Paclitaxel by 1-h infusion in combination with carboplatin in advanced non-small cell lung carcinoma (NSCLC).

In our previous study, FCCC 93-024, paclitaxel by 24-h infusion combined with carboplatin yielded a response rate of 62% and median survival of 54 weeks in advanced non-small cell lung cancer (NSCLC). Myelosuppression proved dose-limiting, requiring the routine use of granulocyte-colony stimulating factor (G-CSF). Based on the reported activity of 1-h paclitaxel infusion in NSCLC and minimal myelosuppression at doses of 135 and 200 mg/m2 every 3 weeks and the suggestion of a dose-response relationship, we launched an intrapatient dose escalation trial of combination carboplatin and 1-h paclitaxel. Chemotherapy-naïve patients with advanced NSCLC received paclitaxel 175 mg/m2 1-h and carboplatin dosed to a fixed targeted area under the concentration-time curve (AUC) of 7.5 at three weekly intervals for six cycles. In the absence of grade 4 myelosuppression, paclitaxel was escalated by 35 mg/m2/cycle on an intrapatient basis to a maximum dose of 280 mg/m2 by cycle 4. G-CSF was not routinely used. 57 patients (pts) were accrued from November 1994 through to April 1996. 44 pts (77%) had Eastern Cooperative Oncology Group (ECOG) performance status 1. Median age was 64 (range: 34-80) years. Cumulative peripheral sensory neuropathy proved dose-limiting and prohibitive in the first 20 evaluable patients (cohort A): grade > or = 1 in 15 patients (75%), grade 3 in 6 (30%), generally occurring at paclitaxel doses > or = 215 mg/m2 and obligating 3 patients to have treatment halted in the absence of disease progression. The protocol, therefore, was revised and the initial paclitaxel dose reduced to 135 mg/m2 with intrapatient dose escalation of 40 mg/m2/cycle to a maximum dose of 215 mg/m2, recapitulating the original dosing schema used in FCCC 93-024. 35 patients were enrolled in this second cohort (B); 33 proved evaluable. Whilst 17 (52%) experienced peripheral sensory neuropathy, grade 3 neurotoxicity developed in only 3 (9%). Myelosuppression also was less pronounced, with 42% exhibiting grade 4 granulocytopenia and 30% grade > or = 3 thrombocytopenia in cohort B compared with 70% and 50%, respectively in cohort A. Of the first 22 patients accrued to cohort A, 12 (55%) had major objective responses. Median survival was 48.5 weeks, 1-year survival rate 45% and 2-year survival rate 18%. Of 33 evaluable patients in cohort B, 9 (27%) had major objective responses. Median survival was 46 weeks, 1-year survival rate 47% and 2-year survival rate 12%. Combination paclitaxel by 1-h infusion and carboplatin at a fixed targeted AUC of 7.5 is active in advanced NSCLC. Neurotoxicity, not myelosuppression, proved dose-limiting at paclitaxel doses exceeding 215 mg/m2. Lower doses may be associated with lower response rates, but do not appear to compromise survival.

Psychological distress and the frequency of perfectionistic thinking.

Five studies tested the hypotheses that there are individual differences in the frequency of automatic thoughts involving perfectionism and that these thoughts are associated with psychological distress. Research with the Perfectionism Cognitions Inventory (PCI) established that this new measure has adequate psychometric properties, and high PCI scorers tend to spontaneously report perfectionistic thoughts in naturalistic situations. Additional research confirmed that frequent perfectionism thoughts account for unique variance in distress, over and above variance predicted by standard measures of negative automatic thoughts and trait perfectionism measures. Overall, the findings support the view that personality traits involved in depression and anxiety have a cognitive component involving ruminative thoughts and that activation of this cognitive personality component contributes to distress.

Long-term survival results for patients with locally advanced, initially unresectable non-small cell lung cancer treated with aggressive concurrent chemoradiation.

PURPOSE: Patients with locally advanced, initially unresectable non-small cell lung cancer (NSCLC) have a median survival time of 9 to 11 months, a 2-year survival rate of 13%, and a long-term survival rate of 5% to 7% when treated with radical thoracic radiation alone. Because of the preclinical radiosensitizing capabilities of 5-fluorouracil and cisplatin and the therapeutic synergy of etoposide and cisplatin, we combined these agents with full-dose radical thoracic radiation to determine the feasibility and efficacy of this approach in locally advanced NSCLC. METHODS: Patients with clinical stage IIIb and bulky IIIa NSCLC and ECOG performance status 0 or 1 received 5-fluorouracil infusion (640-800 mg/m2/d CVI days 1-5, 29-34), cisplatin (20 mg/m2/d, days 1-5, 29-34), etoposide (50 mg/m2, days 1, 3, 5, 29, 31, 33) and concurrent thoracic radiation (60 Gy/2 Gy/d/30 Fx). Patients with adequate cytoreduction proceeded to surgical resection. RESULTS: From March 1987 to July 1990, 41 patients were enrolled on study; 40 are evaluable. The objective response rate was 90%. Thirteen patients (39%), five with clinical stage IIIb disease and eight with IIIa disease, underwent thoracotomy and resection; three proved to have pathological complete remissions. Ten of 77 chemotherapy courses were complicated by neutropenic fever. Grade 3 or 4 esophagitis occurred in 21 patients (52%). Cardiac ischemia or infarction occurred in two patients (5%). There were seven deaths in the first 6 months in the absence of disease progression. Two-year survival was 38%, 3-year survival 25%, and 4- to 5-year survival 18%. Six patients (15%) remain alive at the median follow-up time of 66 months (range, 64-84). CONCLUSIONS: Despite substantial early morbidity and mortality, concurrent, aggressive chemoradiation produced a long-term survival rate in locally advanced NSCLC comparable to other combined modality approaches. However toxicity, particularly esophagitis and postoperative complications, preclude the use of this regimen in phase III studies. Combined modality approaches for locally advanced, initially unresectable NSCLC have become standard; research must simultaneously focus on ways to enhance efficacy and reduce toxicity.

Report of phase II trial of concurrent chemoradiotherapy with radical thoracic irradiation (60 Gy), infusional fluorouracil, bolus cisplatin and etoposide for clinical stage IIIB and bulky IIIA non-small cell lung cancer.

PURPOSE: To assess the response rate, median and long-term survival of patients (pts) with locally advanced, initially inoperable non-small cell lung cancer (NSCLC) treated on a phase II study of radical thoracic radiotherapy (TRT) and concurrent radiosensitizing chemotherapy. METHODS AND MATERIALS: From 3/87 to 7/90, 41 previously untreated patients at Fox Chase Cancer Center with locally advanced non-small cell lung cancer, 24 with bulky clinical Stage IIIA, and 17 with IIIB disease, received concurrent thoracic radiotherapy (60 Gy/2.0 Gy/d in 6 weeks) and 2 cycles of infusional 5FU (640-800 mg/m2/24 hrs x 5 d); cisplatin (20 mg/m2 qd x 5); and etoposide (50 mg/m2 d 1, 2, 5) administered days 1 and 28 of TRT. RESULTS: Forty of 41 were evaluable. Response rate was 90%, with radiographic CR in 20%. Thirteen pts (33%) underwent thoracotomy and complete resection with clinical downstaging in 10, including three pathologic CR's. Overall median survival was 14 months and 2-year survival was 38% with no difference between CS IIIA and IIIB pts (p = 0.2224). At median potential follow-up of 42 months, 8/40 pts. (20%) are alive and progression-free, including 4 of 13 resected pts. The chief toxicity was esophagitis, occurring in 32 pts. (80%), Grade 3-4 in 21 (52%), with 13 (33%) requiring hospitalization and 7 (18%) needing TPN. Grade 3-4 granulocytopenia was noted in 20 pts. (50%) with ten episodes of fever mandating intravenous antibiotics. Cardiac ischemia was documented in 2 (5%). Of 13 thoracotomy pts, six underwent lobectomy without perioperative mortality; 3 of 7 pneumonectomy pts died post-operatively, two from broncopleural fistula, and one from ARDS. CONCLUSION: This aggressive regimen produced a 2-year survival (38%) comparable to the best arm of cancer and leukemia groups B study 8433, which administered radical thoracic radiotherapy after protoadjuvant vinblastine and cisplatin in similar and earlier stage non-small cell lung cancer patients. Toxicity, particularly esophagitis, was severe, but of short duration. An unacceptably high complication rate was seen following pneumonectomy, but not lobectomy.

Depression, problem-solving ability, and problem-solving appraisals.

Behavioral analytic methods were used to create a college student version of the Means Ends Problem Solving Procedure (MEPS). This instrument then was administered with measures of perceived problem-solving ability to depressed and nondepressed students to determine whether differences exist in both problem-solving ability and problem-solving appraisal. Analyses revealed that depressed subjects had more negative expectations and lower appraisals of their problem-solving ability. However, the groups did not differ in terms of the actual quality of their behavioral solutions to interpersonal, intrapersonal, and emotional problem situations. The results are interpreted as support for the role of cognitive factors in depression and problem-solving across a range of problem-solving situations.

Coping and academic problem-solving ability in test anxiety.

The present study examined coping tendencies and perceptions of problem-solving ability in test anxiety. A sample of 125 students completed the revised Ways of Coping Questionnaire, the Academic Problem-Solving Inventory, and measures of state and trait test anxiety. Correlational analyses confirmed that emotion-focused coping (i.e., avoidant and confrontive coping) was associated positively with test anxiety. Also, test-anxious individuals reported poorer ability to solve academic problems. Finally, regression analyses revealed that coping tendencies and perceived problem-solving ability predicted unique variance in test-anxiety scores. The results are discussed in terms of the need for a multidimensional model of test anxiety that includes coping processes and self-evaluations of problem-solving ability.

A double-blind comparison of low-dose intravenous ketamine and methohexital in adults.

Two ultralight general anesthetic techniques, one using low-dose ketamine and the other using methohexital as the primary anesthetic agent, were compared for efficacy, safety, and psychomotor recovery in a double-blind fashion for use during third molar surgery. Low-dose intravenous ketamine as the primary anesthetic following premedication with fentanyl and midazolam, and in conjunction with nitrous oxide, appeared to produce less hypoxia, hypercarbia, and apnea than when methohexital was used. No significant differences were noted in heart rate or blood pressure between the techniques. The ketamine technique was universally preferred by the surgeons and anesthesiologists because of superior patient cooperation and airway management. No unpleasant psychomimetic side effects of significance were noted with the use of ketamine. Postoperative recovery took slightly longer in the ketamine group, with patients being judged fit for discharge approximately 10 to 15 minutes later than the patients who received methohexital.

Regulation of factor XIa activity by platelets and alpha 1-protease inhibitor.

We have studied the complex interrelationships between platelets, Factor XIa, alpha 1-protease inhibitor and Factor IX activation. Platelets were shown to secrete an inhibitor of Factor XIa, and to protect Factor XIa from inactivation in the presence of alpha 1-protease inhibitor and the secreted platelet inhibitor. This protection of Factor XIa did not arise from the binding of Factor XIa to platelets, the presence of high molecular weight kininogen, or the inactivation of alpha 1-protease inhibitor by platelets. The formation of a complex between alpha 1-protease inhibitor and the active-site-containing light chain of Factor XIa was inhibited by activated platelets and by platelet releasates, but not by high molecular weight kininogen. These results support the hypothesis that platelets can regulate Factor XIa-catalyzed Factor IX activation by secreting an inhibitor of Factor XIa that may act primarily outside the platelet microenvironment and by protecting Factor XIa from inhibition, thereby localizing Factor IX activation to the platelet plug.

Biofeedback and relaxation effects in electromyographic biofeedback training: a methodological note.

The present study documented progressive reductions of electromyographic potentials in a biofeedback study involving instructions to 11 female and 5 male college students to both increase and decrease the feedback (and therefore the muscle tension). When only pre-experimental baselines were employed, electromyographic reductions were found with instructions to decrease the feedback. When repeated, nontreatment baseline conditions were employed as references for analysis, no electromyographic reductions were detected beyond the progressive reductions that occurred during those baselines.

Relationships between Spielberger trait anxiety and Lykken social and physical trait anxiety.

To determine the relationship between Spielberger's measure of trait anxiety and social-interpersonal vs. physical danger trait anxiety, Ss were administered and trait scale of the State-Trait Anxiety Inventory (STAI) and Lykken's Activity Preference Questionnaire (APQ). Results of correlative analyses indicated that the STAI-Trait measure correlated significantly with APQ-Social Anxiety, but not with APQ-Physical Anxiety. Results were discussed in terms of the implications for predicting state anxiety in different situations by the use of unidimensional vs. multidimensional trait anxiety measures.

Within-subject control designs and voluntary bidirectional control of cardiac rate: methodological comparison between pre-experiment and pretrial baselines.

The purpose of this study was to compare two methods of analyzing the effects of exteroceptive feedback training on the voluntary bidirectional control of human cardiac rate with the use of a within-subject control design. In this design heart rate (HR) during an experimental period (increase or decrease) is compared with that recorded during some other control period, generally a baseline "rest" period. Ten male undergraduates were instructed to control HR and given visual feedback of heart activity. Trials on which Ss were to raise and to lower HR were both given in a single training session. The data were analyzed in two ways: (a) cardiac rate during HR control periods was compared to an initial pre-experimetn baseline; (b) cardiac rate during HR control periods was compared to a running pretrial baseline. The results support the argument that the former procedure fails to take account of habituating levels of cardiac rate and favors finding large magnitude decreases in HR but small increases, whereas the latter procedure favors finding large magnitude increases but small decreases. It is suggested that magnitude of directional control will be artifactual when initial values are used to assess change. Contaminating influences on the running pretrial baseline were also discussed.

The sensation seeker and anxiety reactivity: relationships between the sensation-seeking scales and the activity preference questionnaire.

The five scales of the Zuckerman Sensation-Seeking Scale and Lykken's Activity Preference Questionnaire were administered to 83 male and female college students to test the hypothesis that there is an inverse relationship between sensation seeking and anxiety reactivity. The data were intercorrelated separately for males and females. Results were, in general, consistent with expectations: individuals high in optimal level of stimulation are low in anxiety reactivity in situations that involve physical danger and in situations related to social fears or embarrassment. This relationship was found for most of the dimensions of sensation seeking for males, but was confined to specific subscales for females.

Note on relation of autonomic perception to voluntary control of heart rate.

Relationships between subscores of the Autonomic Perception Questionnaire and ability to raise and lower heart rate voluntarily were examined in 40 subjects. Subscores which reflected autonomic awareness in anxiety and pleasure states were not predictive of degree of cardiac control, while the subscore specific to reported awareness of heart functioning during pleasure states only was positively correlated with ability to raise heart rate.