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Background S1400D is a biomarker-driven therapeutic substudy of Lung-MAP evaluating the fibroblast growth factor (FGF) receptor (FGFR) inhibitor AZD4547 in patients with FGF pathway-activated squamous cell. This is the first phase II trial to evaluate AZD4547 as a targeted approach in patients with previously treated FGFR-altered squamous cell NSCLC and is the first demonstration of successful implementation and conduct of a national umbrella protocol in this disease setting. Methods Eligible patients had tumoral FGFR alteration or mutation and had progressive disease after at least one line of platinum-based systemic therapy. Patients received AZD4547 80 mg twice daily orally. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival, and duration of response (DoR). Results Ninety-two patients were assigned to S1400D, 43 were enrolled, and 27 AZD4547-treated patients were evaluable. Evaluable patients were predominantly white (n = 24, 89%), median age 66 years (range, 49–88 years old), and female (n = 7, 26%). FGFR alterations included FGFR1 amplification (n = 23; 85%), FGFR3 amplification (n = 2; 7%), FGFR3 S249C (n = 2; 7%), and FGFR3 fusion (n = 1; 4%). Treatment with ADZ4547 was well tolerated; grade 3 adverse events occurred in six patients, and one patient had grade 4 sepsis. Of 27 response-evaluable patients, 1 patient with FGFR3 S249C had unconfirmed partial response with a DoR of 1.5 months and 1 patient with FGFR1 amplification had a confirmed partial response with a DoR of 2.9 months (7%, 95% confidence interval [CI]: 0%–17%). Median progression-free survival and overall survival for the AZD4547-treated cohort were 2.7 months (95% CI: 1.4– 4.5 months) and 7.5 months (95% CI: 3.7–9.3 months). Conclusions AZD4547 had an acceptable safety profile but minimal activity in this predominantly FGFR1/FGFR3–amplified cohort. Evaluation of other targeted agents in Lung-MAP is ongoing.

This study tested the effectiveness of a facilitated educational program in a museum for promoting family conversations and children's learning about STEM. A sample of 130 families (71 European-American; 33 African-American; and 26 Hispanic-American) with children M age = 6.42 years were observed in a building construction exhibit. Prior to building, families were randomly assigned to conditions that varied in terms of the instructions about a key engineering principle and elaborative question-asking they received. Conversation instruction resulted in adults’ asking double the number of Wh -questions compared to families who did not receive the instruction. The building instruction was important in promoting increases in adults’ STEM-related talk during the building activity, as well as in the children's STEM talk when prompted for information about what they had learned. The effects of the instructions did not vary by families’ ethnic background. Implications for facilitating family conversations and children's learning related to STEM are discussed.

Introduction: Outcomes data treating patients with oligometastatic (⩽5 metastases) non-small cell lung carcinoma (NSCLC) with hypofractionated image-guided radiotherapy (HIGRT) are limited. Methods: Consecutive oligometastatic NSCLC patients were reviewed from a prospective database. Patients were included if all active diseases were treated with HIGRT. Lesions that had received prior radiation or had radiographic/metabolic resolution after chemotherapy were not treated with HIGRT. Local control of all treated lesions, distant control, progression-free survival (PFS), overall survival (OS), and control of individual lesions (LeC) were calculated. Results: Twenty-five patients with median of 2 treated oligometastatic lesions were included. Median follow-up was 14 months. Median age was 66 years. Nineteen patients received systemic therapy before HIGRT and 11 had progressive disease after their most recent systemic therapy before HIGRT. Median OS and PFS were 22.7 and 7.6 months. The 18 months local control, distant control, OS, and PFS were 66.1%, 31.7%, 52.9%, and 28.0%. Greater than two sites treated with HIGRT, nonadenocarcinoma histology, prior systemic therapy, and progression after systemic therapy were associated with worse PFS. Sixty-two individual lesions of median size 2.7 cm were treated. For extracranial lesions, median total and fraction dose were 50 and 5 Gy. Median standard equivalent dose in 2 Gy fractions for extracranial lesions was 64.6 Gy yielding 18 months LeC of 70.7%. Standard equivalent dose ≥64.6 Gy increased LeC ( p = 0.04). Two patients experienced grade 3 toxicity. Conclusions: HIGRT for oligometastatic NSCLC provides durable LeC and may provide long-term PFS in some patients. Future HIGRT studies should optimize patient selection and integration with systemic therapy.

Introduction Treatment of technically operable, medically fit locoregionally advanced non-small cell lung cancer (NSCLC) patients is a controversial therapeutic challenge. Our group routinely uses a trimodality approach. Recent advances in radiotherapy allow for improved tumor targeting and daily patient positioning. We hypothesized that these technologies would improve pathologic response rates. We analyzed consecutively treated stage IIIA/IIIB NSCLC patients undergoing chemoradiotherapy before major lung resection, with particular attention paid to the impact of advanced technologies. Methods Locoregionally advanced NSCLC patients (N2) staged in a multidisciplinary forum with mediastinoscopy were planned to receive platinum-based chemotherapy and 60 Gy and major lung resection. Four-dimensional CT (4DCT) and image-guided radiotherapy (IGRT) were used as available. Survival endpoints were estimated using the Kaplan–Meier method and compared using the log-rank test. Multivariate analysis was performed using Cox proportional hazards models. Results We identified 53 patients from 2/1999 to 2/2010. Median RT dose was 59 Gy. 68% underwent lobectomy. Forty-three patients were downstaged pathologically (81%), 38 experienced mediastinal sterilization (72%), and 21 (40%) had complete pathologic response (pCR). 1 and 2 year OS were 85.5% and 61.6%. Superior OS and DFS were associated with nodal downstaging and mediastinal sterilization (pN0). Treatment with IGRT/4DCT in 10 patients resulted in high rates of nodal downstaging (100% vs 77%, p = 0.0452), mediastinal sterilization (90% vs 67%, p = 0.0769), and pCR (60% vs 35%, p = 0.0728). Conclusions In selected patients, definitive dose CRT followed by major lung resection results in promising DFS and OS. The use of advanced radiotherapy techniques (4DCT and IGRT) appears to result in promising pathologic response rates.

Lung cancer is a heterogenous group of disorders, and a difficult disease to treat. The traditional approach of surgical resection for early-stage disease, potentially followed by chemotherapy, as well chemotherapy (with or without radiation) in later stages of disease is being supplemented with a personalized approach. The personalized approach has classically been used by the oncologist based on clinical/pathological parameters such as the performance status of the patient and histology of lung cancer. As molecular mechanisms have been explored in lung cancer more recently, the personalized approach also has incorporated molecular abnormalities. In particular, EGFR, K-ras, ALK, MET, CBL, and COX2, have come to the forefront as potential biomarkers and therapeutic targets. Thus, we review the various molecular mechanisms in lung cancer and the role of novel therapeutics.

Background The aim of this study was to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and determine the phase II dose for the combination of irinotecan-carboplatin-paclitaxel given as induction chemotherapy and with concomitant chest radiotherapy for patients with Stage III non-small cell lung cancer. Methods Patients with Cancer and Leukemia Group B performance status of 0 to 2, stage IIIA and IIIB NSCLC patients with resectable or unresectable disease were treated with induction chemotherapy (irinotecan 100 mg/m 2 , carboplatin AUC 5, and paclitaxel 175 mg/m 2 days 1 and 22) followed by concomitant chemotherapy (irinotecan, carboplatin, and paclitaxel) and chest radiotherapy (66 Gy for unresectable and 50 Gy for resectable disease) beginning on week 7. The primary objective was to escalate the dose of irinotecan during chemoradiation in sequential cohorts to determine the DLT and MTD of the regimen. Results Thirty-eight patients were enrolled (median age 63 years, 57% male, 41% performance status 0, 30% resectable). Induction chemotherapy was tolerable and active (response rate 26%; stable disease 60%). Eight patients did not receive concurrent chemoradiotherapy because of progressive disease (5), death (1), hypersensitivity reaction to paclitaxel (1), and withdrawal of consent (1). Twenty-nine patients received concurrent chemoradiotherapy. The concomitant administration of chest radiotherapy with weekly irinotecan, carboplatin, and paclitaxel was not feasible at the first, second, and third dose levels. DLT was failure to achieve recovery to ≤ grade 1 absolute neutrophil count by the day of scheduled chemotherapy administration. Dose de-escalation to irinotecan 30 mg/m 2 , paclitaxel 40 mg/m 2 (with omission of carboplatin) delivered on weeks 2, 3, 5, and 6 of radiotherapy was the MTD. After induction chemotherapy, partial responses, stable disease, and progressive disease was observed in 26%, 60%, and 14% of patients, respectively. After chemoradiotherapy, partial responses were attained in 16 (55%) patients, whereas 12 patients (41%) attained disease stabilization. Median overall survival was 21 months for the entire cohort. Resectable patients had a median survival of 24 months, whereas unresectable patients had a median survival of 19 months. Differences in overall and progression-free survival rates between resectable and unresectable patients was not statistically significant ( p = 0.52 and p = 0.90, respectively). Discussion Carboplatin, paclitaxel, and irinotecan with concurrent chemoradiotherapy was poorly tolerated as a result of neutropenia. Although dose de-escalation was required for delivery of the regimen, the response rates and survival outcomes were comparable to other similar regimens.

Background The aim of this study was to evaluate feasibility and tolerability of the three-drug combination of paclitaxel, ifosfamide and carboplatin (TIC) in patients with advanced non-small-cell lung cancer. The specific objectives of the study were: (i) to define the dose-limiting toxicities (DLTs) and the maximum-tolerated dose of ifosfamide administered as part of the combination; and (ii) to determine the overall response rate and overall survival of patients treated with this regimen. Patients and methods Patients with untreated, stage IIIB (pleural effusion) or stage IV non-small-cell lung cancer were enrolled in one of three cohorts. Patients received paclitaxel 200 mg/m2 as a 1-h infusion on day 1 with carboplatin at an area under the concentration–time curve (AUC) of 6 mg·min/ml on day 2. For dose level I, ifosfamide was administered at a dose of 2 g/m2 on days 1 and 2. For dose levels II and III, the dose of ifosfamide was decreased to 1.5 g/m2 on days 1 and 2 and the dose of carboplatin was decreased to AUC 5 mg·ml/min. Therapy for dose levels I and III included filgrastim support (5 µg/kg/day), which was initiated on day 3 and continued until after day 11 or until an absolute neutrophil count >10 000/µl. Treatment cycles were repeated every 21 days. Once the phase II dose was established, a full cohort of patients received therapy at this dose level to examine further the regimen’s activity and tolerability. Results Neutropenia was the DLT encountered for dose levels I and II. No DLT was encountered inthe initial six patients treated at dose level III, and therefore this dose level was declared the recommended phase II dose. A total of 49 patients were treated at the recommended phase II dose. The predominant non-hematological toxicity encountered with this triplet regimen was cumulative peripheral neuropathy. Of the 65 eligible patients enrolled in this study, 17 (26%) responded. There were 15 patients with partial responses (23%), two with regression, and 26 with stabilization of disease (40%). Median progression-free and overall survival were 4.8 and 9.4 months, respectively. Conclusions The combination TIC is well-tolerated. This triplet regimen produced response and survival rates in advanced non-small-cell lung cancer similar to those of other current combination chemotherapy regimens.

Background: Bryostatin-1 is a macrocyclic lactone, which exhibits pleiotropic biological effects via protein kinase C and has shown preclinical synergy with paclitaxel for enhanced tumor cell apoptosis. Patients and Methods: Patients had stage IIIB (pleural effusion)/IV non-small cell lung cancer, measurable disease, performance status 0–2 Eastern Cooperative Oncology Group, adequate organ function, and no prior chemotherapy. Patients received dexamethasone premedication followed by paclitaxel at a dose of 90 mg/m 2 on days 1, 8, and 15 along with bryostatin-1 50 μg/m 2 on days 2, 9, and 16 every 28 days until disease progression. Correlative assays measuring serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and T-lymphocyte numbers were performed based on a previous study showing cytokine induction in vivo by bryostatin-1. Fifteen patients were enrolled. Results: Thirty cycles of the bryostatin-1 and paclitaxel were delivered with a median of 2 per patient (range 1–4). Myalgia was the predominant non-hematologic toxicity encountered as 3 patients developed grade 4 and 1 patient developed grade 3 myalgia. Four patients were removed from the study during cycle 1 for rapid disease progression or myalgia. Eleven patients could be evaluated for response. Five patients had stable disease, two had a mixed response, and four had progressive disease. Ten patients received second-line chemotherapy after leaving the study. Median survival was 31 weeks (95% confidence interval: 5.4–49.3). Correlative data showed a trend towards decreased plasma IL-6 and TNF-α after each cycle of therapy presumably due to the dexamethasone premedication and/or paclitaxel. Conclusions: This drug combination showed no significant clinical response and was associated with reproducible toxicity. The predominance of myalgia in the absence of elevated serum cytokines suggests a non-inflammatory etiology of this toxicity.

Summary Background 9-Aminocamptothecin (9-AC) is a synthetic analogue of camptothecin. Phase I studies, identified the maximum tolerated dose as 1416 μg/m2/day × 3 as continuous intravenous infusion (CVI) with dose-limiting neutropenia. Patients and methods Eligible patients had stage IIIB or IV non-small-cell lung cancer (NSCLC) with measurable disease. Patients were initially treated at 1416 μg/m2/d × 3 by CVI followed by granulocyte-colony stimulating factor (G-CSF) support. This dose was decreased to 1100 μg/m2/d after the first 13 patients. Cycles were repeated every 14 days until tumor progression. Results Fifty-eight patients were treated, thirteen at 1416 μg/m2/d and 45 at 1100 μg/m2/d. Fifty percent had adenocarcinoma and 17% squamous cell carcinoma. Seventy-one percent had stage IV disease. Five patients had a partial response (response duration 9–28 weeks) for an overall response rate of 8.6%, (95% confidence intervals (CI): 2.9%–19%). Median time to progression was 2.3 months and the median survival for the entire study population 5.4 months with a one-year survival rate of 30%. The one-year survival rate for 27 patients who received second line chemotherapy was 56.7%. Toxicities at 1416 μg/m2/d included grade 4 neutropenia and thrombocytopenia in six and five of 13 patients, respectively; at 1100 μg/m2/d these toxicities were observed in 12 and three of 45 patients, respectively. Conclusion 9-AC has modest single-agent activity in previously untreated NSCLC. Its further evaluation at the dose and schedule employed in this study does not seem indicated. Exploration of more prolonged administration schedules may be warranted.

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.

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.

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.

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).