Multicenter evaluation of a pathogenic mycobacterium screening probe.

The introduction of nucleic acid amplification assays into the clinical laboratory has reduced the time needed to diagnose diseases caused by members of the Mycobacterium tuberculosis complex (MTBC). However, several mycobacterial species other than those of the MTBC are known to cause disease, especially in immunocompromised individuals. A screening assay has been developed for the detection of the major pathogenic mycobacterial species. The assay utilizes pan-genus primers to amplify mycobacterial DNA and a screening probe (KY493) that detects all major pathogenic mycobacteria. A multicenter European study was conducted to assess the performance of the screening probe in the clinical laboratory. The screening probe was evaluated against individual probes specific for M. tuberculosis, M. avium, and M. intracellulare, a genus-specific probe with broader species coverage, and culture. The screening probe had a sensitivity equivalent to that of the species-specific probes; all specimens positive with any of the species-specific probes were also positive with the screening probes. Compared to culture, the sensitivity of the screening probe was 89% (154 of 173) for all culture-positive specimens tested. This value was 89.6% for the genus-specific probe. The screening probe was more specific than the genus-specific probe. Specificity was 93.9% (661 of 704) compared to culture results alone. The comparable specificity value for the genus-specific probe was 84.8%. When clinical data were taken into consideration, the sensitivity of the screening assay was similar to that of culture (81% versus 76.2%) but the positive predictive value of the test was lower (76.2% versus 100% for culture). However, the screening probe was more sensitive than smear and may be a useful tool in the rapid diagnosis of mycobacterial disease.

Why history is important for thoracic surgeons.

There are numerous examples of lessons to be learned from acquaintance with surgical history. Notwithstanding these considerations--the admonition to read and think about history, the lessons learned from technical misadventures, and the need to add humanistic practices to our scientific endeavors--the real reward from our study of medical history lies in the pure job of being educated in one more way. This implies understanding our contemporary position in the unrolling course of medical history: from remote history through the enlightenment after the reawakening from the dark ages, to the surgical spurt in the latter half of the nineteenth century, and onward through the dramatic advances of our passing millennium.

Long-segment colon interposition for acquired esophageal disease.

BACKGROUND: Long-segment colon interposition has been used for esophageal replacement for acquired esophageal disease. The indications for use, morbidity, and functional results of these conduits have been debated. METHODS: We reviewed the medical records, office visits, and operative reports of patients undergoing long colon interposition for acquired esophageal disease at our institution from 1956 to 1997. RESULTS: Long colon interposition was performed in 52 patients for caustic injury (n = 20), gastroesophageal disease (n = 16), previous irradiation (n = 8), primary motility disorders (n = 4), and acquired absence of the esophagus (n = 4). From 1976 to 1997, acquired diseases accounted for 62% of long colon interposition. The left colon was used in 46 patients and the right colon in 6. The in-hospital mortality rate was 4%. Early complications included graft ischemia in 5 patients, anastomotic leak in 3, and small bowel obstruction in 1. Late complications included anastomotic stenosis requiring dilation in 26 patients, with 2 requiring surgical revision, and bile reflux requiring surgical diversion in 1 patient. Swallowing function was excellent in 24% of patients, good in 66%, and poor in 10%. CONCLUSIONS: Long colon interposition can be performed safely, with acceptable long-term functional results in patients with acquired esophageal disease.

Thymoma. Histologic subclassification is an independent prognostic factor.

BACKGROUND: Several histologic classifications of thymomas have been proposed, and attempts have been made to correlate the different histologic subtypes to clinical behavior and prognosis. Recently, Marino and Müller-Hermelink and Kirchner et al. proposed a new morphologic classification of thymomas based on the resemblance of the neoplastic cells to subtypes of the normal thymic epithelial cells. In this classification, six categories of thymic epithelial tumors are recognized. They define four categories of thymoma: medullary, mixed, organoid (predominantly cortical), and cortical, and two subgroups of thymic carcinomas: well differentiated thymic carcinoma and high grade carcinomas. METHODS: The authors studied 116 patients with thymic epithelial tumors classified according to the proposals of Marino and Müller-Hermelink and Kirchner et al. to assess the effect of histologic classification and other factors (stage, size of tumor, lymphoid hyperplasia, myasthenia gravis, age, sex, and treatment) on survival, and freedom from relapse. RESULTS: Eight cases (7%) were medullary, 32 cases (28%) mixed, 20 cases (17%) organoid (predominantly cortical), 21 cases (18%) cortical, 29 cases (25%) well differentiated carcinoma (WDTC), two cases (2%) high grade carcinoma, and four cases (3%) unclassifiable. Fifty-two patients were in stage I, 32 stage II (16 IIA, 16 IIB), 28 stage III, and four Stage IVA. Only stage (P = 0.0001; hazard ratio = 5.36) and histology (P = 0.0019; hazard ratio = 8.010) were significant in predicting recurrence. Histology was highly correlated with stage, but by multivariate analysis was an independent factor in predicting relapse (P = 0.0281; hazard ratio = 5.92). None of the medullary or mixed thymomas recurred, even though 30% were invasive. Patients with WDTC recurred more often and earlier than patients with organoid and cortical thymoma (log rank, P = 0.0001). The actuarial freedom from relapse for patients with WDTC was 58% at 5 years and 46% at 10 years compared with 100% for other subtypes. Both advanced stage (III and IV) and the WDTC histologic subtype significantly increased the risk of death from thymoma (log rank, P = 0.0001). The actuarial survival of patients with WDTC was 80% at 5 years and 54% at 10 years, whereas that of patients with the other subtypes was 100% at 5 and 10 years. Five of seven relapses and six of seven deaths from thymoma occurred in patients with WDTC. In Stage II patients, one of 16 minimally invasive (Stage IIA) tumors recurred, compared with 3 of 16 grossly invasive (Stage IIB) tumors, indicating that microscopic assessment of invasion is important in staging. CONCLUSIONS: The histologic classification of Marino and Müller-Hermelink has prognostic significance, independent of tumor stage. Medullary and mixed thymomas were benign tumors with no risk of recurrence, even when capsular invasion was present. Organoid and cortical thymoma showed intermediate invasiveness and a low, but significant, risk of late relapse, even with minimal invasion. WDTC were always invasive and had a significantly increased risk of relapse and death, even for Stage II patients. Adjuvant therapy appears unnecessary for medullary and mixed thymomas, even when invasive.

Thymoma--morphologic subclassification correlates with invasiveness and immunohistologic features: a study of 122 cases.

We applied the classification system of Marino and Müller-Hermelink (Virchows Arch A Pathol Anat Histopathol 407:119-149, 1985) and Kirchner and Müller-Hermelink (Prog Surg Pathol 10: 167-189, 1989) to 122 thymic epithelial tumors to evaluate the utility of this classification and to determine its correlation with invasiveness, follicular lymphoid hyperplasia, myasthenia gravis, and immunophenotype. The majority of cases could be classified according to this scheme: eight cases (7%) were medullary thymoma, 34 cases (28%) were mixed thymoma, 20 cases (16%) were predominantly cortical (organoid) thymoma, 22 cases (18%) were cortical thymoma, 32 cases (26%) were well-differentiated carcinoma (WDC), two cases (2%) were high-grade carcinoma, and four cases (3%) were unclassifiable. We report a detailed histologic analysis of these subtypes, with criteria for diagnosis. We propose that the term "organoid thymoma" be replaced by "predominantly cortical thymoma." We also observed a previously unrecognized subtype of WDC with spindle-shaped epithelial cells, which must be distinguished from medullary thymoma. There was a strong correlation between histologic subtype and invasion (P < .0001). All medullary and mixed thymomas were either completely encapsulated (64%) or had only invasion through the capsule (36%). Organoid and cortical thymomas showed an intermediate degree of invasiveness, with 36% invasive into mediastinal fat and 14% into adjacent structures. All the cases of WDC were invasive either through the capsule (19%) or into adjacent structures (81%); five cases (16%) also showed distant spread in the form of pleural seeding (four cases) or lymph node metastasis (one case). Microscopic evaluation disclosed invasion in a substantial number of cases (28.5%) thought by the surgeon to be encapsulated. The presence of follicular lymphoid hyperplasia, either within the tumor, in the residual normal thymus, or in both, was a significant predictor of myasthenia gravis (P < .0015); there was an increased association of myasthenia gravis and thymomas with cortical type epithelium (organoid thymoma, cortical thymoma, and WDC). There was no correlation between epithelial cell morphology and antigen expression; however, the immunophenotype of the associated lymphocytes corresponded closely to the morphologic classification of the thymomas. The Müller-Hermelink morphologic classification can be applied to most cases of thymoma and strongly predicts invasive behavior. The correlation of lymphocyte immunophenotype with the morphologic classification of the epithelial cells suggests that it is biologically accurate.

Bronchial carcinoid tumors in pediatric patients.

Bronchial carcinoid tumors (BCT) are the most frequent primary pulmonary neoplasms of childhood. Seventeen of 208 patients diagnosed as having BCT at the Massachusetts General Hospital were between 10 and 21 years of age. We reviewed our records of the 17 patients and 8 other pediatric cases and compared their findings with those of seven large series of adults. Distribution was equal between the sexes. The average age at diagnosis was 17 years; 4 patients were < or = 15 years old. The duration of symptoms prior to diagnosis varied from 2 weeks to 2.6 years, with a median duration of 8.5 months. In contrast to adults, no child was asymptomatic. The majority of children presented with wheezing and atelectasis in addition to the characteristic adult triad of cough, hemoptysis, and pneumonitis. Five patients presented with weight loss and one patient presented with hoarseness. One of the 17 pediatric patients presented with Cushing's syndrome and a functional BCT. Twelve of 14 patients were disease free for 9 months to 34 years after surgical resection. We conclude that BCT should be suspected in children with pneumonitis resistant to therapy, atelectasis, wheezing, and hemoptysis. Surgical resection will result in symptom-free recovery in the majority of cases in spite of low-grade malignancy.

Long-term follow-up of neoadjuvant chemotherapy with 5-fluorouracil and cisplatin with surgical resection and possible postoperative radiotherapy and/or chemotherapy in squamous cell carcinoma of the esophagus.

Seventy patients with local squamous cell carcinoma of the esophagus were treated between 1981 and 1990 with preoperative chemotherapy, surgical resection, and possible postoperative radiation therapy and/or chemotherapy. Chemotherapy included two cycles of 5-fluorouracil (1000 mg/m2) by continuous intravenous infusion on days 1-4 and cisplatin (100 mg/m2) on day 4. Complete clinical response (CCR) was achieved in 28 (41%) patients, partial clinical response (PCR) in 17 (25%), and no response in 23 (34%). Fifty-five (81%) patients were resected, 6 (9%) were explored, and 7 (10%) were unable to have surgery. Microscopic analysis of 55 resected patients showed 50 (91%) with active tumor, 1 (2%) with necrotic tumor, and 4 (7%) with a pathological complete response to chemotherapy. Twenty-six of the 55 resected patients (47%) had no gross evidence of disease at the time of surgical inspection. Median overall survival was 21.86 months (range 2-107 months) for all patients and 26.71 months (range 2-107 months) for resected patients. Actuarial 5-year survival rate was 31% for all patients and 39% for resected patients. Prolonged survival correlates with complete clinical response to chemotherapy, low pathological stage of disease, and successful resection of the lesion.

J. Maxwell Chamberlain Memorial Paper. Role of staging in prognosis and management of thymoma.

Eighty-five patients operated on for thymoma from 1972 to 1989 were evaluated, 32 with myasthenia gravis and 53 without. Masaoka staging revealed stage I disease in 45 (53%), stage II in 23 (27%), stage III in 14 (16%), and stage IVa in 3 (4%). There was no operative mortality. Actuarial survival at 10 years was 63.7% for all patients: 78.3% for those in stage I, 74.7% for those in stage II, and 20.8% for those in stage III. There was no recurrence in patients in stage I. Mediastinal recurrence developed in 4 patients in stage II considered to have noninvasive disease by the surgeon. It is recommended that all patients be followed up for a minimum of 10 years and that all patients in stages II and III receive postoperative radiotherapy. The presence of myasthenia gravis is no longer considered as an adverse factor in survival.

Three decades of treatment of esophageal squamous carcinoma at the Massachusetts General Hospital.

Seven hundred one patients with squamous cell carcinoma of the esophagus who were treated between 1950 and 1979 were retrospectively studied. The percentage of male patients decreased over the three decades (80% to 69%); the proportion of cigarette and alcohol abusers doubled. The esophageal carcinoma was located as follows: upper third, 24.7%; middle third, 52.8%, and lower third, 22.5%. There was disparity in clinical, surgical, and pathologic staging. More than two thirds of the patients thought to have stage II lesions preoperatively proved to have stage III lesions on pathologic examination; nearly one half of patients thought to have stage II disease intraoperatively were found to have pathologic stage III lesions. This "upgrading" of stage was chiefly a result of histologic recognition of nodal metastasis or extension of carcinoma into surrounding tissues. Operation was performed in 411 cases (58.6%) and resection was performed in 261 (37.2% overall). The postoperative death rate after resection fell from 30.5% in the 1950s to 10.4% in the 1970s, with respiratory complications the predominant cause of death. Analyses were based on treatment directed at the carcinoma itself: radiotherapy, 340 cases (48.5%); resection, 176 cases (25.1%); resection plus radiotherapy, 85 cases (12.1%); no definitive treatment, 100 cases (14.3%). Overall survival for the 701 patients was 13% at 2 years and 6% at 5 years (mean survival, 16.4 months); this did not differ by decade. Survival clearly differed by treatment (p = 0.001); resection plus radiotherapy provided the best survival (35% at 2 years; 20% at 5 years; mean of 32.5 months) followed by resection (18% at 2 years; 7% at 5 years; mean of 17.5 months), radiotherapy (9% at 2 years; 3% at 5 years; mean of 12.7 months), and no treatment (0% at 2 years; 0% at 5 years; mean of 2.5 months). Survival in patients who did not have resection did not differ by decade but survival in patients with resections improved in the last two decades. Patients with pathologic stage II lesions had greatly improved survival (54% at 2 years; 25% at 5 years; mean of 42.7 months) compared with patients with stage III disease (12% at 2 years; 6% at 5 years; (mean of 15.1 months) (p = 0.001).

Preoperative chemotherapy, surgical resection, and selective postoperative therapy for squamous cell carcinoma of the esophagus.

In an attempt to improve on the long-term survival rate of patients with esophageal squamous cell carcinoma, we designed a study in which treatment included preoperative chemotherapy with fluorouracil and cisplatin, surgical resection, and selective postoperative chemotherapy or radiation therapy. Between 1981 and 1986, 35 patients with potentially resectable lesions were entered into the study. After chemotherapy, 13 of 35 patients (37%) had a complete clinical response, 7 (20%) had a partial response, and 15 (43%) had no response. One patient sustained a serious toxic reaction (renal failure). Twenty-seven patients underwent surgical resection, with 1 hospital death (3.7%). Selective postoperative radiotherapy or chemotherapy was administered to 69%. The actuarial survival of all resected patients at 42 months was 54% (standard error, 10%). Multivariate analysis showed significant factors associated with 3-year survival were: (1) complete clinical response to chemotherapy; (2) absence of wall penetration in the specimen; and (3) microscopic or no disease in the specimen. We conclude that this multimodality treatment method improves the intermediate-term survival of patients with squamous cell carcinoma of the esophagus.

Transthoracic esophagectomy: a safe approach to carcinoma of the esophagus.

Transthoracic esophagogastrectomy is a safe operation. Mechanical staplers and a cervical anastomosis have been emphasized to avoid catastrophic consequences of anastomotic leaks in the chest. Transhiatal esophagectomy has been proposed to bring the anastomosis into the neck. It is meant to be a palliative procedure and consequently denies the patient the best chance for surgical cure. The emphasis should be on anastomotic technique and sound principles of surgical oncology. Since 1980, we have performed 104 esophagectomies for carcinoma of the esophagus. We used a left thoracoabdominal incision for distal tumors (64) and the Ivor Lewis technique (40) for more proximal tumors. A two-layer inverting interrupted silk suture technique was used for all anastomoses. More than 90% of the procedures were performed by resident staff. The operative mortality was 2.9% (3 patients). There were no anastomotic leaks. Five patients required between one dilation and three dilations postoperatively. A positive smoking history was present in 83 patients and substantial alcohol use, in 33. Median estimated blood loss was 500 ml, and 60% of patients required no transfusions. Major complications included pneumonia (12 patients) and reexploration for bleeding (2). Minor complications included atelectasis (71 patients), atrial fibrillation (9), ventricular arrhythmias (9), urinary tract infection (3), and wound infection (2). Squamous cancer was present in 31 patients and adenocarcinoma, in 73. Positive lymph node metastases were present in 75%. Anastomotic recurrence was documented in 6 patients. Standard techniques of esophagogastrectomy and a two-layer anastomosis will give excellent results with low mortality and acceptable morbidity.

Acute putrid abscess of the lung. By Harold Neuhof and Arthur SW Touroff. 1936.

This 51-year-old report detailed the principles of operative treatment of acute putrid abscess of the lung in the era prior to antibiotic availability. The technical aspects of the surgical approach advocated by Neuhof and Touroff were based on careful clinical and pathological review. In an era of increasing immunosuppressive therapy, both for transplantation and the treatment of malignant disease plus the emergence of new diseases such as acquired immune deficiency disease, there may be a re-emergence of lung abscess in patients too sick to undergo resection. Hence, the technique has present applicability.

Superior sulcus lung tumors. Results of combined treatment (irradiation and radical resection).

Twenty-one patients underwent combined therapy (irradiation and radical resection) for a Pancoast tumor at the Massachusetts General Hospital between 1976 and 1985. All patients underwent en bloc removal of the apical chest wall and underlying lung. In addition four patients required subclavian artery resection, and in five patients a portion of the vertebral body was resected. There were three operative deaths. Median survival was 24 months and actuarial survival rate was 55% at 3 years and 27% at 5 years. Long-term palliation of pain was achieved in 72% of the patients. Involvement of the subclavian artery, vertebral body, or rib did not preclude long-term survival. Computed tomographic scanning in these patients is often indeterminate regarding invasion of chest wall structures but is more helpful than plain films alone. When compared to recent series in which irradiation alone was used, the combined approach appears to produce better results.

Small cell carcinoma of the lung. A progress report of 15 years' experience.

To assess the results of therapeutic advances in the treatment of small cell carcinoma of the lung (SCCL) achieved during the past 15-year period at a single large institution, 508 patients treated between 1968 and 1982 were divided into two groups: 157 patients (66 in the category of limited-stage disease and 91 in the extensive-stage disease category) treated with low-dose small-volume radiotherapy (RT) (time dose fractionation [TDF] 49-66) and with cyclophosphamide alone or a COPP program during the first period of 7 years (1968-1974); 351 patients (180 in limited and 171 in extensive stage) treated with multidrug chemotherapy (CT) and high-dose large-volume RT (TDF 73-89) during the second period of 8 years (1975-1982). For patients with limited-stage cancer, 5-year actuarial survivals were 3% versus 7% for the periods 1968-1974 versus 1975-1982, respectively, P less than 0.01. For patients with extensive-stage cancer, the median survival time (MST) and 2-year actuarial survivals were 5 months and 2% versus 7 months and 4% for the periods 1968-1974 versus 1975-1982, respectively. To evaluate the outcome of a contemporary approach, i.e., CT alone, with RT reserved for locoregional failure, 180 patients with limited-stage cancer who were treated (1975-1982) were further analyzed for MST, 2- and 5-year actuarial survival figures, and local-tumor control rates according to the therapeutic approaches employed: CT + RT (112); CT alone (36); RT alone (17); and surgery (S) +/- CT +/- RT (15). Although the 36 patients in CT alone seems a small number, 17 of the 36 patients were enrolled in this approach in 1981-1982, reflecting a shift of emphasis from RT to CT. The MST and 2-year actuarial survival figures were 11 months and 0% versus 13 months and 21% for CT alone versus CT + RT respectively, P less than 0.05. CT + RT achieved a 5-year cure rate of 8%. S +/- CT +/- RT or RT alone also achieved 5-year cure rates of 8% and 10.5%, respectively, in selected subsets of patients. Local relapse rates were 80% (29/36) versus 25% (28/112) for CT alone versus CT + RT. These data emphasize the importance of thoracic RT given at the early phase of treatment to improve long-term survival for patients with limited-stage SCCL.

Radiation therapy alone or in combination with surgery in the treatment of carcinoma of the esophagus.

The role of radiation in the treatment of squamous cell carcinoma of the esophagus was examined in a review of 74 patients treated with curative intent between 1974 and 1981. Aspects studied included the pattern of failure, the use of radiation as a surgical adjuvant, achievement of palliation, and the presence of technical or clinical factors predicting for a better outcome. The group was divided into 9 patients irradiated after esophageal resection, 14 patients irradiated before resection, and 51 patients treated with radiation and no resection. Median and 2-year survival rates among 51 patients treated by radiation without esophagectomy were 8.8 months and 11%, whereas they were 9.7 months and 0% in patients treated by radiation followed by resection, and 9.5 months and 28% in patients undergoing resection followed by radiation. Local failures were suffered in 28/51 patients treated without esophagectomy with rates of 2/4, 7/10, 7/15, and 5/10 after 50-55 Gy, 55-60 Gy, 60-65 Gy, and 65-69 Gy, respectively. Although prognosis for patients presenting with unresectable disease remains poor, a somewhat better outcome may be expected in patients treated with postoperative radiation after potentially unfavorable resections. Other predictors include sex and disease stage.

Preoperative chemotherapy followed by surgery with possible postoperative radiotherapy in squamous cell carcinoma of the esophagus: evaluation of the chemotherapy component.

Twenty-four patients with squamous cell cancer of the esophagus were entered into a treatment protocol consisting of preoperative chemotherapy (CT), surgical resection (SR), and possible postoperative CT or radiation therapy (RT) beginning August 1981. CT consisted of two cycles of 5-fluorouracil, 1,000 mg/m2, by continuous intravenous infusion for 4 days and cisplatin, 100 mg/m2, on day 4 with mannitol-induced diuresis at 4-week intervals. Postoperatively, RT was administered when resection margins were minimal or if paraesophageal nodes were abnormal; the RT consisted of 5,000 to 5,400 cGy to the tumor area plus a 800- to 1,200-cGy boost to known abnormal tumor margins. Nineteen of 24 patients were resectable (79%). There was one SR death (5%). One of 22 had a normal barium swallow post-CT, no visible tumor at SR, and no pathologic evidence of any residual disease. There was complete radiologic and gross clinical disappearance of tumor post-CT or post-SR in ten of 22 patients (45%). Four of 22 (18%) had greater than or equal to 50% regression, and five of 22 (23%) had no response. Toxicity of CT was mild. Eight of 19 patients (42%) received RT, and six of 19 (32%) received CT postoperatively. Sixteen of 24 (67%) are alive with a median duration of observation of 9.5 months. Eight of 24 (33%) are dead, five of whom had not responded to preoperative CT. Ten of 14 responders are alive and disease free. The mean survival time for nonresponders was 6.70 months and for responders, 20.40 months, with the longest survivor disease free at 45 months.

Pulmonary resection for metastases from gynecologic cancers: Massachusetts General Hospital experience, 1943-1982.

Fifteen patients with pulmonary metastases from gynecologic cancers have been evaluated and treated surgically at the Massachusetts General Hospital from 1943 to 1982. These women have had primary tumors involving the cervix (6), endometrium (3), and ovary (2) as well as uterine sarcomas (2) and choriocarcinomas (2). Two-year Kaplan-Meier survival for this group was 71%; the corresponding survival at 5 years was 36%. No hospital mortality was encountered. Patients with solitary lesions of less than 4 cm diameter appeared to have the most favorable prognosis in the group. A prolonged time to initial recurrence (latent period) of greater than 36 months was associated with improved survival and there was a 60% survival among patients with latent periods of 60 months or more. An aggressive approach to resection of pulmonary metastases in selected patients provides gratifying palliation for the majority of women and long-term cure in a significant minority.

Changing times in surgical management of bronchopulmonary carcinoid tumor.

The bronchopulmonary carcinoid tumor occurs at all levels from trachea to lung periphery. It should be managed by conservatism in airway or lung resection. The long-term survival is excellent: 82% at 10 years in this series of 111 resected patients. The atypical carcinoid tumor (10% of this series) has a more ominous prognosis and requires special surgical attention. Six conceptual changes in the evolution of management of the tumor are presented (the "changing times").