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An experience with 27 patients with malignant respiratory tract fistula (RTF) is presented. The RTF was related to carcinoma of the thoracic esophagus in all the patients, involved the trachea in 11, left main bronchus in 7, right main bronchus in 3, and was more distal in 6 patients. Metastases were detectable in only four patients (15%) at the time of RTF diagnosis. Bronchoscopy examination in 13 patients prior to RTF development showed tracheobronchial invasion or impingement in all. The RTF was present at initial presentation in 11 patients (Group I), and developed after/during radiation therapy (RT) in 16 patients (Group II). Median survival from tumor diagnosis was 17 weeks in Group I and 37 weeks in Group II, while survival from RTF diagnosis was 16 weeks in Group I and 11 weeks in Group II. Cancer 53:1322-1328, 1984.

Forty-one patients with two subtypes of stage IIIM0 non-small-cell lung cancer treated over a 7-year period were evaluated. The first group of 20 patients had ipsilateral parietal pleural involvement not contiguous with the primary tumor but no distant metastases. Fifteen had positive pleural fluid cytology, seven with positive pleural biopsy in addition; four had extensive pleural studding or a positive biopsy but no effusion; and one had negative pleural fluid cytology. Treatment consisted of radiation therapy followed by combination chemotherapy in all. Due to symptoms, eight patients first had fluid drainage with or without sclerosis and two patients had a pleurectomy. Nine had progressive pleural disease despite the local treatment. To all modalities of therapy, only two patients had a partial response. One patient who had a pleurectomy lived 25 months. Median survival was 6.9 months. Cause of failure involved local progression in 17 patients. There was no difference in median survival by age, sex, histology, side of effusion, location of nodal disease, or use of local therapy. The second group of 21 patients had localized involvement of the parietal pleura by the primary tumor. There was deeper chest wall invasion in nine. All patients were rendered free of known disease by surgical resection, were stage T3N0-2M0, and received radiation and chemotherapy in addition to resection. The median survival was 13.5 months. There was local recurrence in nine patients but only one developed an effusion. Five patients were alive at 29-82 months. No variable unfavorably influenced survival except a central versus peripheral primary. Thus, the median survival of the patients in the first group with multiple sites of pleural involvement was similar to that of patients with distant metastases but with the cause of failure primarily local progression. In the majority of patients in the second group, parietal pleural and chest wall involvement, even with nodal metastases, did not translate into local failure, and long-term survival was possible.

A review of atypical mycobacterial infections complicating cardiac operations is presented. Proven sources of infections at different institutions include contaminated porcine valves and municipal water supply, but the mode of transmission in the great majority of patients remains unclear. There are two principal clinical forms of atypical mycobacterial infections after cardiac operations—endocarditis and sternal osteomyelitis. The latter has characteristics resembling tuberculotic "cold abscess." Specialized laboratory testing is necessary to confirm the diagnosis, and surgeons may have to take the initiative to request special microbiological investigation in cases where infection is clinically suspected but routine cultures are reported as "negative." The prognosis for patients who have any atypical mycobacterial infection after a heart operation is severe. Those infected with the strain chelonei and those whose cardiac chambers were entered during operation fare worse. This dim clinical prognosis may be improved by appropriate and aggressive antibiotic and surgical therapy. Awareness of the urgency of special bacteriological studies is the key to successful management.

We treated 27 patients with regionally advanced non-small-cell lung cancer (NSCLC) with two cycles of neoadjuvant chemotherapy with etoposide, vindesine, and cisplatin. Twenty-three patients were evaluable for response; 13 had a partial response while ten patients had stable disease or disease progression. Subsequent local therapy consisted of surgery followed by radiotherapy in four patients and of radiotherapy alone in 14 patients. Five patients did not receive local therapy. At completion of local therapy, seven patients were considered free of disease including all four who had undergone surgery. Median time to disease progression for the 13 patients who had a partial response to neoadjuvant chemotherapy was eight months (three to 51+ months). The median survival for all patients registered on study was eight months (three days to 53+ months). Chemotherapy induced toxicities included moderate myelosuppression, nausea and vomiting in all patients, and occasional ototoxicity, neurotoxicity, and wasting syndrome. One patient died of intracerebral hemorrhage due to thrombocytopenia. This trial shows that administration of neoadjuvant chemotherapy to patients with locoregionally advanced NSCLC is feasible and may yield an increased response rate compared to patients with stage IV disease. While no clearly beneficial effect of the use of chemotherapy on patient survival is apparent in this study, further studies utilizing neoadjuvant chemotherapy in patients with NSCLC are warranted and should attempt to identify more active combinations of drugs. (Chest 1989; 96:110-13)

To determine the regional accuracy of computed tomography of the mediastinum in staging lung cancer, we compared the results of preoperative computed tomographic staging to pathologic findings in lymph nodes taken at mediastinoscopy and/or thoracotomy in 61 patients. Twenty-two patients had adenocarcinoma, 24 had squamous cell carcinoma, eight had large cell tumors, and seven had small cell cancer or mixed cellular types. Sixteen patients had Stage I, eight had Stage II, and 37 had Stage III disease. Thirteen patients had mediastinoscopy only, and the remaining 48 patients had thoracotomy. Computed tomographic staging of the mediastinum as a whole had an accuracy of 88% with a negative predictive index of 96.1%. In examining the differential regional accuracy within the mediastinum we found results in the aortopulmonary window to be inferior to those of other regions, with an accuracy of 80% and a negative predictive index of 83.3%. The reliability of computed tomographic scan staging varied relative to cell type. The accuracy rate in adenocarcinoma was 94.7% compared to 70.6% in squamous cell carcinoma. Computed tomography is accurate for staging the mediastinum in lung cancer, and this accuracy holds over the regions of the mediastinum except the aortopulmonary window. Computed tomography is more accurate for staging adenocarcinoma than squamous cell cancer.

Idiopathic thrombocytopenic purpura (ITP) frequently occurs in young women, and is therefore encountered in pregnancy. Any woman with a history of ITP, regardless of her clinical status, has some risk of delivering a thrombocytopenic infant, since the antiplatelet antibodies cross the placenta. Methods for predicting which infants are at high risk, for choosing which pregnancies should be delivered by cesarian section, and for managing the mother and infant at term are reviewed.

To assess the efficacy of performing both computed tomography (CT) of the thorax and upper abdomen and whole-body gallium scintigraphy for staging lung cancer, the results of each test were compared with those obtained by chest radiography and clinical examination in 100 patients. Clinical efficacy was defined in terms of accuracy in staging the tumor based either on surgery, biopsy, or clinical and radiologic follow-up. The CT provided significantly superior accuracy in 27 patients and minor additional staging information in 17 patients compared with the gallium scan. Whole-body gallium scintigraphy provided important additional information in nine patients and minor additional information in a further eight. The diagnostic yield of CT and gallium scanning was considered equivalent in 39 cases. Of the nine cases in which gallium was significantly superior to CT, clinical findings which suggested the presence of metastases had been noted before the scan in four cases. The authors' results confirm the utility of CT for staging lung cancer and indicate that the additional yield from gallium scintigraphy is relatively low provided a thorough history and physical examination have been performed.

Prognostic factors were examined in 38 patients with nonsmall cell lung carcinoma and brain metastases. The most important factors were the response to total therapy (corticosteroids, radiotherapy, and chemotherapy) and the presence of brain metastases alone; these factors had the most impact on survival. Age, sex, histologic type of lung cancer, and initial performance status were not prognostically important. Our results indicate that certain subgroups of patients with nonsmall cell lung carcinoma and brain metastases have a favorable prognosis and should be treated aggressively.

In the past five years, we have treated 89 patients with small-cell carcinoma of the lung with radiotherapy plus one of three chemotherapy programs. The 24 patients with disease confined to the chest (Stage IIIMO) had an 87% response rate to the combined modalities (79% complete responses) and a median survival of 18 months; 13 patients with disease confined to the chest and ipsilateral supraclavicular nodes (Stage IIIMOSCN +) had an 84% response rate (69% complete responses) and 11-month median survival; the 52 patients with distant metastases (Stage IIIMI) had a 71% response rate (15% complete responses) and eight-month median survival. Survival was not affected by adding prophylactic cranial irradiation to the latest regimen, although the CNS relapse rate was reduced. We conclude that our three chemotherapy programs to date differ very little in their effect on survival of patients with metastatic disease. New and more vigorous approaches, possibly including surgery, need to be tested for the management of disease confined to the chest. The designation of patients as Stage IIIMOSCN + is valid because such patients have better survival rates than patients with distant metastatic disease.

Twenty patients with postsurgical, modified Stage II (T2 N1 M0, T1 N1 M0) non-small cell bronchogenic carcinoma were seen between 1974 and 1981 and were evaluated in a retrospective manner. Fifteen patients had T2 N1 M0 lesions, while 5 patients had T1 N1 M0 disease. Eight patients were treated with surgical resection alone, of whom seven had died, with a median survival of 12.0 months. Four patients received surgical resection and postoperative radiation therapy, of whom two have died, with a median survival not reached at 37 months. Eight patients were treated with surgical resection, radiation therapy, and adjuvant chemotherapy including cyclophosphamide (C), doxorubicin (A), methotrexate (M), and procarbazine (P). Six patients are alive and free of disease, with a median survival not yet reached at 72 months. There is a significant survival advantage for the 12 patients treated with combined modality therapy (surgical resection + radiation therapy; surgical resection + radiation therapy + chemotherapy) compared to the eight patients treated with SR alone (p less than 0.01), and for the eight patients receiving chemotherapy versus the 12 patients who did not (p less than 0.01). In spite of thorough clinical and surgical staging, patients with T1 and T2 primary tumors with N1 disease have a high relapse rate, predominantly in metastatic sites. Adjuvant radiation therapy and chemotherapy appear to benefit these patients with modified Stage II non-small cell bronchogenic carcinoma.

The records were reviewed of 111 consecutive patients who had lung cancer resected and who were followed with serial postoperative whole-body gallium scans. Scans were obtained preoperatively at intervals of 3-6 months for about 1 year after surgery and subsequently at yearly intervals. The period of follow-up varied from 1 1/2 to 8 years. Of 55 patients who developed tumor recurrence, a gallium scan was the first indicator of recurrence in 11 (20%) and was judged helpful in confirming or localizing a recurrence in another 14 patients (25%). False-positive rates were determined from 175 postoperative scans in the other 56 patients who did not suffer recurrence. Of these 175 scans, 15 (9%) demonstrated abnormalities that were sufficiently suspicious that an additional diagnostic procedure, other than chest radiography, was performed for clarification. However, in no case did the gallium scan result adversely affect the management of the patient. Our data demonstrate that routine postoperative whole-body gallium scanning can facilitate early detection of recurrence in some cases. Judicious use of gallium scanning in cases with clinically suspected recurrence can enable prompt localization, diagnosis, and treatment of recurrent tumor.

Thirty-four consecutive patients with non-small cell lung cancer plus N1 nodal metastases (eight with T1 N1 M0 and 26 with T2 N1 M0) were retrospectively reviewed. Nineteen had adenocarcinoma, 11 had squamous disease, and four had large cell carcinoma. Eleven patients had surgical resection alone (32.3%), with a median survival of 13 months. Seven patients (20.6%) had resection followed by radiation therapy, with a median survival of 19.2 months. Sixteen patients (47.1%) had resection followed by radiation therapy and chemotherapy, consisting of cyclophosphamide, doxorubicin, methotrexate, and procarbazine. Median survival for the latter group was 45.5 months, significantly greater than for those treated with resection alone (p less than 0.005). We did not observe any relationship between survival and age, cell type, number or location of diseased hilar nodes, distance of tumor from the resected bronchial margin, tumor size, the presence or absence of visceral pleural involvement, or the type of resection performed. Resection in combination with adjuvant radiation therapy and chemotherapy offers improved median survival over resection alone in patients with T1 N1 M0 and T2 N1 M0 non-small cell lung cancer.

Oxygenated sterol compounds are potent inhibitors of sterol and DNA synthesis in mammalian cells. We studied the effects of oxygenated sterols on human marrow granulocytic progenitor cells in vitro (CFU-C). 25-Hydroxycholesterol was found to be a potent inhibitor of sterol synthesis in marrow mononuclear cells, with 50% inhibition occurring at approximately 10(-7) M. This compound, as well as 6-ketocholestanol, 7- ketocholesterol, and 20 alpha-hydroxycholesterol, also demonstrated marked inhibition of CFU-C proliferation. The latter effect, which was not a result of direct cytoxicity of the compounds, was reversible by cholesterol, but not by mevalonic acid. We conclude that inhibition of sterol synthesis by oxygenated sterol compounds may be insufficient to explain their suppression of CFU-C proliferation.

ML-236B is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the key regulatory enzyme in the sequence that catalyzes the conversion of acetate to mevalonic acid in cholesterol biosynthesis. This compound caused marked inhibition of human bone marrow granulocyte progenitor cell (CFU-C) proliferation, the 50% inhibitory concentration (IHD50) being 2.0 X 10(6)M. Inhibition of colony formation was reversed by mevalonic acid but not by cholesterol. ML-236B also inhibited DNA synthesis and acetate incorporation into cholesterol in marrow mononuclear cells (IHD50 = 5.6 x 10(6)M and 3.2 x 10(7)M, respectively). No inhibition of mevalonate incorporation into cholesterol was observed. These results differ from those observed with 25-hydroxycholesterol, another inhibitor of HMG CoA reductase. The latter compound also inhibited CFU-C proliferation and cholesterol biosynthesis from acetate; inhibition of colony formation was reversed by cholesterol but not by mevalonic acid. In addition, 25- hydroxycholesterol inhibited cholesterol synthesis from mevalonic acid precursor. We conclude that: (1) ML-236B is a potent inhibitor of CFU-C proliferation, DNA synthesis, and cholesterol biosynthesis from acetate precursor in marrow mononuclear cells; (2) the effects of ML-236B are completely reversed by mevalonic acid but not by cholesterol, suggesting that mevalonic acid per se or one or more of its nonsterol products are critical for cell growth; (3) the inhibitory effects of 25- hydroxycholesterol on CFU-C proliferation and cholesterol biosynthesis are not solely a result of its inhibition of HMG CoA reductase, but are due in part to inhibition of enzymatic steps distal to mevalonic acid in the sterol synthetic pathway; and (4) mevalonic acid and cholesterol are independent requirements for CFU-C proliferation and differentiation in vitro.

Combination chemotherapy is frequently used in the therapy of advanced non-small-cell lung cancer (NSCLC), but late complications are rarely recognized because of the short survival of most patients. Of 119 patients with advanced NSCLC treated with cisplatin and other drugs, four patients developed acute nonlymphocytic leukemia (ANLL). All four patients received etoposide and cisplatin with or without vindesine. Leukemia was diagnosed at 13, 19, 28, and 35 months after start of treatment. Three patients had morphologic and/or cytogenetic features of acute leukemia with significant monoblastic involvement; the fourth patient had trilineage dysplasia and cytogenetic abnormalities more commonly associated with therapy-related leukemia. Detailed analysis of the subgroup who survived longer than 1 year (24 patients) suggests that high cumulative doses of etoposide are leukemogenic; the median etoposide dose was 6,795 mg/m2 (first year only) in the four leukemic patients compared with 3,025 mg/m2 in the 20 nonleukemic patients (P less than .01). The rate of ANLL was 0.30 per person-year after the first year (95% confidence limits 0.11 to 0.90), with a cumulative risk of 15% +/- 11% at 2 years, and 44% +/- 24% at 2.5 years. We conclude that high doses of etoposide are potentially leukemogenic, and can induce a syndrome with features of acute monoblastic leukemia de novo that is distinct from other secondary leukemias.

Fifteen patients with Stage IV lung cancer both untreated and previously treated were enrolled into a high-dose chemotherapy program with multiple alkylating agents and autologous bone marrow reinfusion. Eight patients received cyclophosphamide at 7.5 gm/m2 over 3 days with thiotepa escalated from levels of 1.8 mg/kg to 6.0 mg/kg over 3 days. Seven patients received the above dose of cyclophosphamide plus thiotepa at 675 mg/m2 and oral melphalan escalated from levels of 0.75 mg/kg to 2.5 mg/kg over 3 days. Both regimens are part of larger Phase I-II clinical studies. The median time to recovery of more than 500 granulocytes and more than 50,000 platelets per microliter was 16 and 27 days, respectively. Two patients died as a consequence of severe, overwhelming infections during their period of aplasia. Of the 13 evaluable patients, no patients achieved a complete response and seven patients (47%) obtained a partial response. The median duration of response was 12 weeks. Other nonhematologic toxicities included nausea/vomiting, diarrhea, mucositis, skin rash, hemorrhagic cystitis, and cardiomyopathy. Since there are substantial toxicities associated with high-dose chemotherapy and responses of such brief duration, further investigation with these drug combinations is not warranted.

During the past 10 years, 240 patients with Stage III small cell lung carcinoma (SCLC) were treated with one of five chemotherapy programs plus thoracic irradiation. In addition, prophylactic cranial irradiation was administered concurrently with thoracic irradiation to 194 patients receiving CAML-HC, VCAM, or MOCA. Seventy-two patients had disease confined to the chest (Stage IIIM0), 30 patients had disease in the chest plus ipsilateral supraclavicular nodal involvement (Stage IIIM0SCN+), and 138 patients had distant metastatic disease (Stage IIIM1); the median survivals were 15.2 months, 12.6 months, and 8.4 months, respectively. The overall complete response rate was 30% and the overall response rate (complete and partial) was 76%. The overall response rates by stage were 86% for Stage IIIM0, 90% for Stage IIIM0SCN+, and 67% for Stage IIIM1. Eight patients (3%) were alive and free of disease at 24 months. Due to continued disease relapse in this group (four of eight patients), long-term survivors should not be identified for a minimum of 3.5 years from the time of initial therapy. Prophylactic cranial irradiation (PCI) effectively reduced the incidence of central nervous system (CNS) relapse in patients with a complete response to therapy (44% relapse without PCI versus 13% relapse with PCI, P less than 0.01). More effective chemotherapy is required for the successful treatment and improved long-term survival of patients with SCLC.

Traditional therapy for malignant pleural effusions includes thoracentesis or tube drainage with instillation of irritants to achieve pleurodesis. This can require a lengthy hospitalization, causes pain and discomfort, and has an appreciable failure rate. Because of these drawbacks, the authors used a shunting device to transfer fluid to the peritoneal cavity in 17 patients with malignant pleural effusions. Eleven patients had undergone previous therapeutic thoracenteses and three had chest tube placement with failed sclerosis. The shunt was a subcutaneous valved pump chamber with attached pleural and peritoneal catheters, which used manual compression to transfer fluid against the normal abdominal/pleural pressure gradient. Operative placement under local or general anesthesia was performed without complication. Five patients achieved minimal benefit, either because of moribund status (2) or their inability to compress the pump effectively (3). In the other 12 patients, there was radiographic evidence of diminished or stabilized pleural effusion; respiratory symptoms were effectively palliated, and no further treatment for their effusion was required. Peritoneal dissemination of malignant cells has not been clinically detected. We feel that pleuroperitoneal shunting is a valid new method for treatment of malignant pleural effusions which can effectively palliate respiratory symptoms with low morbidity. Advantages include the absence of external tubing and the possibility for only a short hospitalization or even outpatient placement. Shunting is applicable for patients who are able to perform the requisite pumping and is particularly suitable for those with trapped lungs or who have failed attempted pleural sclerosis. Cancer 58:2740-2743, 1986. RADITIONAL THERAPY for malignant pleural effuT sions consists of thoracentesis or intercostal tube drainage with subsequent instillation of pleural irritants to achieve pleurodesis. These processes can require a lengthy hospitalization, cause pain and discomfort for the patient and have an appreciable complication and failure rate.' Because of these drawbacks we have used a shunting device to transfer pleural fluid to the peritoneal cavity in patients with symptomatic malignant pleural effusions to determine the risks of placement, to evaluate associated morbidity, and to assess efficacy of palliation of respiratory symptoms.

Light microscopic biopsy specimens from 48 patients were reviewed by two independent pathologists and classified as large cell carcinoma of the lung by 1981 World Health Organization (WHO) criteria. Sites of primary disease were hilar/mediastinal in 26 patients, large mid-lung field in 17, and peripheral lung in 5. All material was examined by electron microscopy (EM) for evidence of squamous (“squamous”: 15 patients), glandular (“adenacarcinoma”: 17 patients), or nonspecific (“large cell”: 14 patients) ultrastructural differentiation. Two patients had mixed adenosquamous features. There were 6 patients with Stage I tumors; 5, Stage II; 24, Stage IIIMO; and 13, Stage IIIMl. Of the 14 patients with large cell by EM, 11 had unresectable Stage IIIMO or metastatic disease. Only 3 of 27 patients not undergoing resection responded to combined modality therapy. There were two long-term survivors free of disease in the resected Stage IIIMO patient category. Overall median survival by stage was analyzed, with no statistically significant difference between seveTal of the stage groupings, suggesting a worse prognosis for the entire group overall compared to all patients with non-small cell lung cancer. The median survival by EM subgroup was also without significant difference, both overall and within various stage groupings, despite more patients in the large cell categbry with advanced disease. These data support the unique behavior of patients with large cell carcinoma on light microscopy, but fail to demonstrate that ultrastructural differentiation is of prognostic importance for response or survival. Cancer 56: 1618- 1623. 1985. ARGE CELL undifferentiated carcinoma is one of the L four common primary carcinomas of the lung, as defined by histologic criteria, accounting for from 9% to 20% of all cases of non-small cell bronchogenic carcinoma (NSCBC).IW3 Classically, large cell tumors are bulky, peripheral, subpleural lesions with limited-stage disease on presentation and late di~semination.~.’ Although large cell tumors are apparently monomorphous at the light microscopy (LM) level, ultrastructural examination by electron microscopy (EM) has revealed three different types of morphologic differentiation: adenocarcinoma (AD), squamous cell carcinoma (SQ), and large cell undifferentiated carcinoma ( LG).6-9 Such histologic subtyping may possibly be useful for the prediction of tumor behavior and responsiveness to therapy as well as patient From the Departments of *Medicine, ?Pathology, and #Surgery, The

Seventy-eight patients with modified Stage II or Stage IIIM0 adenocarcinoma of the lung were evaluated retrospectively with regard to the impact of prophylactic cranial irradiation (PCI) (30 Gy in 15 fractions) in preventing central nervous system (CNS) metastases. Twenty patients received PCI and 58 did not. There were no significant differences between these groups with respect to age, sex, stage, or median survival (17.4 months with PCI versus 16.9 months without PCI; P = 0.6). One (5%) of 20 patients receiving PCI developed CNS metastases, compared with 14 (24%) of 58 patients not receiving PCI (P = 0.06). The time from diagnosis to development of CNS metastases and survival after CNS involvement was 51 weeks and 14 weeks, respectively, for the patient who received PCI; and a median time of 50 weeks and 26 weeks, respectively, for the patients not receiving PCI. In nine (64%) of the 14 non-PCI patients the CNS was the first and only site of relapse. A Cox regression analysis demonstrated that nodal involvement was significantly associated with an increased risk of CNS metastases. These data suggest that PCI may decrease the incidence of CNS metastases, and that it may be beneficial in the management of patients with N1 or N2 disease.

Between January 1975 and December 1981, 160 patients with metastatic non-oat cell bronchogenic carcinoma (MNOBC) were treated with cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP), or with a CAMP-like regimen. Forty-two (26%) of these patients demonstrated an objective response to the chemotherapy with a median survival of 61 weeks. Thirty-nine (24%) patients had stable disease (SD) with a median survival of 45 weeks. Seventy-nine patients (49.4%) were nonresponders with a median survival of 15 weeks. There was a significant difference in survival times between the responders and the SD patients, and between the responders and SD patients and the nonresponders. Responses were seen in 11% of the patients with squamous cell carcinoma and in 37% of the patients with adenocarcinoma. There was a significant difference in the response and SD categories in favor of adenocarcinoma over squamous cell carcinoma. Once a response was achieved, the median survival of the patients with adenocarcinoma was not significantly longer than that of the patients with squamous cell carcinoma.

Adenosquamous carcinoma of the lung is a rare and poorly described entity. At the University of Chicago between 1974 and 1985, 2.3% (20/873) of patients with lung cancer had well-differentiated adenosquamous carcinoma. As in non-small cell lung cancer, patients with Stage I disease were amenable to operation with 60% (3/5) free from disease between one and six years postoperatively. However, Stage II adenosquamous carcinoma (14 patients) exhibited highly aggressive behavior with rapid progression of disease (mean interval, 2.1 months). Despite combinations of surgery (6 patients), chemotherapy (6 patients, one response), and radiotherapy (10 patients, no response), median survival for patients with Stage III adenosquamous carcinoma was 5.0 months, worse than that for Stage III small cell cancer (9.6 months), adenocarcinoma (9.0 months), and squamous cancer (7.8 months).

IntroductionWe investigated dose-dense docetaxel and cisplatin in patients with measurable non-small cell lung cancer in a randomized phase II study without [A] or with [B] a putative chemoprotective agent, BNP7787.Patients and MethodsChemotherapy-naive patients with stage IIIB (effusion) or IV, performance status 0 to 1, and adequate organ function were eligible. Treatment with docetaxel 75 mg/m2 followed by cisplatin 75 mg/m2 over 1 hour day 1 with darbepoetin 200 μg day 1 and pegfilgrastim 6 mg day 2 without/with BNP7787 before cisplatin was repeated every other week for up to 6 cycles. The primary end point was to differentiate between grade ≥2 neurotoxicity rates of 30% on [A] and 10% on [B]. Feasibility was prospectively defined as febrile neutropenia in

Introduction This Phase I trial aimed to determine the maximum-tolerated-dose of erlotinib administered with two standard chemoradiotherapy regimens for non-small cell lung cancer. Methods Unresectable stage III non-small cell lung cancer patients were enrolled in this 2-arm dose-escalation study. Erlotinib, given only during chemoradiotherapy, was escalated from 50 to 150 mg/d in 3 to 6 patient cohorts. Arm A: erlotinib with cisplatin (50 mg/m 2 IV days 1, 8, 29, 36), etoposide (50 mg/m 2 IV days 1-5, 29-33) and chest radiotherapy (66 Gy, 2 Gy/d) followed by docetaxel (75 mg/m 2 IV Q21 d) for 3 cycles. Arm B: induction carboplatin (AUC 6) and paclitaxel (200 mg/m 2 ) for two 21-d cycles then radiotherapy with erlotinib, carboplatin (AUC = 2/wk) and paclitaxel (50 mg/m 2 /wk). Results Seventeen patients were treated in each arm. Patient characteristics: performance status 0 to 24 patients, 1 to 10 patients, median age 63 years, adenocarcinoma 21% and female 14 patients. Dose-escalation of erlotinib to 150 mg/d was possible on both chemoradiotherapy regimens. Grade 3/4 leukopenia and neutropenia were predominant toxicities in both arms. Grade 3 chemoradiotherapy toxicities in arm A were esophagitis (3 patients), vomiting (1), ototoxicity (1), diarrhea (2), dehydration (3), pneumonitis (1); and arm B was esophagitis (6). Seven patients (21%) developed rash (all grade 1/2). Median survival times for patients on Arm A and B were 10.2 and 13.7 months, respectively. Three-year overall survival in patients with and without rash were 53% and 10%, respectively (log-rank P = 0.0807). Epidermal growth factor receptor IHC or FISH positive patients showed no significant overall survival difference. Conclusion Addition of standard-dose erlotinib to chemoradiotherapy is feasible without evident increase in toxicities. However, the survival data are disappointing in this unselected patient population and does not support further investigation of this approach.

Introduction Eribulin mesylate (E7389) is an analog of halichondrin B with a unique mechanism of microtubule binding. The activity and toxicity of eribulin were assessed in patients with advanced non-small cell lung cancer (NSCLC) previously treated with a taxane. Methods An open-label phase II study included patients with NSCLC previously treated with platinum and taxane-based therapy, with up to two prior cytotoxic regimens, given for metastatic disease or as adjuvant therapy. Patients were stratified by taxane-sensitivity: taxane-sensitive (TS, progression >90 days after taxane) or taxane-resistant (TR, progression ⩽90 days after taxane). Patients received an intravenous infusion of eribulin at 1.4 mg/m 2 on days 1 and 8 every 21 days. The primary end point was objective response rate and secondary end points included progression-free survival and overall survival. Results Sixty-six patients were accrued. The objective response rate was 5% with a median duration of response of 7.8 months. In the TS arm, 3 of 45 patients (7%) achieved a partial response and another 11 of 45 (24%) achieved stable disease for at least 3 months, whereas in the TR arm, no patients achieved a partial response and 4 of 21 (19%) achieved stable disease for at least 3 months. Median progression-free survival was 2.9 months in the TS subgroup and 1.2 months in the TR subgroup. The median overall survival was 12.6 months in the TS subgroup and 8.9 months in the TR subgroup. Toxicities were primarily hematologic; only two patients developed grade 3 neuropathy. Conclusions Eribulin mesylate is well tolerated and demonstrates activity in pretreated, TS NSCLC.

Background This study was performed to evaluate the tolerability and efficacy of temozolomide and irinotecan as a second-line regimen in recurrent/metastatic non–small cell lung cancer (NSCLC). Methods Patients with recurrent/metastatic NSCLC, including those with treated brain metastases, following one prior platinum-based regimen received temozolomide 75 mg/m2 daily on days 1 through 15 and irinotecan 100 mg/m2 on days 8 and 15 every 21 days. Results The authors treated 46 patients, of whom more that 90% had a performance status of 0 or 1. Four patients (8.7%) attained partial response and 17 (37.0%) had disease stabilization as their best response. The median time to progression was 1.8 months, median overall survival was 9.8 months, and 1-year overall survival was 34%. Grade 1/2 fatigue (63%), anemia (61%), nausea (52%), and diarrhea (44%) were the most common toxicities. Grade 3/4 leukopenia and diarrhea were each observed in 9% of patients. One unexpected death occurred, possibly related to the regimen. Conclusion Second-line treatment with temozolomide and irinotecan showed tolerable toxicities. The response rates, median survival times, and 1-year survival rates were comparable to other active NSCLC agents.

Enterobacter aerogenes bacteremia associated with the infusion of contaminated admixed intravenous (IV) fluid occurred in seven patients in a pediatric hospital over a five-day period. Clinical illness was characterized by spiking fever in all patients. The temporal clustering of cases allowed for rapid recognition of the problem. The primary control measure was the prompt replacement of the IV fluids, although IV antibiotics were also administered. Hospital pharmacy practices for admixing IV solutions should follow published recommendations to minimize this source of potential contamination of fluids.

Two outbreaks of postoperative wound infections due to organisms of the Mycobacterium fortuitum complex (Mycobacterium chelonei and M. fortuitum) occurred among patients who underwent open-heart surgery. In one hospital, 19 of 80 patients who underwent cardiac surgery within a 10-week period developed sternal infection with M. chelonei. In the second hospital, four of nine patients who underwent cardiac surgery within a two-week period developed sternal incisional infection with M. fortuitum. Although epidemiologic investigations uncovered factors that were significantly associated with the development of infection, the source of the infections could not be determined. The results of numerous cultures were negative, but because the investigations were conducted at least two months after many of the patients had had surgery, the materials in use at the time of the surgery were not available for culture. These results emphasize that physicians should be aware that rapidly growing mycobacteria may produce postoperative wound infections.

Gallium-67 scanning was evaluated in 100 patients with proved carcinoma of the lung. It was valuable in separating primary from secondary lung tumors, determining the extent of contralateral hilar or mediastinal lymph node involvement, and detecting distant organ metastases. In addition to multiplane whole-body Ga-67 tomographic scanning, colloid liver scans, bone scans, and computerized axial tomography scans of the brain were obtained to determine the presence of distant metastasis. The gallium scan detected 11 of 12 occult metastases and identified 7 of 7 liver, 9 of 14 brain, 4 of 4 soft tissues, 1 of 4 contralateral lung, and 9 of 11 bone metastases. The whole-body gallium scan accurately detected or excluded extrathoracic metastatic disease in 11 of 12 patients examined postmortem within three months of a gallium scan. An approach is recommended using gallium scanning along with chest roentgenograms for clinical staging and preoperative evaluation of patients with carcinoma of the lung. Specific organ scans should be reserved for the occasional symptomatic patient with a negative gallium scan or for clarification of an indeterminate gallium scan.

Clinical evaluation by noninvasive methods is an important approach, if not the most critical initial step, toward the assessment of response to any therapy under study. The methods employed should be simple, reliable, reproducible, safe, and cost-effective; they should assure a reliable first assessment of the quality of response obtained prior to proceeding to more invasive, more accurate, but more uncomfortable and riskier tests.

Nosocomial transmission of influenza has been reported infrequently; however, patients in general hospitals are often among the most susceptible to the complications of influenza infection. Hospital-acquired influenza may occur more often than is reported, but it may be recognized because of lack of diagnostic facilities or the time required for virus isolation and identification. Based on the mode of transmission in the hospital, the established reservoirs of influenza virus, and duration of virus shedding, isolating patients with influenza may occasionally be useful but restricting visitors is probably not required. Vaccinating hospital personnel with influenza vaccine and, if influenza A is prevalent, giving amantadine hydrochloride to high-risk patients or personnel should both be considered.

Dissociated, 14-day-old embryonic cells of the rostral mesencephalic tegmentum (RMT), including the dopamine neurons of this region, were allowed to reaggregate and develop in rotatory culture for 7 days in the presence of dissociated embryonic cells from the target areas of the dopaminergic neurons, corpus striatum (CS) or frontal cortex (FCx). Alternatively, RMT cells were allowed to reaggregate by themselves or in the presence of dissociated cells from a telencephalic area, occipital cortex (OCx), or mesencephalic area, tectum (T), which are not target areas for the dopamine neurons. Histofluorescence analysis revealed the number of dopamine neurons contained within reaggregates of any given type. Approximately 4 times as many dopamine neurons were found in RMT-CS coaggregates and 1.5 times as many in RMT-FCx coaggregates than in aggregates constituted from cells of the RMT either alone, or in coaggregates from RMT-OCx or RMT-T. Since axonal process formation and maintenance can only be observed in RMT-CS and RMT-FCx coaggregates, the enhanced dopamine neuron survival is probably due to an interaction of dopaminergic axonal processes with target cells within the reaggregates.

Thirty-four previously untreated patients with histologically proven small cell carcinoma of the lung were treated with a combined modality therapy program that incorporated VP16-213, an epipodophyllotoxin derivative, into the chemotherapy regimen. Initial therapy for two cycles was with V-CAM, VP16-213, cyclophosphamide, doxorubicin and methotrexate. Following two cycles of V-CAM each patient received radiation therapy consisting of 4000 rads to the primary site, both hila and the mediastinum, as well as 2000 rads as prophylaxis to the whole brain. After a one-week rest period the patients received monthly cycles of V-CAM until death. Of 10 patients with stage III M0 disease, 7 had a complete response (CR), 1 a partial response (PR) and 2 had progressive disease. The median survival was still not reached by approximately 18 months. Of 24 patients with supraclavicular and/or metastatic disease there were only 5 patients with a CR, 11 with a PR and 8 with progressive disease. Their median survival was approximately 9 months. The 70% overall response rate and 9.3-month median survival of the entire group are essentially the same results as those in previously reported studies. There appears to be no additional benefit when VP 16-213 is incorporated into our combined modality program.

Background Candidate predictive biomarkers for epidermal growth factor receptor inhibitors (EGFRi), skin rash and serum proteomic assays, require further qualification to improve EGFRi therapy in non-small cell lung cancer (NSCLC). In a phase II trial that was closed to accrual because of changes in clinical practice we examined the relationships among candidate biomarkers, quantitative changes in tumor size, progression-free and overall survival. Methods 55 patients with progressive NSCLC after platinum therapy were randomized to receive (Arm A) cetuximab, followed by pemetrexed at progression, or (Arm B) concurrent cetuximab and pemetrexed. All received cetuximab monotherapy for the first 14 days. Pre-treatment serum and weekly rash assessments by standard and EGFRi-induced rash (EIR) scales were collected. Results 43 patients (20-Arm A, 23-Arm B) completed the 14-day run-in. Median survival was 9.1 months. Arm B had better median overall (Arm B = 10.3 [95% CI 7.5, 16.8]; Arm A = 3.5 [2.8, 11.7] months P = 0.046) and progression-free survival (Arm B = 2.3 [1.6, 3.1]; Arm A = 1.6 [0.9, 1.9] months P = 0.11). The EIR scale distributed ratings among 6 rather than 3 categories but ordinal scale rash severity did not predict outcomes. The serum proteomic classifier and absence of rash after 21 days of cetuximab did. Conclusions Absence of rash after 21 days of cetuximab therapy and the serum proteomic classifier, but not ordinal rash severity, were associated with NSCLC outcomes. Although in a small study, these observations were consistent with results from larger retrospective analyses. Trial registration Clinicaltrials.gov Identifier NCT00203931

7061 Background: Erlotinib (Tarceva) is a potent HER1/EGFR tyrosine kinase inhibitor (TKI). Monotherapy trials of EGFR-TKIs have suggested never smokers and pts with bronchioloalveolar cell carcinoma (Shah, Proc ASCO 2003 #2524; Miller, Proc ASCO 2003 #2491) are more likely to benefit from these agents. TRIBUTE was a placebo-controlled study randomizing pts with previously untreated advanced NSCLC to receive erlotinib, 150 mg/d, or placebo (PBO) with 6 cycles of carboplatin/paclitaxel (CP) followed by maintenance monotherapy. Methods: Pts with performance status (PS) of 0 or 1 were eligible. Randomization was stratified by stage, >5% weight loss (WL) prior 6 mos., measurable disease (MD), and study site. The primary endpoint was overall survival (OS). Other endpoints included time to progression (TTP), objective response (OR) and duration of response. Results: 1059 pts randomized/treated (526 erlotinib; 533 PBO). No difference was observed in OS (p=0.95), OR (p=0.36) or TTP (p=0.36) with erlotinib and CP ...

A substantial increase in blood cultures positive for a Serratia marcescens strain unusually sensitive to antibiotics was noted in two large hospitals within six months. Because the patients' illnesses seemed incompatible with Serratia bacteremia, contamination of blood cultures was suspected. Investigation suggested that pediatric-sized vacuum tubes containing ethylenediamine tetraacetic acid (EDTA) were the source of the organisms, and the epidemic strain of Serratia was recovered from 41 (35%) of the 116 tubes cultured. Mock trials showed that reflux from tube to syringe can occur while vacuum tubes are being filled. Because contaminated EDTA tubes were sometimes inoculated before blood culture bottles in these hospitals, cross-contamination occurred. Most evacuated specimen tubes are not guaranteed sterile by the manufacturer. False-positive blood cultures stemming from the use of nonsterile tubes can be eliminated by inoculating blood culture bottles before other specimen tubes. Because false-positive blood cultures may lead to unnecessary antibiotic therapy, health-care workers should guard against the potential hazard associated with use of these tubes. (JAMA236:2073-2075, 1976)