Gastric tuberculosis. Endoscopic cytology as a diagnostic tool

OBJECTIVE: To highlight the utility of endoscopic brush smears in the diagnosis of gastric tuberculosis in clinically unsuspected cases. STUDY DESIGN: A retrospective analysis of endoscopic brush smears from 210 patients with gastric symptoms. In seven of these patients (3.3%) the possibility of gastric tuberculosis was suggested in Giemsa-stained smears. Biopsy was available in all cases. Ziehl-Neelsen stain to demonstrate tubercle bacilli was used in brush smears and biopsies in seven and three cases, respectively. RESULTS: Endoscopically the sites involved were antrum (two), pylorus (two), pylorus and duodenum (three). One patient had an ulcerative lesion, and six had growths. Granulomas and/or epithelioid cells were seen in brush smears in all cases. Tubercle bacilli could be demonstrated in cytologic smears in four cases. Endoscopic biopsy showed granulomas in five cases and non-specific gastritis in two. Tubercle bacilli could not be demonstrated in any of the biopsy sections. On further clinicoradiologic investigation, two patients were found to be follow-up cases of pulmonary and nodal tuberculosis. Enzyme-linked immunosorbent assay for HIV, done in three cases, was negative. A final diagnosis of primary gastric tuberculosis in five patients and secondary in two was considered. Six patients responded to antituberculosis treatment and showed healing of the lesions on repeat endoscopy after six months of therapy, while one was a recent case with four weeks' follow-up. CONCLUSION: Endoscopic brush cytology is a reliable modality for the diagnosis of gastric tuberculosis.     

Stereotactic biopsy and cytological diagnosis of solid and cystic intracranial lesions

Cytological smears from 115 consecutive cases of stereotactic biopsies of intracranial lesions were reviewed. Ninety-five lesions were solid and 20 cystic. Material from 90 solid and 13 cystic lesions was sent both for cytological and histological examination. In 66 of the solid lesions, the cytological diagnosis was confirmed by histology (five were benign lesions and 61 malignant tumours: 56 primary brain tumours, three metastases and two lymphomas). In 24 cases with discrepant cytology and histology, the histology was inconclusive or insufficient in 14 cases, while cytology established the diagnosis of astrocytoma grade II (seven cases), metastases (two cases), gliosis (one case) and benign (four cases). Necrosis of tumour type was observed cytologically in six patients representing glioblastoma (two cases), anaplastic astrocytoma (one case), lymphoma (one case) and normal brain (two cases) histologically. Three cases reported cytologically as benign were primary brain tumour (two cases) and gliosis (one case). One smear of a glioblastoma was insufficient for cytological diagnosis. Cystic lesions were cytologically benign in 17 cases and malignant in three cases. Histology from the cyst wall confirmed the malignant diagnosis in three cases and showed tumour in six more cases, a benign process (two cases), changes induced by radiotherapy for arteriovenous malformation (one case) and insufficient material (one case). In conclusion, cytology from solid brain lesion allows an accurate diagnosis and subtyping of tumours in a majority of cases, and can thus be used to choose type of therapy. In cystic brain tumours, however, examination of the cystic fluid, is often inconclusive and a biopsy from the cyst wall should be performed if there is clinical or radiological suspicion of tumour.     

Re-evaluation of histological diagnoses of malignant mesothelioma by immunohistochemistry

Background

In order to provide reliable tissue material for malignant mesothelioma (MM) studies, we re-evaluated biopsies and autopsy material from 61 patients with a diagnosis of MM from the period of 1980-2002.

Methods

Basic positive (Calretinin, EMA, Podoplanin, Mesothelin) and negative (CEA, Ber-Ep4) immunohistochemical (IHC) marker reactions were determined. If needed, more markers were used. Histological diagnoses were made by three pathologists. Survival data were calculated.

Results

49 cases (80%) were considered being MM by a high degree of likelihood, five more cases possible MM. Of the remaining seven cases, three were diagnosed as adenocarcinoma, three as pleomorphic lung carcinoma, in one peritoneal case a clear entity diagnosis could not be given. One of the possible MM cases and two of the lung carcinoma cases had this already as primary diagnoses, but were registered as MM. With a sensitivity of 100%, Calretinin and CEA were the most reliable single markers. The amount of MM cells with positive immunoreactivity (IR) for Podoplanin and Mesothelin showed most reliable inverse relation to the degree of atypia. In the confirmed MM cases, there had been applied either no IHC or between one and 18 markers. The cases not confirmed by us had either lacked IHC (n = 1), non-specific markers were used (n = 4), IR was different (n = 1), or specific markers had not shown positive IR in the right part of the tumour cells (n = 3). 46 of the 49 confirmed and three of the not confirmed cases had been diagnosed by us as most likely MM before IHC was carried out.

Conclusions

In order to use archival tissue material with an earlier MM diagnosis for studies, histopathological re-evaluation is important. In possible sarcomatous MM cases without any positive IR for positive MM markers, radiology and clinical picture are essential parts of diagnostics. IHC based on a panel of two positive and two negative MM markers has to be adapted to the differential diagnostic needs in each single case. New diagnostic tools and techniques are desirable for cases where IHC and other established methods cannot provide a clear entity diagnosis, and in order to improve MM treatment.     

胆囊结石患者超声诊断结果漏诊及误诊分析

目的:探讨我院胆囊结石患者超声诊断漏诊、误诊的超声诊断结果,并分析出现漏诊、误诊的原因。方法:选取我院肝胆外科经彩色多普勒超声诊断确诊并实施手术治疗的胆囊结石患者260例,结合临床资料分析患者彩色多普勒超声图的特点,并在术后一周进行随访,对彩色多普勒超声诊断的漏诊率及误诊率并分析原因。结果:1、胆囊结石分型:典型胆囊结石167例(64.3%)、充满型胆囊结石50例(19.2%)、多发性胆囊结石28例(10.8%)、泥沙样胆囊结石10例(3.8%),另外5例患者属非胆囊结石(1.9%);2、彩色多普勒超声确诊的260例胆囊结石患者经手术病理证实其中255例为胆囊结石,5例为非胆囊结石(2例为误诊,3例为漏诊),超声诊断的准确率98.1%。误诊、漏诊的发生与病灶部位、患者肥胖程度、仪器操作及医师经验等因素有关。结论:虽然彩色多普勒超声对胆囊结石的诊断率较高,但仍需完善,以减少或避免临床误诊和漏诊的发生。     

Phyllodes tumour: cytologic and histologic presentation of 22 cases, and immunohistochemical demonstration of p53

A retrospective study of 22 cases of phyllodes tumour (PT) was undertaken to evaluate the potential value of fine needle aspiration (FNA) cytology in the diagnosis of benign and borderline PT. Histological material was available from 12 patients with typical benign PT (group 1), six patients with less typical changes (group 2) and four cases of borderline PT (group 3). Cytological presentation of PT in these cases was similar to that described by other cytologists, although abundant cellular material was obtained in only eight FNAs, naked nuclei were present in nine cases only, and atypical or suspicious cytological features were found in seven cases. Comparative analysis of p53 was made in nine patients with PT, five cases with other benign breast lesions and five with malignant lesions. p53 reaction was positive in five of nine patients with PT (all cases from groups 2 and 3), compared with two of five cases of carcinoma. p53 was negative in all patients with PT from group 1 and the five other benign cases. We suggest that cytopathologists should be careful when a myxoid stromal component is present in cytological smears.     

Inter- and intraobserver reproducibility of thyroid fine needle aspiration cytology: an analysis of discrepant cases

OBJECTIVE: To determine the inter- and intraobserver reproducibility and analyse the discrepant cases of fine needle aspiration cytology (FNAC) of the thyroid. METHODS: Cases of thyroid FNAC with a corresponding histological diagnosis were reviewed regarding the original cytological diagnoses by two observers. The final cytological diagnoses (FCD) included both concordant and consensus diagnoses. The inter- and intraobserver reproducibility and efficacy of thyroid FNAC were calculated based on the FCD. RESULTS: A total of 97 FNAC cases with corresponding histopathological specimens were analysed. Although inter- and intraobserver disagreement in the cytological diagnoses occurred in about one-quarter of the cases analysed (24.7% and 23.7%, respectively), a substantial level of diagnostic interobserver (kappa = 0.71) and intraobserver (kappa = 0.66) reproducibility was observed. The efficacy of the method was 94.4%. Disagreement in the diagnosis was detected in 24 cases (24.7%), most of them (41.7%) for follicular lesions. Discordant cytological diagnoses between the two observers were represented by six (16.2%) of the 37 cases with an FCD of colloid nodule, five (41.7%) of the 12 cases of cellular follicular lesion, all three cases of follicular neoplasm, in two (6.3%) of the 32 cases of PTC, one (16.7%) of six cases of follicular neoplasm with a predominance of Hürthle cells and in one case of poorly differentiated neoplasia. Similarly, major disagreement in intraobserver cytological diagnoses was observed for the diagnosis of follicular lesions: 18 (78.3%) of a total of 23 discordant cases. CONCLUSION: As discrepancies in the cytopathological diagnosis can have repercussions in the management of patients, all cases with a cytological diagnosis of follicular lesions/neoplams should be reviewed in multidisciplinary meetings thus minimizing interobserver variability.     

Esophageal tuberculosis. Endoscopic cytology as a diagnostic tool

OBJECTIVE: To study the utility of endoscopic cytology in the diagnosis of esophageal tuberculosis in clinically unsuspected cases. STUDY DESIGN: During a period of four years, endoscopic cytology of esophageal lesions was performed on 228 patients. In eight (3.5%) the cytologic diagnosis of esophageal tuberculosis was suggested on smears. Upon endoscopic examination, the sites of involvement were mid esophagus (five cases), upper esophagus (two cases) and lower esophagus (one case). Linear ulcer was seen in six cases; growth and narrowing of the lumen were seen in one case each. Endoscopic brush smears in seven cases and fine needle aspiration cytology smear in one case were collected. Air-dried smears stained by Giemsa stain were reviewed for detailed cytologic assessment. RESULTS: Smears showed well-defined granulomas with necrosis in five cases and granulomas without necrosis in three. Cytologic evidence of concurrent poorly differentiated squamous cell carcinoma was observed in one case. Tubercle bacilli were demonstrated in five cases. Endoscopic biopsy showed granulomas in three cases and tubercle bacilli in one case. In six cases there was no clinical or radiologic evidence of tuberculosis at other sites, thereby suggesting the possibility of primary esophageal tuberculosis. The remaining two cases had a past history of tuberculosis; one presented with cervical lymphadenopathy and one mediastinal lymphadenopathy. All patients received antitubercular treatment, and the patient with concurrent malignancy also received radiotherapy. All but one of the patients who succumbed to aspiration pneumonia responded to treatment. CONCLUSION: Endoscopic cytology is a useful modality in the diagnosis of esophageal tuberculosis in clinically unsuspected cases.     

Cryptococcosis associated with AIDS in the Muñiz Hospital of Buenos Aires

Some epidemiologic, diagnostic and immunologic aspects of 93 (75 males and 18 women) cases of cryptococcosis (CRY) associated with AIDS, hospitalized in the Muñiz Hospital (MH) in Buenos Aires during 1994, were retrospectively studied. The median age (MA) of the patients under study was 28 years (17–49 y); 30 (17–49) y for males and 23 (22–34) y for women. Intravenous drug addiction (34% of patients) and homo/bisexuality in men (17%) were the most frequent risk factors for HIV infection. The MA of these groups were 27.5 (17–41) y and 34 (25–41) y, respectively. Microscopic CSF examination with India ink and the blood cultures (lysis-centrifugation) achieved the diagnosis of CRY in 67 (72%) and 16 (17%) patients, respectively. At diagnosis, the median titers for Cryptococcus neoformans capsular antigen were 1/1,000, 1/100 and 1/1 in serum, CSF and urine, respectively. Sixty five strains of C. neoformans were insolated from clinical samples; all were identified at variety neoformans employing the culture medium proposed by Salkin &; Hurd and the D-proline assimilation test. At diagnosis, CD4⁺lymphocytes counts were <50/μl in 46 patients (83.63%), and were between 51 and 200/μl in 9 (16.4%). The CD4⁺CD8⁺ ratio was <1 in all patients. Most patients were born (83%) and lived at diagnosis (96%) in Buenos Aires (Bs As) city, Bs As outskirts towns and cities located in Bs As province.     

Vaginal intraepithelial neoplasia and the Pap smear

OBJECTIVE: To assess the sensitivity of the vaginal smear cytologic examination in detecting vaginal intraepithelial neoplasia (VAIN) and to evaluate the cytologic findings of cases of VAIN. STUDY DESIGN: Cases with a histologic diagnosis of VAIN were identified from the Barnes-Jewish Hospital South and North Campus over a period of five and nine years, respectively. Only posthysterectomy patients with a tissue biopsy diagnosis of VAIN and with a vaginal smear obtained within three months of the biopsy were included in the study. Pertinent clinical information was obtained by reviewing the medical records. Two pathologists reviewed the pathologic samples. RESULTS: Thirty-five vaginal smears from 31 posthysterectomy patients were included in the study. The mean age was 57 years (range, 29-84). The cytologic diagnoses of smears from patients with VAIN included: high grade squamous intraepithelial lesion (19 cases), low grade squamous intraepithelial lesion (10 cases), atypical squamous cells of uncertain significance (5 cases) and negative for malignancy (1 case). CONCLUSION: The sensitivity of the vaginal smear cytologic examination in detecting VAIN is 83%. Obscuring inflammation contributed to false negative diagnoses in two cases.     

Fine needle aspiration cytology of focal nodular hyperplasia of the liver

In five cases, the fine needle aspiration (FNA) cytologic study of ultrasonically detected solitary liver tumors yielded a diagnosis of focal nodular hyperplasia. Cytomorphologically, the lesions were characterized by the presence of both abundant normal hepatocytes and numerous epithelial cells in ductal formations, clusters or tightly packed groups in the FNA samples. In two of the five cases, the cytologic diagnosis was confirmed by subsequent histologic studies; in the remaining three cases, the clinical data were consistent with focal nodular hyperplasia of the liver. All five patients were women, four of whom had used oral contraceptives for long periods of time (5 to 15 years), which has previously been linked to the development of focal nodular hyperplasia of the liver. Based on the findings in this study, FNA cytology should be adequate for making the differential diagnosis of focal nodular hyperplasia versus liver-cell adenoma when solitary liver tumors are detected in such cases; it can yield a morphologic diagnosis and facilitate the decision as to whether surgical intervention is required.     

Cytomorphological study of soft tissue neoplasms: role of fluorescent immunocytochemistry in diagnosis

OBJECTIVES: Exact categorization of soft tissue tumours (STTs) on smears requires application of various ancillary techniques. This study was aimed at evaluating the role of fluorescent immunocytochemistry (FICC) in cyto-diagnosis of 30 STT cases. METHODS: Thirty cases of soft tissue tumours were included in the present study. All cases were subjected to routine Giemsa and Papanicolaou stain. Extra smears were made and kept for fluorescent immunostaining. A panel of cytoskeletal antibodies, tagged with FITC (Fluorescein isothyocynate), was employed in all these cases. Fluorescent immunostained smears were examined under Zeiss Confocal Laser scanning microscope, using double immunofluorescence (red-green). Finally, all cases were subjected to biopsy and again immunoperoxidase staining. RESULTS: Among the 30 cases in the present study, unaided cytological diagnoses ranged from 'spindle cell' tumour in four (13.3%) cases, benign and malignant spindle cell tumour in 17 (56.6%) cases, to malignant mesenchymal tumour in nine (30%) cases. FICC helped in further correct categorization of 25/30 (83.3%) cases viz. leiomyoma (three), benign neurogenic tumour (six), schwannoma (one), dermatofibrosarcoma protuberans (three), synovial sarcoma (two), rhabdomyosarcoma (two), malignant fibrous histiocytoma (five) and malignant peripheral nerve sheath tumour (three). Aggressive fibromatosis was found to be a missed diagnosis in two cases. Overall concordance between cyto-diagnosis with FICC, and histopathology results was 83.3% (P < 0.05). CONCLUSION: Fluorescent immunocytochemistry is a significant ancillary technique for making a rapid and specific diagnosis of STT, as required for their timely management. Incorporation of a wide panel of antibody markers with clinico-cytological correlation is recommended in forming an exact diagnosis in these cases.     

Evaluation of fine needle aspiration of the male breast for the diagnosis of gynaecomastia

Fine needle aspiration of the male breast can present problems of diagnosis because the cytological presentation of gynaecomastia can be confused with that of adenocarcinoma. We reviewed breast aspirates from 24 male patients in order to determine the accuracy of cytology as a method of diagnosing gynaecomastia. Discrepancies were observed between the original cytology reports on one hand and the review cytology and biopsies on the other. Of the 24 aspirates from the male breast, the cytology was reported as negative in 16 cases, suspicious in three cases and malignant in five. In four cases of the negative group, a specific diagnosis of gynaecomastia was made. In two of the negative cases the subsequent biopsies revealed adenocarcinoma. Of the five cases reported on the original cytology as adenocarcinoma, two on review showed the features of florid gynaecomastia and this was confirmed on biopsy and three confirmed the initial diagnosis of adenocarcinoma. The cytological features of gynaecomastia which distinguish it from adenocarcinoma are discussed.     

Role and accuracy of rapid on‐site evaluation of CT‐guided fine needle aspiration cytology of lung nodules

A. Fassina, M. Corradin, D. Zardo, R. Cappellesso, F. Corbetti and M. Fassan
Role and accuracy of rapid on‐site evaluation of CT‐guided fine needle aspiration cytology of lung nodules Objective: To prospectively investigate the role of trans‐thoracic fine needle aspiration cytology (FNA) and the value of rapid on‐site evaluation (ROSE) in the clinical management of patients with pulmonary nodules/masses. Computed tomography (CT)‐guided FNA is commonly employed for the diagnosis of lung lesions although its position in the diagnostic work‐up is still a matter of debate. Methods: We reviewed 311 patients (211 males and 100 females, mean age 69.5 years) admitted to the University of Padova from 2004 to 2008, correlating the results of cytology with the available histological findings obtained from biopsies, surgery or autopsy. Results: Smears were adequate in 305 cases (98%) and inadequate in six (2%); a diagnosis of malignancy was achieved in 263 cases (86.2%); 39 cases (12.8%) were classified as non‐malignant; and three cases (1%) were classified as suspect for malignancy. When correlated with histology, FNA with ROSE discriminated malignant versus non‐malignant lesions (Cohen’s kappa 0.78), with three false negatives (sensitivity 96.3%, specificity 100%). Moreover, a satisfactory overall agreement of 71.4% was achieved in differentiating the cancer histological types. Pneumothorax occurred in 13 cases, haemoptysis in four, and chest pain in three. A single aspiration was sufficient in 79.6% of patients; two aspirations were needed in 17.4% and three in 3%. The low complication rate was related to the limited number of aspirations needed due to ROSE. Conclusions: FNA with ROSE is a safe and useful tool in the diagnostic work‐up of lung cancer patients, with no contraindications to its use as the first diagnostic procedure for all patients with peripheral lung lesions. FNA with ROSE should be reconsidered in the guidelines for diagnosing and managing lung cancer.     

Neuroparacoccidioidomycosis (NPCM): Magnetic Resonance Imaging (MRI) Findings

Objective

To describe the magnetic resonance imaging (MRI) patterns of the central nervous system (CNS) involvement by neuroparacoccidioidomycosis (NPCM).

Methods

Between January 1999 and March 2011, a review of MRI data analysis from 8 cases of NPCM was performed. The following MRI characteristics were examined by an experienced neuroradiologist: topography of lesions, aspects on T1- and T2-weighted images (WI), contrast enhancement, diffusion and spectroscopy.

Results

All patients had evidence of paracoccidioidomycosis infection outside the nervous system. Regarding CNS involvement, five patients had only supratentorial lesions; three had infra- and supratentorial ones. Meningeal extension occurred in three patients. The lesions were predominantly hyperintense on T1WI. At T2WI, a hypointense component was present in five cases as well as a perilesional abnormal white matter. A ring-enhancement pattern was seen in five cases. Spectroscopy was performed in three patients and showed an increased lipid peak in all of them. In one case, there was also an increased choline peak.

Conclusion

NPCM is rare, and MRI may help its differentiation from other inflammatory lesions. However, the presence of active infection outside CNS and some imaging characteristics should point to this diagnosis.     

DPY19L2 deletion as a major cause of globozoospermia

Globozoospermia, characterized by round-headed spermatozoa, is a rare (< 0.1% in male infertile patients) and severe teratozoospermia consisting primarily of spermatozoa lacking an acrosome. Studying a Jordanian consanguineous family in which five brothers were diagnosed with complete globozoospermia, we showed that the four out of five analyzed infertile brothers carried a homozygous deletion of 200 kb on chromosome 12 encompassing only DPY19L2. Very similar deletions were found in three additional unrelated patients, suggesting that DPY19L2 deletion is a major cause of globozoospermia, given that 19% (4 of 21) of the analyzed patients had such deletion. The deletion is most probably due to a nonallelic homologous recombination (NAHR), because the gene is surrounded by two low copy repeats (LCRs). We found DPY19L2 deletion in patients from three different origins and two different breakpoints, strongly suggesting that the deletion results from recurrent events linked to the specific architectural feature of this locus rather than from a founder effect, without fully excluding a recent founder effect. DPY19L2 is associated with a complete form of globozoospermia, as is the case for the first two genes found to be associated with globozoospermia, SPATA16 or PICK1. However, in contrast to SPATA16, for which no pregnancy was reported, pregnancies were achieved, via intracytoplasmic sperm injection, for two patients with DPY19L2 deletion, who then fathered three children.     

Yersinia enterocolitica arthritis in southern Sweden: a four-year follow-up study.

Thirty-eight cases of suspected yersinia arthritis occurring in southern Sweden in 1975-6 were reviewed four to five years later. In 31 cases the diagnosis was confirmed. At follow-up three of the patients had definite ankylosing spondylitis, three radiologically confirmed sacroiliitis, three extensor tenosynovitis, five isolated articular joint disease, and 10 localised arthralgias; one patient had developed seropositive rheumatoid arthritis. Only six of the 31 patients were free of joint symptoms. These results suggest that although the acute symptoms of yersinia arthritis disappear within 12 months, the long-term prognosis may be less favourable than previously thought.     

Subacute bacterial endocarditis; a report on 57 patients treated with massive doses of penicillin

Fifty-seven patients with subacute bacterial endocarditis were treated with doses of penicillin varying from 500,000 to 20,000,000 units per day. Diagnosis was confirmed in some cases by growths on blood culture, in others by postmortem examination. In those cases in which the diagnosis was established by blood culture, the in vitro sensitivity of the organism to penicillin was determined and penicillin then was administered by continuous intramuscular infusion in a dosage calculated to produce blood levels of penicillin four to five times that required for in vitro inhibition. Penicillin was given for a period of 21 days, and blood cultures were made periodically during and after treatment. Of the 57 patients, 38 were cured (66.7 per cent), and 19 died (33.3 per cent). Of the 19 who died, three did so within 48 hours of hospitalization and seven died despite adequate treatment. Of these seven, three died of cerebral emboli, two because of resistance to penicillin and streptomycin, one because of congestive heart failure, and one of undetermined cause. The remaining nine who died were considered to have been inadequately treated in that there was (1) failure to obtain sensitivity, (2) inadequate dossage of penicillin, (3) delay in starting treatment, or (4) failure to recognize mixed infections. There were five patients with repeatedly sterile blood cultures during life. In all of these cases, streptococcus viridans was recovered at postmortem examination. In an attempt to determine how long therapy should justly be withheld in patients with repeatedly sterile blood cultures, 140 cases of subacute bacterial endocarditis in which positive blood cultures had been obtained were reviewed. From the review it was determined that if blood cultures taken during the first two days are reported sterile, the chance of subsequent cultures proving positive is minimal. Therefore, for patients in whom the diagnosis seems otherwise obvious, delaying treatment for more than two days is not justified even though the blood culture be sterile. In cases in which blood cultures are repeatedly sterile, a dosage of 6,000,000 to 10,000,000 units of penicillin daily for 21 days is advisable.High bacterial resistance to penicillin and streptomycin was found in four fatal cases. In one of these, the infecting organism was streptococcus viridans, and in three it was staphylococcus albus. There was one patient with penumococcal meningitis complicated by unrecognized streptococcal viridans bacterial endocarditis.     

SUBACUTE BACTERIAL ENDOCARDITIS—A Report on 57 Patients Treated with Massive Doses of Penicillin

Fifty-seven patients with subacute bacterial endocarditis were treated with doses of penicillin varying from 500,000 to 20,000,000 units per day. Diagnosis was confirmed in some cases by growths on blood culture, in others by postmortem examination. In those cases in which the diagnosis was established by blood culture, the in vitro sensitivity of the organism to penicillin was determined and penicillin then was administered by continuous intramuscular infusion in a dosage calculated to produce blood levels of penicillin four to five times that required for in vitro inhibition. Penicillin was given for a period of 21 days, and blood cultures were made periodically during and after treatment.Of the 57 patients, 38 were cured (66.7 per cent), and 19 died (33.3 per cent).Of the 19 who died, three did so within 48 hours of hospitalization and seven died despite adequate treatment. Of these seven, three died of cerebral emboli, two because of resistance to penicillin and streptomycin, one because of congestive heart failure, and one of undetermined cause. The remaining nine who died were considered to have been inadequately treated in that there was (1) failure to obtain sensitivity, (2) inadequate dossage of penicillin, (3) delay in starting treatment, or (4) failure to recognize mixed infections.There were five patients with repeatedly sterile blood cultures during life. In all of these cases, streptococcus viridans was recovered at postmortem examination. In an attempt to determine how long therapy should justly be withheld in patients with repeatedly sterile blood cultures, 140 cases of subacute bacterial endocarditis in which positive blood cultures had been obtained were reviewed. From the review it was determined that if blood cultures taken during the first two days are reported sterile, the chance of subsequent cultures proving positive is minimal. Therefore, for patients in whom the diagnosis seems otherwise obvious, delaying treatment for more than two days is not justified even though the blood culture be sterile. In cases in which blood cultures are repeatedly sterile, a dosage of 6,000,000 to 10,000,000 units of penicillin daily for 21 days is advisable.High bacterial resistance to penicillin and streptomycin was found in four fatal cases. In one of these, the infecting organism was streptococcus viridans, and in three it was staphylococcus albus. There was one patient with penumococcal meningitis complicated by unrecognized streptococcal viridans bacterial endocarditis.