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Cancer and cardiovascular disease share several risk factors. Clonal heamatopoiesis, a novel risk factor associated with both diseases, has received increasing attention in the fields of cardiology, heamatology and oncology. Clonal heamatopoiesis of indeterminate potential refers to the presence of at least one driver mutation in the heamatopoietic cells of peripheral blood without heamatological malignancy. Clonal heamatopoiesis of indeterminate potential is a common age-related condition that affects up to 60% of individuals aged > 80 years. Importantly, clonal heamatopoiesis of indeterminate potential carriers have a 2- to 4-fold higher risk of developing cardiovascular disease than non-carriers. Therefore, we performed an up-to-date review of clonal heamatopoiesis and its association with various forms of cardiovascular disease, including atherosclerotic disease, heart failure, aortic stenosis and pulmonary hypertension. In addition, we reviewed experimental studies that examined the causality and directionality between clonal heamatopoiesis and cardiovascular disease. Lastly, we discussed future research directions that will aid in the design of personalized therapies and preventive strategies for individuals with clonal heamatopoiesis. This review showed that clonal heamatopoiesis of indeterminate potential is a common condition, especially in older patients, and is associated with an increased risk of cardiovascular disease and worse prognosis. However, further research is needed to determine whether anti-inflammatory therapies or therapies that can reduce or eliminate clone size are effective in preventing cardiovascular disease in patients with clonal heamatopoiesis of indeterminate potential.

Lymphocytes play an important role in the cancer immune system. In the present study, we aimed to evaluate the associations of lymphopenia during proton beam therapy (PBT) and concurrent chemotherapy with clinical outcomes and to determine whether lung or bone is more influential on lymphopenia during PBT. Data from 41 patients with stage III non-small cell lung cancer (NSCLC) who received PBT of 74 GyE with concurrent chemotherapy between 2007 and 2017 were reviewed retrospectively. The correlation between dosimetry parameters obtained from dose–volume histograms of the bone and lung and lymphopenia during PBT were analyzed. Minimum absolute lymphocyte count (ALCmin) and maximum neutrophil/lymphocyte ratio (NLRmax) were used as indicators of lymphopenia. Bone V5–20 and lung V5–50 were significantly correlated with the ALCmin and NLRmax during PBT. Multivariable analysis showed that the NLRmax, but not the ALCmin, was associated with overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). The 3-year rates of OS, PFS and DMFS of patients with a low (≤ 6.3) versus high (> 6.3) NLRmax were 73.9% vs 44.4% (P = 0.042), 26.1% vs 5.6% (P = 0.022) and 39.1% vs 5.6% (P

Objective Onco-cardiology services are expanding rapidly in Japan. To provide a better service, it is important to consider the needs of oncologists. However, little is known regarding specific needs for which oncologists should consult cardiologists to manage cardiovascular problems of their patients. We analysed cardiology consultations sought by oncologists to evaluate the role of cardiologists in cancer treatment. Method We retrospectively investigated consecutive 2064 cardiology consultations of cancer patients in the University of Tsukuba Hospital, Tsukuba, Japan, between January 2014 and December 2018. Results The most common timing of cardiology consultation was before the commencement of cancer treatment (n = 1355; 65.7%), followed by after the commencement of cancer treatment (n = 686; 33.2%). Among the 361 consultations before the administration of anticancer drugs, 235 (65.1%) were for anthracycline-based regimens. There were 506 (24.5%) consultations for the management of cardiovascular emergencies developing after the commencement of cancer treatment; venous thromboembolism was the most frequent (n = 125; 24.7%), followed by atrial fibrillation (n = 110; 21.7%) and heart failure (n = 74; 14.6%). There were marked differences in the types of cardiovascular emergencies depending on the type of cancer. Conclusions This survey revealed the various cardiovascular problems for which oncologists sought interventions by cardiologists. A multidisciplinary approach in an onco-cardiology service is essential to achieve optimal long-term outcomes.

Immune checkpoint inhibitors have demonstrated significant clinical benefit in many cancers. The clinical benefit afforded by these treatments can be accompanied by a unique and distinct spectrum of adverse events. Recently, several fatal cases of immune checkpoint inhibitor-related myocarditis were reported. Although its frequency is comparatively lower than that of other immune-related adverse events, myocarditis can lead to circulatory collapse and lethal ventricular arrhythmia. Immune checkpoints, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), play important roles in establishing peripheral tolerance to the heart. Evidence from studies using genetically engineered mouse models suggests that CTLA-4 signaling terminates proliferation and promotes anergy during the primary response to cardiac self-peptide recognition. PD-1 signaling restrains autoreactive T cells that enter the peripheral tissues and recognize cardiac-peptide, maintaining them in an anergic state. Patients affected by immune checkpoint inhibitor-related myocarditis often experience rapid onset of profound hemodynamic compromise progressing to cardiogenic shock. Early diagnosis is mandatory to address specific therapy and correct the timing of circulatory support. However, the diagnosis of myocarditis is challenging due to the heterogeneity of clinical presentations. Owing to its early onset, nonspecific symptomatology and fulminant progression, especially when these drugs are used in combination, oncologists should be vigilant for immune checkpoint inhibitor-related myocarditis. With many questions yet to be answered, from basic immune biology to clinical management, future research should aim to optimize the use of these drugs by identifying predictive biomarkers of either a response to therapy or the risks of myocarditis development.

Objective: Extravasation, the accidental leakage of an anticancer agent from a vessel into the surrounding tissues, can lead to irreversible local injuries and severe disability. Despite its considerable clinical importance, evidence-based information on extravasation in chemotherapy is lacking. This study characterized the clinical features of extravasation and identified issues to be resolved in current cancer chemotherapy performed in outpatient settings. Methods: We retrospectively reviewed the medical charts of patients who received chemotherapy and sustained extravasation in our Outpatient Chemotherapy Clinic from April 2007 to August 2012. Chemotherapy administration and extravasation management procedures were standardized using the in-house chemotherapy guideline. Results: Among 43 557 patients who received chemotherapy, 35 (0.08%) experienced extravasation. The duration between the start of infusion and extravasation was . 2hi n 28 (80.0%) patients. The severity of extravasation was Grades 1, 2 and 3 in 28, 2 and 5 patients, respectively—three of whom were associated with port trouble. The contributing factor for extravasation was walking in 11 (31.4%) patients. All extravasations were cured without surgical intervention by management according to our guidelines. Conclusions: The incidence of extravasation is as low as 0.08%, using our in-house chemotherapy guideline. Extravasation from implanted ports tends to be severe.

Objective We previously reported that 22% of lung cancer patients experienced a Grade 2 or 3 elevation in creatinine after chemotherapy containing cisplatin. We conducted a Phase II trial to evaluate the safety and efficacy of short hydration. Methods The major eligibility criteria included patients with lung cancer for whom a ≥75 mg/m(2) cisplatin-based regimen was indicated and adequate organ function. Cisplatin was administered with pre- and post-hydration containing 10 mEq of potassium chloride in 500 ml of fluid over a 60-min period. Immediately before the administration of cisplatin, mannitol (20%, 200 ml) was administered as forced diuresis over 30 min. And magnesium sulfate (8 mEq) was added to pre-hydration. Results Forty-four patients were enrolled between April and December 2011. The patients included 29 men and 15 women with a median (range) age of 64 (42-74) years. Twenty patients received cisplatin and pemetrexed as their most frequent regimen and 38 patients received three to four cycles of chemotherapy. The median (range) duration and volume of the chemotherapies were 4.0 (3.3-6.8) h and 1600 (1550-2050) ml, respectively. Of the 44 patients, 43 (97.8%) completed the cisplatin-based chemotherapy without Grade 2 or higher renal dysfunction. The only patient who had Grade 2 elevation in creatinine (maximum value 1.7 mg/dl) had prompt improvement in creatinine levels and completed four cycles of chemotherapy. Conclusions The short hydration is safe without severe renal toxicities in regimens containing cisplatin (≥75 mg/m(2)) for patients with lung cancer.

Background: Severe hematological toxicity has been frequently observed during amrubicin monotherapy for patients with lung cancer despite the favorable anti-tumor response. The purpose of this retrospective study was to identify pretreatment factors associated with severe hematological toxicity. Methods: The medical records of lung cancer patients treated with amrubicin monotherapy were reviewed, and univariate and multivariate analyses were conducted. Results: From January 2003 to December 2006, the medical records of 103 patients were extracted. Grade 4 neutropenia was frequently observed in females (male, 66% and female, 90%, P ¼ 0.036 in a univariate analysis). In a multivariate analysis, female gender (P ¼ 0.019), body weight loss (P ¼ 0.021) and amrubicin dose (P ¼ 0.028) were significantly correlated with Grade 4 neutropenia. Conclusion: Gender could be considered as one of the important predictive factors associated with Grade 4 neutropenia in patients receiving amrubicin monotherapy.

Objective No standard chemotherapy has been established yet for large-cell neuroendocrine carcinoma of the lung. Amrubicin is active for both small cell and non-small cell lung cancers, but its activity for large-cell neuroendocrine carcinoma is still unknown. Methods From January 2002 to December 2009, 18 patients with previously treated advanced large-cell neuroendocrine carcinoma received amrubicin monotherapy. The efficacy and toxicity of the treatment were analyzed retrospectively. Results The patients comprised 17 males and one female with a median age of 62 years (range, 51-77). Fourteen and four patients had a performance status of 0-1 and 2, respectively. Thirteen (72%) patients had received one prior chemotherapy, while the others had received two or more chemotherapies. All the patients had received platinum-based chemotherapy before the amrubicin treatment. A total of 63 cycles of amrubicin chemotherapy was administered in the 18 patients, with a median number of cycles per patient of 2.5 (range, 1-10). The median dose of amrubicin in the 63 cycles was 40 (range, 30-45) mg/m(2)/day for 3 days. Grades 3-4 neutropenia, thrombocytopenia and anemia were seen in 89, 17 and 22% of the patients, respectively. Grade 3 febrile neutropenia occurred in 33% of the patients. Non-hematological toxicity was generally mild and manageable. There were five cases of partial response, six of stable disease and six of progressive disease among the 18 patients, yielding an objective response rate of 27.7%. The median progression-free and overall survivals of the patients were 3.1 and 5.1 months, respectively. Conclusion Amrubicin was potentially active against previously treated large-cell neuroendocrine carcinoma.

Preliminary safety findings are presented from the open-label Phase I part of a combined Phase I/II study of BLP25 liposome vaccine (L-BLP25) in Japanese patients with unresectable Stage III non-small-cell lung cancer after primary chemoradiotherapy. Six patients received four or more once-weekly vaccinations with L-BLP25 1000 μg subcutaneously prior to a preliminary safety evaluation. Treatment continued with once-weekly vaccinations with L-BLP25 1000 μg subcutaneously until week 8, then maintenance vaccinations every 6 weeks until progressive disease. Cyclophosphamide (300 mg/m(2) i.v. single dose) was given 3 days before first vaccination. Median age was 63.5 years and performance status was 0-1. No serious adverse events occurred; none necessitated discontinuation. L-BLP25-related adverse events (Grade 1) were myalgia, arthralgia and nausea; cyclophosphamide-related adverse events comprised dysgeusia, anorexia and nausea. The first evaluation of L-BLP25 in Japanese patients shows that it is well tolerated, and the safety profile is consistent with that seen in previous studies of Caucasian patients.

Objective: The aim of this study was to investigate the safety, pharmacokinetic and pharmacodynamic profiles of pegfilgrastim (KRN125), a long-acting granulocyte colony-stimulating factor, in lung cancer patients with chemotherapy-induced neutropenia. Methods: Eighteen Japanese lung cancer patients who had experienced severe neutropenia (absolute neutrophil counts ,0.5 � 10 9 cells/l) were enrolled. Six patients were sequentially enrolled in each pegfilgrastim dose cohort (dose levels of 30, 60 or 100 mg/kg). Patients received the same chemotherapy regimen as in their previous cycle and pegfilgrastim was injected subcutaneously the day after chemotherapy ended in each treatment cycle. Pharmacokinetic, pharmacodynamic and safety analyses were performed. Results: Dose-limiting toxicity and serious adverse events related to pegfilgrastim were not observed in any patients. Pegfilgrastim antibodies were not detected. Maximum serum concentrations and area under the serum concentration‐time curves of pegfilgrastim were dependent on the pegfilgrastim dose in a non-linear manner. Of the 18 patients, severe neutropenia occurred in 4 (22.2%), and, of these, 1 patient (5.5%) required rescue treatment by filgrastim. Conclusions: A single dose of pegfilgrastim increases the serum concentration of pegfilgrastim for several days in a dose-dependent manner and is not associated with significant toxicity. Good efficacy of pegfilgrastim for the prevention of severe neutropenia was observed at all dose levels. Based on these data, further studies are warranted to determine the recommended dose of pegfilgrastim for Japanese patients with chemotherapy-induced neutropenia.

Systemic chemotherapy is the mainstay of treatment in patients with advanced non-small cell lung cancer. Local control of regional and metastatic lesions may be needed before systemic therapy can be started in patients with pleural effusions or bone or brain metastases. The indication for systemic chemotherapy depends on the symptoms and performance status of the patient. In addition, a risk assessment considering complications such as hemodynamic and respiratory compromise by effusions, pathological bone fractures, and neurologic deterioration caused by brain metastases is critical in selecting which patients should receive first-line systemic chemotherapy before local therapy, although predictive factors for these complications have not yet been established. Chemotherapy has been considered to have only a limited role in the treatment of patients with pleural effusions and brain and bone metastases, but recently developed anticancer agents have shown substantial antitumor effects in these types of patients with a good general condition.

The optimal treatment for limited-disease small cell lung cancer (LD-SCLC) in patients aged 75 years or older remains unknown.Elderly patients with LD-SCLC who were treated with chemoradiotherapy were retrospectively reviewed to evaluate their demographic characteristics and the treatment delivery, drug toxicities and antitumor efficacy.Of the 94 LD-SCLC patients treated with chemotherapy and thoracic radiotherapy at the National Cancer Center Hospital between 1998 and 2003, seven (7.4%) were 75 years of age or older. All of the seven patients were in good general condition, with a performance status of 0 or 1. Five and two patients were treated with early and late concurrent chemoradiotherapy, respectively. While the four cycles of chemotherapy could be completed in only four patients, the full dose of radiotherapy was completed in all of the patients. Grade 4 neutropenia and thrombocytopenia were noted in seven and three patients, respectively. Granulocyte-colony stimulating factor support was used in five patients, red blood cell transfusion was administered in two patients and platelet transfusion was administered in one patient. Grade 3 or more severe esophagitis, pneumonitis and neutropenic fever developed in one, two and three patients, respectively, and one patient died of radiation pneumonitis. Complete response was achieved in six patients and partial response in one patient. The median survival time was 24.7 months, with three disease-free survivors for more than 5 years.Concurrent chemoradiotherapy promises to provide long-term benefit with acceptable toxicity for selected patients of LD-SCLC aged 75 years or older.

Background To assess the pharmacokinetic profile and time-course of trough concentrations and hemoglobin levels associated with subcutaneous weekly administration of epoetin beta in lung cancer patients with chemotherapy-induced anemia. Methods Epoetin beta was subcutaneously administered to 15 anemic lung cancer patients once weekly for 8 weeks at doses of 9000, 18,000 and 36,000 IU. Pharmacokinetic parameters (C(max), AUC(inf) and T(1/2)) were determined after the first single dose administration on a model-independent basis, and the relationship between the dose and these parameters was examined for linearity. Results Weekly administration of epoetin beta at 9000, 18,000 and 36,000 IU produced C(max) values of 308 +/- 117 (mean +/- standard deviation), 678 +/- 86.7 and 1316 +/- 766 mIU/ml, and AUC(inf) values of 15,300 +/- 9524, 54,574 +/- 16,265 and 88,501 +/- 55,687 hr mIU/ml, respectively, showing dose-proportional increases. Trough concentrations tended to increase in the presence of severe bone marrow suppression induced by chemotherapy or other factors. Extremely high values were seen in three patients, but there was no apparent trend toward an increase with repeated doses. After 8 weeks' administration at 9000, 18,000 and 36,000 IU, hemoglobin levels were changed by -0.37 +/- 1.26, 2.15 +/- 1.36 and 2.82 +/- 2.17 g/dl, respectively. Conclusions Epoetin beta exhibited linear pharmacokinetics when administered to anemic cancer patients at weekly doses of 9000-36,000 IU and did not cause drug accumulation. Hemoglobin levels increased with weekly doses of 18,000 or 36,000 IU.

We conducted a dose-finding and feasibility study in which we administered a fixed dose 3-h infusion of paclitaxel and an escalating dose of cisplatin in Japanese patients with advanced non-small cell lung cancer.Chemotherapy consisted of fixed dose (210 mg/m(2)) paclitaxel given over 3 h on day 1 and an escalating dose of cisplatin on day 2, every 3-4 weeks. The dose of cisplatin was 40 mg/m(2) at level 1, 60 mg/m(2) at level 2 and 80 mg/m(2) at level 3.Between October 1999 and February 2001, 24 patients were enrolled and 58 cycles were administered. The major hematological toxicities were leukopenia and neutropenia. Grade 4 neutropenia developed in 83.3%, 66.7% and 83.3% of patients at the dose levels of 1, 2 and 3, respectively. The major non-hematological toxicities consisted of alanine aminotransferase (ALT) elevation and peripheral neuropathy. Grade 3 ALT elevation was observed in two of the 12 patients at level 3, but both recovered within 3 days. The peripheral neuropathy was sensory-dominant and frequent, and it was almost tolerable. The maximum tolerated dose was not identified even at the highest dose of paclitaxel (210 mg/m(2)) and cisplatin (80 mg/m(2)) administered in the study. The recommended dose was determined to be paclitaxel 210 mg/m(2) on day 1 and cisplatin 80 mg/m(2) on day 2, every 3-4 weeks. Seven partial responses were observed in the 24 patients.The combination of paclitaxel 210 mg/m(2) and cisplatin 80 mg/m(2) was found to be a well-tolerated active regimen in Japanese patients with advanced non-small cell lung cancer.

Background: A combination of cisplatin and vinorelbine chemotherapy is effective in cases of advanced non-small cell lung cancer, but the optimum administration schedule for both drugs has not yet been defined. The aim ofthis study was to determine the maximum dose of vinorelbine that can be tolerated while receiving a fixed dose of cisplatin every 3 weeks and to observe the response in Japanese patients with advanced non-small cell lung cancer who had not previously received chemotherapy. Methods: Cisplatin was given at a dose of 80 mg/m 2 on day 1. Vinorelbine was administered on days 1 and 8 at a starting dose of 25 mg/m 2 that was then increased by 5 mg/m 2 increments. This treatment was repeated every 3 weeks. Results: Twenty-one patients received a total of 54 chemotherapy cycles consisting of three different vinorelbine dosages. Toxicity and efficacy were evaluated in all of the patients. The main dose-limiting toxicity was neutropenia. Grades 3-4 leukopenia and neutropenia were observed in 57% and 86% of all cycles, respectively. These conditions were reversible and did not result in death from toxicity. The most severe non-hematological toxicity symptom was a grade 3 infection and reaction at the site of injection. The maximum tolerated dose of vinorelbine was 35 mg/m 2 . The objective response was noted in one of six patients at dose level 1, in four of 12 patients at dose level 2 and in two of three patients at dose level 3. Conclusion: The recommended doses were 80 mg/m 2 for cisplatin and 30 mg/m 2 for vinorelbine. The combination of cisplatin and vinorelbine repeated every 3 weeks is well tolerated and has shown promising anti-tumor activity against non-small cell lung cancer.

Background: The combination of paclitaxel (225 mg/m 2 , 3-h infusion) and carboplatin (area under the curve 6) is widely used for non-small cell lung cancer in the USA. In Japan, however, the recommended dose for single-use paclitaxel in 3-h infusion is 210 mg/m 2 and the optimal dose of this agent in combination with carboplatin has not been established. This dose escalation study was designed to determine the maximum tolerated dose of paclitaxel in 3-h infusion plus carboplatin at a fixed dose of area under the curve 6 for Japanese patients with advanced, untreated non-small cell lung cancer. Methods: Between October 1999 and May 2000, 19 patients were enrolled and 18 of these patients were evaluable for toxicity. Chemotherapy consisted of carboplatin area under the curve 6 and an escalated dose of paclitaxel on day 1 every 3-4 weeks. The initial dose of paclitaxel was 175 mg/m 2 and was increased by 25 mg/m 2 at each dose level. Results: Neutropenia was the major toxicity observed, but was not dose related. Febrile neutropenia was not observed. No grade 3 or more peripheral neuropathy, myalgia or arthralgia was reported. The maximum tolerated dose was not determined even at the highest paclitaxel dose level (225 mg/m 2 ) in this study. Partial responses were observed in six of the 19 patients (31.6%). Conclusion: We conclude that paclitaxel at 225 mg/m 2 in 3-h infusion and carboplatin area under the curve 6 can safely be given to Japanese patients with non-small cell lung cancer.

As the geriatric population is growing, it is increasingly important to be familiar with chemotherapy for the elderly. Age-related changes in pharmacokinetics are documented for doxorubicin, etoposide, ifosfamide, daunorubicin, mitomycin, cisplatin and methotrexate. The hematological toxicity of most standard-dose chemotherapy is not affected by age in patients with normal organic functions and good performance status, although increased toxicity with aging is suggested in the use of actinomycin-D, etoposide, vinblastin, methotrexate, methyl-CCNU, doxorubicin and mitomycin, and in dose-intensive chemotherapy. Among non-hematological toxicities, only doxorubicin-induced cardiomyopathy and bleomycin-induced pulmonary toxicity are demonstrated to be accelerated in the elderly. There is no evidence that advanced age decreases the efficacy of chemotherapy for tumors, except for Hodgkin's disease and acute leukemia. These results suggest that advanced chronological age alone is not always associated with severe toxicity and poor prognosis, and that many elderly patients with cancer will benefit from chemotherapy. To answer questions regarding the optimal chemotherapy regimen, dose and intensity in this population, the influence of age should be analyzed in a multivariate approach in future studies.

BACKGROUND It is important to minimize the incidence of ineligible cases to improve the quality of clinical trials. To determine factors which may influence the incidence of ineligible cases, the incidence of and reasons for ineligibility in clinical trials were retrospectively analyzed. METHODS We retrospectively examined the incidence of and reasons for ineligibility for inclusion in eight clinical trials conducted by the Lung Cancer Chemotherapy Study Group of the Japan Clinical Oncology Group and four trials financed by trust funds from a pharmaceutical company. RESULTS In these 12 clinical studies, the incidence of ineligibility was 4.2% (32/762) (range 0-10.6%). Specific factors that might influence the incidence of ineligible cases were then analyzed. There was a significant difference in the incidence of ineligibility between the methods of registration (P 0.05). CONCLUSIONS We conclude that the incidence of ineligible cases in our studies is similar to that in clinical trials published in the Journal of Clinical Oncology. Central registration systems are useful for checking for ineligibility, and to increase the quality of clinical trials.

Patients with testicular germ cell tumors who have disease-free remission for more than 2 years are usually considered to be cured of their disease. This report describes a case of a germ cell tumor recurring 12 years after initial diagnosis and its treatment in a 35-year-old man who developed a retroperitoneal mass adhering to the abdominal aorta with a bout of severe colic in the left flank. Although tumor markers were not elevated and histology of the biopsy specimen was initially diagnosed as adenocarcinoma, we finally concluded that the retroperitoneal tumor was teratoma developing as a recurrence of the germ cell tumor for the following reasons: (1) the histology of the specimen was similar to an epithelial component of teratoma found in the tissue resected 12 years before; (2) systemic survey failed to detect any other primary site; (3) the young age of this patient was consistent with germ cell tumor rather than adenocarcinoma; and (4) the retroperitoneum is the most frequent site of late recurrences of testicular cancer. He was treated successfully with combination chemotherapy of cisplatin, etoposide and bleomycin followed by surgery. It is important to differentiate this treatable disease from metastasis from an unknown primary, because the latter responds poorly to therapy and survival is usually short.

Genetic alterations in exons 5-8 of the p53 gene, determined by single-strand conformation polymorphism and sequencing analyses, and the clinicopathological characteristics of 108 patients with non-small cell lung cancer were compared. Mutations in this gene were found in 37 of the 108 patients (34%): in 30% (23/76) of those with adenocarcinomas, 46% (12/26) of those with squamous cell, 33% (1/3) of those with large cell and 33% (1/3) of those with adenosquamous carcinomas. No associations between the incidence of p53 mutations and the histological or cytological subtypes of adenocarcinomas were found. The analysis of types of mutations, however, showed that GC transversion was relatively common in papillary and clara subtypes, whereas it accounted for only 17% at most of p53 mutations in tubular and bronchial surface epithelial cell subtypes of adenocarcinomas. Univariate analyses revealed that large tumor size, high nodal stage and positive vascular invasion of non-small cell lung cancers, and high nodal stage and high-grade nuclear atypia of adenocarcinomas were associated significantly with p53 mutations. Multivariate analyses showed that the tumor sizes of non-small cell lung cancer correlated with p53 mutations with marginal significance (P = 0.099) whereas nuclear atypia of adenocarcinomas correlated significantly (P = 0.028). No differences between the overall or relapse-free survival rates of patients with and without p53 mutations in non-small cell lung cancers or adenocarcinomas were found. These findings indicate that p53 mutations in adenocarcinomas of the lung are associated with the malignant phenotype of tumor cells, but not with patient survival.

Between January 1985 and August 1991, 159 patients with small cell lung cancer received first-line chemotherapy and 123 (77%) were responders. Of these, 88 relapsed, the remainder having died of other or unknown diseases or being alive without carrying cancer. The relapsed patients were examined to evaluate the outcome of the treatment for relapsed small cell lung cancer and to identify the factors that would contribute to the response rates and the survival durations. Forty-eight of 88 relapsed patients received second-line chemotherapy. Of the 48, 3 were evaluated as showing a complete response, 13 as partial response, 9 as no change, 15 as progressive disease and 8 as not evaluable. The response rate was 33% (95% confidence interval 20.4-48.4%). The median survival time was 146 days. The duration and rate of response in first-line chemotherapy affected the response rates of the second-line chemotherapy, but without statistical significance (P = 0.058 and 0.067 respectively). Increased response duration, time off chemotherapy and previous response to first-line chemotherapy all had a positive effect on the survival times (P < 0.01). Relapsed small cell lung cancer still shows a response to second-line chemotherapy without lessening survival time, and thus clinical trials of new drugs or combination chemotherapeutic regimens for relapsed small cell lung cancer cases would be reasonably justified. Randomized comparative studies are warranted for determining the benefits of second-line chemotherapy for relapsed small cell lung cancer cases.

We studied the role of dexamethasone (DEX) administered on day 1 in controlling cisplatin-induced delayed emesis. Forty patients were randomly allocated to receive either granisetron (GRN) and DEX on day 1, or the same dose of GRN alone. On days 2-5, all the patients received metoclopramide and DEX. They were crossed over to the other antiemetic regimen with their second course of chemotherapy. Thirty-one patients were evaluable for efficacy. The mean visual analogue scale scores for nausea on days 1 and 2 were 9.1 and 18.8 mm for GRN and DEX, and 16.3 and 28.5 mm for GRN alone, respectively (P