Hiroshi Takita

The changing histopathology of lung cancer: a review of 1682 cases.

We have reviewed the histopathology of lung cancer patients seen over the past 13 years at RPMI. Assessment of this data indicates that adenocarcinoma is becoming progressively more prevalent as related to the other forms of lung cancer. Factors which in part may account for this increased prevalence are: 1) changes in criteria for reading histopathology of lung cancer, particularly since 1967; 2) the increased incidence of lung cancer among the female population who have a propensity for adenocarcinoma; and 3) occupational and environmental factors. In 1974 adenocarcinoma for the first time became the most prevalent type of lung cancer at RPMI. Whatever the reason, if our data are truly representative of a national trend, adenocarcinoma will soon become the most prevalent type of lung cancer in the United States. This fact may result in an increasing death rate since the present 18‐month survival rate for adenocarcinoma is substantially less than for squamous cell carcinoma, which has in the past been the prevalent form of the disease. As the smoking habits of women more closely approximate those of men, we expect that the incidence and mortality of lung cancer will prove to be quite similar in both sexes.

Phase I clinical trial of recombinant human tumor necrosis factor

SummaryA phase I and pharmacokinetic study of recombinant tumor necrosis factor (rH-TNF Asahi) was carried out in 29 patients, who received a total of 72 courses with doses ranging from 1 to 48x104 units/m2. Drug was given as 1-h i. v. infusions. Acute toxicities, taking the form of fever, chills, tachycardia, hypertension, peripheral cyanosis, nausea and vomiting, headache, chest tightness, low back pain, diarrhea and shortness of breath, were seen, but were not dose-limiting or dose-related. Some early rise in SGOT, without any change in serum bilirubin, was noted at the highest doses. Eosinophilia, monocytosis, mild hypocalcemia and an increase in fibrin degradation products were seen in a few patients. The dose-limiting toxicity was hypotension, which occurred after the end of the drug infusion and was seen in all 5 patients treated at the highest dose. There was no mortality or long-term morbidity. There were no responses. Pharmacokinetic studies indicated a rapid plasma clearnance and a short plasma half-life, generally less than 0.5 h.

Identification of genes differentially over-expressed in lung squamous cell carcinoma using combination of cDNA subtraction and microarray analysis.

In order to develop effective vaccine products against human cancer, we are interested in identifying genes over-expressed in tumor cells. Through a combination of cDNA library subtraction and microarray technology, we identified seventeen genes preferentially expressed in lung squamous cell carcinoma, including four novel genes. To date, expression profiles of these genes were confirmed by Northern and/or real-time analysis, and several genes were also found to be expressed in head and neck squamous tumors. Thus, these combined methods represent a high throughput approach for identifying tumor specific genes. Furthermore, the report of characterization on these genes will allow them to be exploited for their diagnostic, prognostic, and therapeutic potentials including immunotherapy and antibody based anticancer therapy.

Operation and photodynamic therapy for pleural mesothelioma: 6-year follow-up

BACKGROUND Conventional therapy for pleural mesothelioma has met with disappointing results. METHODS From 1991 to 1996, 40 patients with malignant pleural mesothelioma were treated with surgical resection followed by immediate intracavitary photodynamic therapy. RESULTS The series included 9 women and 31 men with a mean age of 60 years. Morbidity and treatment-related mortality rates for the entire series, pleurectomy, and extrapleural pneumonectomy were 45% and 7.5%, 39% and 3.6%, and 71% and 28.6%, respectively. Median survival and the estimated 2-year survival rate for the entire series, stages I and II patients (n = 13), and stages III and IV patients (n = 24) were 15 months and 23%, 36 months and 61%, and 10 months and 0%, respectively. Multivariate analysis identified stage, length of hospital stay, photodynamic therapy dose, and nodal status as independent prognostic indicators for survival. CONCLUSIONS Surgical intervention and photodynamic therapy offer good survival results in patients with stage I or II pleural mesothelioma. For patients in stage III or IV, better treatment modalities need to be developed. Improvements in early detection and preoperative staging are necessary for proper patient selection for treatment.

Immunologic impairment in bronchogenic carcinoma: A study of lymphocyte response to phytohemagglutinin

The in vitro lymphocyte response to phytohemagglutinin (PHA) was studied in 44 patients with bronchogenic carcinoma. The PHA responses of these patients varied greatly, with a mean which was significantly depressed as compared to that of normal individuals (p < 0.001). The lymphocyte response to PHA was markedly impaired in most patients with inoperable (late stage) disease, as compared to those with resectable tumors (p < 0.05). There may be a correlation between lymphocyte reactivity and survival with bronchogenic carcinoma.

The surgical management of multiple lung metastases.

From 1970 to June, 1976, 56 patients who had multiple metastatic tumors of the lung were treated by lung resection. Most of the bilateral lung lesions were removed through a median sternotomy so as to avoid staged bilateral thoracotomy. The surgical mortality was 1.8%. A total of 26 patients are alive at 7 to 69 months (estimated median survival, 20.7 months). Patients with tumor doubling time of less than 40 days had lower survival results (median, 9.5 months), compared to patients with tumor doubling time of more than 40 days (median not yet reached). The type of primary tumor, tumor-free interval, number of lesions removed, and presence of unilateral as opposed to bilateral lung metastases did not seem to affect the therapeutic results.

A phase I clinical trial of recombinant human tumor necrosis factor given daily for five days.

SummaryA phase I trial of human recombinant tumor necrosis factor (rH-TNF) has been carried out in patients with advanced solid tumors. Sixty-six courses of the drug were given by 1 h IV infusion, daily for 5 days to 33 patients at doses of 5, 10, 20, 30, 45, 60, and 80x104 U/m2/day. All patients received isotonic saline (up to 21/day) and either indomethacin or ketoprofen. Acute toxicity resembled that seen with the phase I study of a single dose (5). Dose limiting toxicity was acute, rapidly reversible, hepatic dysfunction and hypotension. Hypertension during drug infusion and dyspnea were marked in some patients. There was one complete and one minor response, both in patients with renal cell carcinoma. The dose of 80x104 U/m2/day x5 was poorly tolerated and the recommended starting dose for phase II studies is 60x104 U/m2/day x5. Caution is recommended in treating patients with pre-existing hepatic function abnormalities, hypertension, hypotension or significant obstructive airway disease.

Phase II study—intra-arterial bcnu therapy for metastatic brain tumors

Thirty‐one patients with metastatic brain tumors (MBT) from lung cancer and ten patients with MBT from melanoma received BCNU, 100 mg/m2, every four weeks by intracarotid and/or vertebral artery infusion into each involved site. Twenty‐five patients with lung cancer and all melanoma patients are currently evaluable. Twelve patients with lung cancer had complete and partial responses lasting from 1 to 14 months. Four of them with the histologic diagnosis of small cell carcinoma, one with large cell carcinoma and one with squamous cell carcinoma showed complete responses. None of the patients with melanoma MBT experienced any response. All of the patients had periorbital erythralgia and/or occipital pain during the infusion. Four patients manifested mild focal seizures during the infusion or 6 to 24 hours after the treatment. Transient confusion with disorientation was observed in two patients 4 and 24 hours, respectively, after a BCNU infusion. Two patients developed reversible thrombocytopenia after the fifth course of the IA chemotherapy. Median survival of patients with MBT from lung carcinoma was 4 months, with two of them still alive at 10 and 14 months, respectively. Only one patient of the 25 with lung carcinoma died from MBT. Failure to control the primary disease resulted in the deaths of a vast majority of the patients.

Results of surgical resection of pulmonary metastases of squamous cell carcinoma of the head and neck

In this retrospective review of 58 patients (12 females and 46 males) with pulmonary metastases of squamous cell carcinoma of the head and neck treated between January 1, 1970, and December 31, 1989, we evaluated their clinical courses and analyzed the outcomes of those who underwent pulmonary resection. For the entire group of patients, factors predictive of survival in those patients with a diagnosis of pulmonary metastases included pulmonary resection of metastases (p = 0.0001), locoregional control of the head and neck primary tumor at the time of diagnosis of pulmonary metastases (p = 0.007), TNM stage of the head and neck primary tumor (p = 0.02), a single nodule seen on the chest radiograph (p = 0.02), and disease-free interval (DFI) from the primary tumor of the head and neck of 2 years or more (p = 0.05). Twenty-four of 58 patients underwent thoracotomy for resection of metastases. Four (17%) were found to have a second primary tumor of the lung. Of the 20 remaining patients who underwent explorative surgery for possible pulmonary resection, 18 (90%) underwent complete resection of all malignant disease with an estimated 5-year survival of 29%. In these patients, a DFI of less than 1 year was associated with a 5-year survival rate of 0%, whereas a DFI of 1 to 2 years was associated with a 5-year survival rate of 43% and a DFI of 2 years or longer had a 5-year survival rate of 33%. The number of malignant pulmonary nodules that were resected ranged from one to five and was not significant in predicting survival (p = 0.19). Of eight patients who underwent the resection of more than one malignant pulmonary nodule, 50% survived 2 years, but none survived 5 years. Resection of a solitary pulmonary metastasis from squamous cell carcinoma of the head and neck resulted in long-term survival in selected patients. Important prognostic factors included locoregional control of the head and neck primary tumor, the number of nodules seen on chest radiograph, the TNM stage of the primary tumor, and the DFI from the head and neck primary tumor. The value of resection in patients with more than one malignant pulmonary nodule remains to be defined for this group of patients.

Bronchogenic carcinoma in patients under age 40.

Eighty-nine patients aged 19 to 39 years were treated for bronchogenic carcinoma at Roswell Park Memorial Institute between 1973 and 1983. The male to female ratio was 1.6:1. The vast majority of patients were habitual cigarette smokers. Forty-four patients (49%) had adenocarcinoma or bronchoalveolar cell carcinoma. Twenty-seven (30%) had large cell undifferentiated carcinoma. Nine (10%) had small cell carcinoma and 6 (7%), squamous cell carcinoma. At the time of diagnosis, 2 patients (2%) had stage I disease, 3 (3%) had stage II disease, 30 (34%) had stage IIIA disease, 28 (32%) had stage IIIB disease, and 26 (29%) had stage IV disease. Only 3 patients survive. Median survival of all patients was 7.5 months. Median survival of patients whose tumor was surgically resected was 17.5 months. Advanced stage of disease at the time of diagnosis characterized this group of young patients with primary cancer of the lung. The brief duration of symptoms and the poor survival suggest this is a more aggressive tumor in younger patients than in older patients.