Impact of preoperative bimodality induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer.

PURPOSE: The objective of this prospective study was to assess the feasibility, toxicity, and efficacy of an intensive trimodality approach in stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-four patients with NSCLC and biopsy-proven N2 nodes (IIIA; n = 25) or N3 nodes or T4 lesions (IIIB; n = 29) were administered two initial cycles of ifosfamide, carboplatin, and etoposide; subsequent radiotherapy (45 Gy, twice-daily 1.5 Gy) with concurrent carboplatin and vindesine; and surgery if the patient's disease was resectable or conventional radiotherapy (16 Gy, 2 Gy/d) if the patient's disease was not resectable or incompletely resectable. RESULTS: Thirty-seven patients (69%) responded to preoperative induction. Forty of 54 patients (74%) had disease that was resectable, with 34 (63%) complete resections (R0). A substantial pathologic response (tumor regression [TR] > 90%) was achieved in 27 of 54 patients (50%) and is revealed as an independent predictor for long-term survival after surgery. Five treatment-related deaths (9%) occurred. With a median follow-up period of 44 months, calculated survival rates at 3 years were 35% for patients with stage IIIA disease, 26% for patients with stage IIIB disease, and 56% for patients with R0 disease and TR > 90%. CONCLUSION: This trimodality approach is feasible and results in encouraging 3-year survival rates in prognostically unfavorable patients with stage III NSCLC. Patients experiencing a 90% degree of pathologic TR were most likely to achieve long-term survival.

Grading of tumor regression in non-small cell lung cancer : morphology and prognosis.

OBJECTIVE: Different types of multimodality therapy, including chemoradiotherapy and surgery, increasingly are being used for the treatment of patients with locally advanced non-small cell lung cancer (NSCLC; stages IIIA and IIIB). In this context, the applicability of a morphologic regression grading and its prognostic value were investigated. PATIENTS AND METHODS: In a multicenter phase II trial, 54 patients with locally advanced NSCLC received neoadjuvant bimodality treatment (ie, two cycles of ifosfamide, carboplatin, and etoposide, followed by twice-daily radiation up to 45 Gy with simultaneous administration of carboplatin and vindesine). Forty patients underwent resections. Using the corresponding resection specimens of the primary and regional lymph nodes, the following regression grading was established: grade I, no regression or only spontaneous tumor regression; grade II, morphologic evidence of therapy-induced tumor regression with at least 10% (grade IIa) or < 10% (grade IIb) vital tumor tissue; and grade III, complete tumor regression with no evidence of vital tumor tissue. Regression grading then was correlated with the survival time. RESULTS: Three tumors were classified as regression grade I, 10 were classified as regression grade IIa, 20 were classified as regression grade IIb, and 7 were classified as regression grade III. Patients with tumors of regression grades IIb or III showed significantly longer survival times than those with tumors of regression grades I or IIa (median survival time, 36 vs 14 months, respectively; 3-year survival rate, 52% vs 9%, respectively; p = 0.02). These survival times were also compared for patients who had undergone complete resection (median survival time, not reached vs 23 months, respectively; 3-year survival rate, 56% vs 11%, respectively; p = 0.03). The presurgical clinical response after patients had received neoadjuvant multimodality therapy had no predictive value in assessing the extent of therapy-induced tumor regression in the resection specimen. CONCLUSIONS: After neoadjuvant therapy of patients with NSCLC, the proposed tumor regression grading was of predictive value for long-term survival. Beyond the achievement of complete tumor resection (R0), a therapy-induced tumor regression of < 10% of vital tumor tissue is pivotal for superior long-term outcomes.

Tumour regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment.

In the scope of a prospective multi-centre study after neoadjuvant combined chemotherapy (carboplatin, ifosfamide, etoposide, vindesine) and radiotherapy (45 Gy) 40 resection specimens of locally advanced non-small-cell lung cancer were analysed in order to establish reproducible pathological/anatomical results of tumour regression. Resection specimens of 28 squamous cell carcinomas and 12 adenocarcinomas were investigated using serial sections of the primary lesion. The mean age of the patients was 57 years. The results were compared to spontaneous regressive changes in a control group of 50 untreated non-small-cell lung cancers. Marked scarry fibrosis in the region of the former primary tumour, concentric foci of fresh tumour necroses and surrounding foam cell clusters with transition into vascular granulation tissue could be established as characteristic features of therapy-induced tumour regression, whereas untreated carcinomas revealed necroses with adjoining vital tumour tissue. Using a three-step regression system, 3 tumours could be classified as grade I (no or only slight tumour regression), 10 tumours as grade IIA (marked but incomplete tumour regression, more than 10% vital tumour tissue), 20 tumours as grade IIB (less than 10% vital tumour tissue) and 7 tumours as grade III (complete tumour regression without vital tumour tissue). After a median follow-up period of 32.3 months in patients with grade IIB or III tumour regression ("responders") the median survival time of 27.9 months was found to be significantly longer than in patients with grade I or IIA tumour regression ("non-responders") with a median survival period of 13.7 months (log-rank test, P = 0.020). The resection specimens analysed, which were obtained 7 weeks (on average) after the end of radiochemotherapy, did not show specific changes due to preoperative therapy, but quite characteristic histological alterations in the former tumour area were registered, which had been induced by combined neoadjuvant radiation and chemotherapy. The grade of therapy-induced tumour regression could be shown to be a significant prognostic factor in non-small-cell lung cancer.

p53 Gene status in relation to ex vivo chemosensitivity of non-small cell lung cancer.

PURPOSE: About 40% of non-small cell lung cancer (NSCLC) patients are candidates for systemic chemotherapy, despite the fact that at diagnosis most NSCLC are usually chemoresistant both in vivo and ex vivo. It is important to develop sufficient methods of prediction of the response to chemotherapy and to find molecular markers that may prognose this response. Therefore, a study on the relationship of p53gene status to the ex vivo chemosensitivity of primary human NSCLC was performed. METHODS: Three drug combinations (carboplatin/etoposide, cyclophosphamide/etoposide/epirubicin, and paclitaxel/carboplatin) were tested in a modified ATP cell viability assay. A group of 28 cases of primary human NSCLC was assessed. RESULTS: Ex vivo chemosensitivity testing showed that tumors with p53 mutations were significantly more resistant to the cyclophosphamide/etoposide/epirubicin regimen than with normal p53 gene ( P = 0.012). However, no correlation was observed for two other treatment regimens. CONCLUSION: Mutations in the p53gene can lead to enhanced chemoresistance, confirming the hypothesis that the p53 gene may serve as a marker of tumor response to treatment in NSCLC. However, the data also illustrate that some additional factors might contribute to drug resistance of the examined tumors.

Lack of squamous cell lung carcinoma in vitro chemosensitivity to various drug regimens in the adenosine triphosphate cell viability chemosensitivity assay.

A pilot study on squamous cell lung carcinoma (LC) chemosensitivity in adenosine triphosphate cell viability chemosensitivity assay (ATP-CVA) was performed. Besides the histological investigation, a modified ATP-CVA was used for the analysis of cancer cell chemosensitivity to four drug regimens, including topotecan, a promising agent for non-small-cell lung cancer (NSCLC) chemotherapy. Results of in vitro chemosensitivity testing showed chemoresistance or only weak response in the predominant amount of tumors.

Analysis of long-term survival in patients with locally advanced non-small cell lung cancer.

Neoadjuvant combined radiochemotherapy followed by definitive tumor resection improved survival in patients with locally advanced non-small cell lung cancer (NSCLC). Fifty-four patients (NSCLC IIIa + IIIb) were treated with combined radiochemotherapy within a phase I/II study. Twenty-six patients had been resected after combined neoadjuvant treatment and this group was evaluated concerning long-term survival. The median survival for patients with stage IIIa tumor was calculated to be 26 months and 13 months for patients with IIIb status. Patients with no viable tumor cells in the mediastinal lymph nodes had a significantly better survival probability than patients with residual microscopic lymph node disease (p=0.038). Patients with no viable tumor cells had a 1-year (2-year) survival rate of 100% (60%) versus 58% (42%) for patients with residual microscopic tumor in the mediastinal nodes. No significant difference between the N1- and the N2-status was seen. Hence, response to neo-adjuvant radiochemotherapy seems to be an additional important prognostic factor in patients with advanced NSCLC.

Thymus carcinoid.

A carcinoid of the thymus was studied by light- and electron-microscopy, immunohistology and flow-cytometry. The tumor showed a ribbon- and festoon-like growth-pattern with foci of necrosis, invasion of vessels and infiltration of mediastinal lymph nodes. The cytoplasma of the tumor-cells contained neuroendocrine granula and immunohistochemistry of ACTH was positive. The tumor-cells were connected by desmosomes, correlating to a pre-keratin positive immunohistology. In flow-cytometry the tumor-cells showed a near haploid DNA aneuploidy which is an extremely rare finding in solid tumors and in the few cases described indicative for treatment resistance.

[Neoadjuvant therapy in non-small cell lung cancer. Prognostic impact of "mediastinal downstaging"]. / Neoadjuvante Therapie des nichtkleinzelligen Lungenkarzinoms. Prognostische Relevanz des "mediastinalen Downstagings"

In the course of a prospective multicenter study, 40 (26 squamous cell and 14 adenocarcinomas) patients with stage IIIA and IIIB non-small cell lung cancer (NSCLC) were submitted to surgery after neoadjuvant radiochemotherapy. Pretherapeutic clinical lymph node status was compared to the lymph node involvement established in the resection specimens. Therapy-induced tumor regression was classified according to a three-step tumor regression grading system. In 29 patients (72.5%) a downward shift in lymph node involvement could be established,whereas in 27.5% ( n=11) pretherapeutic lymph node status was maintained. Of 26 patients with post-therapeutic N0 or N1 status, 21 revealed less than 10% vital tumor tissue in the resection specimens (regression grades IIb or III). Patients with post-therapeutic N0 or N1 lymph node status were found to have a survival benefit compared to patients with N2 lymph node involvement, though this difference was not statistically significant (p=0.27). On the other hand, tumor regression showed a significant correlation to the overall survival period (p=0.02). Thus, therapy-induced tumor regression grading seems to be a more precise method to predict the outcome of the disease.

[The tumorlet carcinoid in bronchiectasis-changed lungs. An example of a multifocal, endocrine tumor]. / Das Tumorletkarzinoid in bronchiektatisch veränderten Lungen. Beispiel eines multifokalen, endokrinen Tumors.

Tumorlets of the lungs are multifocal hyperplasias of endocrine cells which may develop via nodular hyperplasia into peripheral, occasionally also metastatic, carcinoids. They are observed with a particular frequency in bronchiectasis. Resected material obtained from patients with bronchiectasis (4 women, 3 men, mean age 43.5 years, range 19-66 years) were submitted to conventional histological studies employing HE, PAS and van Gieson staining, and also to an immunohistological analysis. Conventional staining sufficed to identify endocrine cell proliferations in the scarred lung tissue in 3 preparations. An assignment to bronchioles and alveoli with conventional histology was, in view of the extensive scarring of the lung parenchyma, very difficult, but was accomplished with the aid of immunohistological investigation. As a multifocal tumour, the tumourlet suggests itself as a model, employing immunohistochemistry, for studying the formal genesis of neuroendocrine tumours of the lung, since it shows the earliest intra-epithelial neoplastic transformations through in situ tumour to carcinoid.

Morphological hazards of deuterium oxide as a cardioplegic agent.

To determine the cardio-protective effect of heavy water on the ischemic myocardium, a thoracotomy was performed on 18 mongrel dogs. The animals were connected to the extracorporeal circulation in a standardized experimental procedure. Following total cardiopulmonary bypass, 2,000 ml of a standard cardioplegic solution (LK 352) was infused at the aortic root of 10 dogs, which served as controls (group I), and the same solution containing 20% of 99.8% deuterium oxide was given at the aortic root of the remaining animals (group II). At the end of 60 minutes of ischemia, 1,000 ml of the solutions was again administered at the aortic root of the corresponding animals. Myocardial biopsies were taken from the apex of the left ventricle of each dog before cardiopulmonary bypass, immediately after the infusion of the cardioplegic solutions, following 90 minutes of ischemia, and after 30 minutes of reperfusion, and studied ultrastructurally. Whereas the ultrastructure of the myocardium of group I was well preserved at the end of the ischemic period, deuterium-oxide-treated hearts showed extensive focal and global myofilamentolysis and lysis of whole myocytes. Structural damage to glycogen, nuclear chromatin dispersal, severe intracellular edema and complete rupture of the intercalated discs were characteristic findings. At the end of ischemia, all the hearts of group I could be resuscitated. During the ischemia, all the hearts of group II developed into stone hearts. Biochemical studies on a second series showed a higher ATP depletion and a significantly higher lactate accumulation in group II than in group I.(ABSTRACT TRUNCATED AT 250 WORDS)

[Scoring system for indication for operative correction of funnel chest (author's transl)]. / Diagnostiche Kriterien für die Indikation der Trichterbrust-Operation.

Based on 50 consecutive patients whom we operated for funnel chest, we tried to work out the indications for operative correction by developing a scoring system. In this scoring system we considered not only the depth of of the funnel respectively the depth of the impression, but also all the other disturbances of the organs of the chest resulting from the malformation. The possible accompanying deformities of the thoracic cage were taken into account too. The scoring system demands a more stringent indication.

Multicentric metachronous central carcinoid of the lung: a case report.

A 51-year-old female patient with metachronous multiple central typical carcinoid represents the subject of the case discussed. The patient underwent bronchoplastic surgery in order to remove the first carcinoid tumor twelve years ago. She was readmitted to the hospital following a long tumor-free period of disease when two new central carcinoids were diagnosed. The carcinoids were first treated by rigid bronchoscopical removal of the tumors followed by laser coagulation of the bases. Bronchoscopic follow-up one year after the treatment did not reveal any pathological findings.

[Multifocal bronchial cancer]. / Das multilokuläre Bronchialkarzinom.

Since the entire surface of the bronchial mucosa is exposed to carcinogenic stimuli, the possibility of developing multiple primary lung carcinomas must be discussed. Multiple primary lung carcinomas do not necessarily occur simultaneously (synchronous), they can also develop successively (metachronous). They can be localized ipsilateral as well as contralateral, and histologically they have an identical or different character. In our study of 612 patients with bronchogenic carcinoma we found 18 patients (2.9%) to have a synchronous multiple primary carcinoma. The growing clinical relevance of the diagnosis of the multiple primary bronchogenic carcinoma--which is certainly diagnosed to rarely--and the distinction from metastases will be discussed.

The influence of non-coronary collateral blood supply on the electively arrested heart during ischemia and reperfusion.

To study the influence of non-coronary collateral blood circulation (NCCBC) on the integrity of the ischemic myocardium a right-sided thoracotomy was performed on 15 anesthetized dogs. Following a total cardiopulmonary bypass (CPB), ventricular fibrillation was induced, during which 2,000 ml calcium-free cardioplegic solution LK 352 was given at the aortic root over an 8-10 min period. Precautions were taken to prevent retrograde blood flow into the coronary system via the coronary sinus. After 90 min of ischemia, ten of the dog hearts were reperfused with systemic blood for the next 30 min. Transmural biopsies were taken from the apex of the left ventricle at the following intervals: (1) before CPB, (2) immediately after the infusion of LK 352, (3) following 90 min of ischemia, (4) after 5 min, (5) after 15 min, and finally (6) after 30 min of reperfusion and were then studied ultrastructurally. The presence of NCCBC was documented by the observation of erythrocyte-filled blood vessels in the biopsies corresponding to nos. 2 and 3 of the above. To assess the degree of ischemic injury and the extent of myocardial recovery during reperfusion, a scoring system based on a semiquantitative assessment of the characteristic morphological changes was used. The average result of the separately assessed subendo- and subepicardial layers represented the score, which was plotted on the ischemic injury and the recovery scale, thus making a direct comparison of the hearts possible. All the hearts generously supplied with blood via extracoronary routes during ischemia showed minimal and reversible ischemic injuries. They recovered more quickly and more completely following reperfusion than those hearts without NCCBC. From these results we conclude that despite its warming-up effect on the myocardium and its tendency to wash out the cardioplegic solution, the NCCBC generally protects the myocardium from serious ischemic injuries and shortens the period of recuperation during the reperfusion.

[beta-Thromboglobulin in plasma in patients with heart-valve diseases and with prosthetic heart valves (author's transl)]. / beta-Tromboglobnulin im Plasma bei Herzklappenfehlern und nach Herzklappenersatz.

In each 50 patients with rheumatic heart valve diseases and after implantation of prosthetic heart valves and in 20 patients with bioprostheses, beta-thromboglobulin (beta-TG) in plasma was determined. In all cases beta-TG was significantly elevated above the normal range. The levels of beta-TG lay in patients with bioprostheses lower than in the other groups. Bioprostheses are less damaging the thrombocytes than prosthetic heart valves.

[Problems of sigmoid diverticulitis in the female and its differential diagnostic delineation from the left-sided adnexal tumor]. / Die Problematik der Sigmadivertikulitis bei der Frau und ihre differentialdiagnostische Abgrenzung zum linksseitigen Adnextumor.

In the last three years 42 patients with complicated diverticulitis were treated surgically. There were 18 women in all. Nine of these women were believed to have gynecologic disease because of the palbable pelvic tumor and were hospitalized at the Gynecologic Department. 2 patients underwent an exploratory operation by gynecologic surgeons based upon preoperative diagnosis of ovarian mass. The diagnosis at operation in all two cases was perforated sigmoid diverticulitis. Another three of the nine patients had initally emergency exploratory operations by gynecologic surgeons based upon diagnosis of pelvic mass. Also here the diagnosis at operations were perforated sigmoid diverticulitis and they underwent emergency primary resection of the perforated sigmoid by surgeons. In all the cases of complicated diverticulitis the surgical proceature was the primary resection; the anterior resection was combined with a temporare transverse colostomy.--Diverticulitis is an important differential diagnosis of a left pelvic tumor in women with or without clinical and laboratory indications of infections and history of diverticulitis.

[Neoadjuvant radiochemotherapy in locally advanced non-small cell bronchial carcinoma. Initial results of a prospective multicenter study]. / Neoadjuvante Radiochemotherapie beim lokal fortgeschrittenen nichtkleinzelligen Bronchialkarzinom. Erste Ergebnisse einer multizentrischen prospektiven Studie.

PURPOSE: In the last years new encouraging methods in the therapy of bronchial carcinoma have been elaborated. The early stages of bronchial carcinoma are still a domain of operative treatment. The long-term results of surgical treatment for locally advanced disease are considered to be unfavourable. Multimodal treatment concepts with simultaneous or consecutive application of radio-chemotherapy followed by surgical resection seem to reveal improved possibilities of therapy. PATIENTS AND METHODS: General treatment consists of 2 blocks of neoadjuvant chemotherapy with carboplatin, ifosfamide and etoposide, followed by a third course, consisting of carboplatin and vindesine. Simultaneously with the third course a hyperfractionated, accelerated radiotherapy with a single dose of 1.5 Gy 10 times per week is applied. The total dose is 45 Gy in 3 weeks, given at least to the 80% isodose. After restaging, tumor resection is carried out. Patients without tumor are randomized for prophylactic brain irradiation. RESULTS: From January 1992 up to 1.10.1993 25 patients have been treated in accordance to the study. All tumors were locally advanced (stage IIIa and IIIb). Until 1.10.1993 4 patients died, 2 of them certainly related to the tumor. Thirteen patients have been resected after neoadjuvant treatment. In 11 of these cases a R0-, and in 2 cases a R1 resection has been carried out. Tumor cells have been found only in 5 histologies. The hematotoxic side effects under competing RTX/CTX seemed to be unproblematical (RTOG/grade II). Problems occurred with 4 cases of serious esophagitis (RTOG/grade III to IV) and 2 cases of pneumonitis with 1 case ending lethally. CONCLUSION: Preliminary results of our study show the feasibility of multimodal treatment. A favourable 1-year survival rate after aggressive multimodal therapy and a high resection rate in previously unresectable patients could be demonstrated.

[Value and reason for routine rectosigmoidoscopy (author's transl)]. / Wert und Sinn einer Routine-Rektosigmoidoskopie.

Routine rectosigmoidoscopy was undertaken in 700 patients under surgical treatment for disease in other parts of the body. Pathological changes were found in 39 patients (5.6%): 24 with adenomatous polyps, 5 with adenopapillary polyps, 7 with infiltrating growing "carcinomatous" polyps without involvement of the muscularis mucosae, and three with carcinoma. The polyps were removed with an electric loop or haemoclip in 28, by transanal submucous excision in eight. One of the carcinoma cases was treated by resection, the other two by abdominoperineal rectal resection. The results indicate that routine rectosigmoidoscopy is of value.