1+/Lyt 2+) ratio was 1.3 +/- 0.5 on day 5 and reached a peak of 9.1 +/- 3.6 with an increase of Lyt 1+ cells on day 14. Thereafter, NK cells and T cells gradually decreased and could still be seen in fibrotic foci even 3 and 12 months later. B cells were so scarce that no quantitative evaluation could be made. Electron microscopy revealed that macrophages were in close contact with Th/i cells, target cardiocytes and less commonly, B cells; Tc/s and NK cells also occasionally conjugated with apparently viable or degenerated cardiocytes. Some lymphocytes were located in widened intercellular spaces of dissociated intercalated discs, and in intracytoplasmic widened confines of some cardiocytes (emperipolesis). These results suggest that in the acute phase of myocarditis, NK cells initiate the reaction, and then sensitized cytotoxic T cells and activated macrophages aggravate cell-mediated injury by their close contacts with target cardiocytes; close contacts among macrophages; Th/i cells and a few B cells, and the increased T4/T8 ratio may facilitate regulation of the complex immune network; in the chronic phase, residual but active NK and cytotoxic T cells may sustain cytotoxicity. In the endomyocardial biopsies obtained from 8 patients with viral or idiopathic myocarditis from 3 to 48 days after the clinical onset, conventional electron microscopy revealed actual contacts among cardiocytes, macrophages and lymphocytes. As in our murine model, some lymphocytes had emperipolesed in cardiocytes or were located in widened spaces of dissociated intercalated discs. In 4 of these 8 patients infiltration of Leu 2a+ Tc/s, Leu 3+ Th/i and Leu 7+ cells was identified immunohistochemically, and T4/T8 ratios varied widely from 0.1 to 3.8 in the endomyocardial biopsides.(ABSTRACT TRUNCATED AT 400 WORDS)

In situ analysis with monoclonal antibodies of lymphocyte subsets in myocardial biopsies from patients with dilated cardiomyopathy and idiopathic (viral) myocarditis.

This light- and electron-microscopic immunohistochemical study using monoclonal antibodies analyzes of the in situ lymphocyte subsets in endomyocardial biopsies from 11 patients with dilated cardiomyopathy (DCM) and three patients with idiopathic (viral) myocarditis (MYO). In the DCM patients both Leu 2a+ cytotoxic/suppressor T cells (Tc/s) and Leu 3+ helper/inducer T cells (Th/i) were identifiable in the myocardial lesions, and mean Th/i/Tc/s (T4/T8) ratio was 0.7 +/- 0.6 (mean +/- SD). In 9 of the 11 DCM patients, Tc/s were more numerous than Th/i cells, so the T4/T8 ratio was less than 1.0. On the other hand, the T4/T8 ratios varied widely in the three MYO patients; one of them had marked mononuclear cell infiltrates with many Th/i in the inflammatory foci and a T4/T8 ratio of 2.6. Immunoelectron microscopy revealed some Th/i in close contact with macrophages. These T cells in the myocardium of DCM and MYO patients appeared to be in vivo effector cells playing an important role in cell-mediated immune responses.

Experimental coxsackie B3 virus myocarditis in golden hamsters. II. Evaluation of left ventricular function in intact in situ heart 14 months after inoculation.

The hemodynamic changes of the left ventricle (LV) of golden hamsters surviving for 14 months after acute coxsackie B3 virus myocarditis were assessed with the use of a high fidelity micromanometer pressure system. Of 25 infected hamsters, 10 survived to the 14th month, and 4 of these had cardiomegaly. Body weight (BW) was 150.0 +/- 20.7 g (mean +/- SD) (controls, 164.5 +/- 20.1 g, NS); heart weight (HW), 0.499 +/- 0.084 g (controls, 0.448 +/- 0.035 g, NS); and HW/BW, 3.39 +/- 0.79 X 10(-3) (controls, 2.74 +/- 0.23 X 10(-3), p less than 0.05). The hemodynamic data under anesthesia were: HR, 378 +/- 42 (controls, 414 +/- 43, NS); LVSP, 108 +/- 16 mmHg (controls, 126 +/- 16, NS); LVDP, 4.0 +/- 4.8 mmHg (controls, 0.6 +/- 0.7, NS); LVEDP, 9.7 +/- 7.5 mmHg (controls, 3.4 +/- 1.4, NS); peak positive dp/dt, 4960 +/- 1431 mmHg/sec (controls, 6714 +/- 1326, p less than 0.05); (dp/dt)/DP40, 56.8 +/- 9.8 sec-1 (controls, 73.1 +/- 7.0, p less than 0.01); peak negative dp/dt, 3876 +/- 1072 mmHg/sec (controls, 4971 +/- 599, p less than 0.05); and time constant T of LV pressure fall, 7.7 +/- 1.3 msec (controls, 5.9 +/- 0.7, p less than 0.01). Five hamsters had congestion of the lungs and liver with or without an elevation of LVEDP. One of them had an organizing thrombus in the left atrium, and one had an aneurysm in the LV free wall. Though markedly varied in extent, residual myocardial fibrosis was always evident in the hearts in which isovolumic contractility and early diastolic relaxation of the LV were significantly impaired. In a clinical extension of these findings, it may be that some cases of dilated cardiomyopathy in man develop in a way similar to the pathological processes noted in this experiment.

Cell-mediated immunity in Coxsackie B3 virus myocarditis in mice--in situ characterization by monoclonal antibody of mononuclear cell infiltrates.

This light- and electron-microscopic study using monoclonal antibody and anti-immunoglobulin antibodies in murine Coxsackie B3 virus myocarditis provides an immunohistochemical demonstration of surface antigens of lymphocytes. On the 7th and 9th days after inoculation, many necrotic cardiocytes were surrounded by numerous cellular infiltrates, in which macrophages and T lymphocytes predominated, whereas immunoglobulin-bearing B lymphocytes represented a minority. Immuno-electron microscopy showed some T lymphocytes in close contact with other lymphocytes, macrophages, and the sarcolemma of cardiocytes. After the 30th day, significant numbers of T lymphocytes and macrophages were still identifiable in and around the fibrotic foci. Our study suggests that cell-mediated immunity plays a protective role by lysing and scavenging virus-infected cardiocytes and cell debris at least in the early stage of myocarditis. The residual T lymphocytes in the chronic stage suggest their involvement in sustained cardiocyte injury.

Viral and idiopathic myocarditis in Japan: a questionnaire survey.

In order to study the current clinical status of viral and idiopathic myocarditis in Japan, we conducted a questionnaire survey and collected data for 218 cases from 62 institutions. The diagnosis was based on clinical and laboratory findings alone in 45% of the cases, and it included endomyocardial biopsy in 24% and autopsy in 9% of the patients. Endomyocardial biopsies were available in 40% of the patients; definite cellular infiltrations were identified in half the cases. Regardless of the biopsy findings or availability of biopsy, males predominated in the patient population; the mean age range was 30-39 years for both sexes. Cardiac symptoms and signs were common in addition to "common cold" symptoms; ECG abnormalities, leukocytosis, accelerated erythrocyte sedimentation rate, positive CRP, and increased cardiac enzyme levels were also very common in the acute phase of the disease. Serologic tests for virus titers, performed in 80% of the cases, were positive in 21%. There was no apparent correlation between serologic results and endomyocardial biopsy findings. In this survey, complete recovery occurred in 43%, cure with sequelae in 40%, recurrences in 3%, and death in 13% of the total patient population.

Immunohistochemical study of the myocardium in murine Coxsackie B3 virus myocarditis using monoclonal antibodies--significance of Lyt 1 antigen-bearing lymphocytes in cell-mediated immunity.

This light- and electron-microscopic study using monoclonal antibodies provides an immunohistochemical demonstration of lymphocytes in situ in the myocardium in murine coxsackie B3 virus myocarditis. On the 7th and 9th days after virus inoculation, we observed many necrotic cardiocyte foci infiltrated with numerous inflammatory cells including macrophages and T lymphocytes. There were only a few Lyt 1-bearing lymphocytes in this phase of inoculation. On the 14th day there were many Lyt 1-bearing cells among the T cells in the foci. By immuno-electron microscopy, some Lyt 1-bearing T lymphocytes were seen in close contact with macrophages and/or other lymphocytes. These Lyt 1-bearing lymphocytes appeared to represent helper T cells, although Lyt 2.3+ lymphocytes were not examined. It is well known that activation of helper T cells leads to stimulation of B cells and cytotoxic T cells. It is assumed, therefore, that Lyt 1-bearing T lymphocytes that infiltrated into the myocardial foci play an important role in immune responsiveness at this stage of viral myocarditis.