Evaluation of the combination of endothelin receptor antagonists (ERA) and phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension (PAH) in pathologic human pulmonary arteries in an ex-vivo organ bath model.

PURPOSE: Medical combination therapy of pulmonary arterial hypertension (PAH) may alleviate the drawbacks of monotherapy by avoiding drug tolerance and by increasing effectiveness, as shown by the combination of ambrisentan and tadalafil (AMBITION trial). The present ex-vivo study evaluated the combination of the endothelin receptor antagonists (ERA) macitentan and bosentan with the phosphodiesterase-5 (PDE-5) inhibitor vardenafil in pulmonary arteries from patients suffering from terminal lung disease as a model of PAH. METHODS: Segments of the pulmonary vessels were excised from resected lungs of patients requiring lung transplantation (LTX). Contraction of pulmonary arteries (PA) was elicited by consecutive dose-response curves of endothelin-1 (ET-1) followed by norepinephrine (NE) to allow inhibition by different pathways. Forces were measured isometrically in an organ bath in the presence and absence of ERA and PDE-5 inhibitors and their combination. RESULTS: PA of 38 patients were examined between October 2016 and November 2019. Bosentan (1E-7 M) and macitentan (1E-8 M, 3E-8 M, 1E-7 M) inhibited ET-1 induced contractions, whereas vardenafil (1E-6 M, 3E-6 M, 1E-5 M) inhibited only the NE induced part of the contractions. Vardenafil enhanced bosentan-induced inhibition of vasoconstriction in a dose-dependent fashion. Combination effects exceeded single bosentan at 3E-6 M and 1E-5 M vardenafil, and they exceeded single vardenafil at the lower vardenafil concentrations. Macitentan showed a more pronounced inhibition than bosentan regardless of the lower concentrations. Accordingly, combination effects with vardenafil resembled those of macitentan alone. CONCLUSIONS: Macitentan and bosentan were potent antagonists of vasoconstriction in PA of LTX patients. The benefit of drug combinations was demonstrated at selected concentrations only owing to a narrow therapeutic range of vardenafil in this ex-vivo model. These results suggest the utility of drug combinations other than the established pair of ambrisentan and tadalafil in PAH treatment but also make a case for a further assessment of vasodilator properties of drugs complementing ERA.

Association of Higher CD4+ CD25high CD127low , FoxP3+ , and IL-2+ T Cell Frequencies Early After Lung Transplantation With Less Chronic Lung Allograft Dysfunction at Two Years.

Regulatory T cells (Treg) can regulate alloantigens and may counteract chronic lung allograft dysfunction (CLAD) in lung transplantation. We analyzed Treg in peripheral blood prospectively and correlated percentages of subpopulations with the incidence of CLAD at 2 years. Among lung-transplanted patients between January 2009 and July 2011, only patients with sufficient Treg measurements were included into the study. Tregs were measured immediately before lung transplantation, at 3 weeks and 3, 6, 12, and 24 months after transplantation and were defined as CD4+ CD25high T cells and further analyzed for CTLA4, CD127, FoxP3, and IL-2 expressions. Between January 2009 and July 2011, 264 patients were transplanted at our institution. Among the 138 (52%) patients included into the study, 31 (22%) developed CLAD within 2 years after transplantation. As soon as 3 weeks after lung transplantation, a statistically significant positive association was detected between Treg frequencies and later absence of CLAD. At the multivariate analysis, increasing frequencies of CD4+ CD25high CD127low , CD4+ CD25high FoxP3+ and CD4+ CD25high IL-2+ T cells at 3 weeks after lung transplantation emerged as protective factors against development of CLAD at 2 years. In conclusion, higher frequencies of specific Treg subpopulations early after lung transplantation are protective against CLAD development.

Detection and quantification of epithelial progenitor cell populations in human healthy and IPF lungs.

BACKGROUND: In the human lung, epithelial progenitor cells in the airways give rise to the differentiated pseudostratified airway epithelium. In mice, emerging evidence confers a progenitor function to cytokeratin 5 (KRT5(+)) or cytokeratin 14 (KRT14(+))-positive basal cells of the airway epithelium. Little is known, however, about the distribution of progenitor subpopulations in the human lung, particularly about aberrant epithelial differentiation in lung disease, such as idiopathic pulmonary fibrosis (IPF). METHODS: Here, we used multi-color immunofluorescence analysis to detect and quantify the distribution of airway epithelial progenitor subpopulations in human lungs obtained from healthy donors or IPF patients. RESULTS: In lungs from both, healthy donors and IPF patients, we detected KRT5(+)KRT14(-), KRT5(-)KRT14(+) and KRT5(+)KRT14(+) populations in the proximal airways. KRT14(+) cells, however, were absent in the distal airways of healthy lungs. In IPF, we detected a dramatic increase in the amount of KRT5(+) cells and the emergence of a frequent KRT5(+)KRT14(+) epithelial population, in particular in distal airways and alveolar regions. While the KRT14(-) progenitor population exhibited signs of proper epithelial differentiation, as evidenced by co-staining with pro-SPC, aquaporin 5, CC10, or MUC5B, the KRT14(+) cell population did not co-stain with bronchial/alveolar differentiation markers in IPF. CONCLUSIONS: We provide, for the first time, a quantitative profile of the distribution of epithelial progenitor populations in human lungs. We show compelling evidence for dysregulation and aberrant differentiation of these populations in IPF.

Bronchiolitis obliterans syndrome due to donor-specific HLA-antibodies.

Chronic lung allograft dysfunction (CLAD) is a limiting factor for long-term survival in lung transplant recipients. Donor-specific human leukocyte antigen (HLA)-antibodies (DSA) have been suggested as potential risk factors for CLAD. However, their impact on clinical outcome following lung transplantation remains controversial. We performed a single-center study of 120 lung transplant recipients transplanted between 2006 and 2011. Patient sera were investigated before and after transplantation. The sera were screened by means of Luminex(®) technology (Luminex Inc., Austin, TX, USA) for IgG-HLA-class I and class II antibodies (ab). Using single antigen beads, DSA were identified and correlated retrospectively with clinical parameters. After transplantation 39 out of 120 patients (32.5%) were positive for HLA-ab. The incidence of de novo DSA formation was 27 of 120 patients (22.5%). Eleven of 27 (41%) of de novo DSA-positive patients developed BOS compared to 13 of 93 (14%) DSA-negative patients (p = 0.002). Furthermore, the generation of de novo DSA was independently associated with the development of BOS in multivariable analysis [hazard ration (HR) 2.5, 95% confidence interval (CI) 1.0-6.08; p = 0.046). Our results indicate that de novo DSA are associated with the development of BOS after lung transplantation. Monitoring of HLA-ab after transplantation is useful for identifying high-risk patients and offers an opportunity for early therapeutic intervention.

[Pulmonary Tuberculosis--Is Surgery still Necessary?]. / Pulmonale Tuberkulose--ist die Chirurgie noch notwendig?

BACKGROUND: Tuberculosis is still one of the most common infectious diseases along with HIV and malaria and therefore represents a serious problem in the health sector. Due to immigrants and refugees, the disease is also present in Europe. The global increase of multidrug resistant tuberculosis leads to a highly significant and current importance of sufficient therapeutic measures. In recent years, this fact has led to a reevaluation of surgical therapy in the context of an interdisciplinary and multimodal treatment of multidrug resistant tuberculosis. In addition, despite an effective treatment of drug sensitive tuberculosis with antibiotics, there are still indications for surgery in the treatment of tuberculosis. Beside massive hemoptysis as an emergency indication for surgical intervention, secondary complications of tuberculosis such as aspergilloma, chronic hemoptysis, pneumothorax, bronchopleural fistula and destroyed lung remain indications for surgery. CONCLUSION: The indication for surgery should always be made in a multimodal therapeutic approach by an interdisciplinary team, taking patient age and functional analysis into account. Effective antibiotic therapy should be performed before and after surgery in order to achieve a sustained treatment success.

Resection of pulmonary metastases from colon and rectal cancer: factors to predict survival differ regarding to the origin of the primary tumor.

BACKGROUND: The purpose of the present study was to determine differences in prognostic factors for survival of patients with pulmonary metastases resected in curative intent from colon or rectum cancer. METHODS: Between 1980 and 2006, prognostic factors after resection of pulmonary metastases in 171 patients with primary rectum or colon tumor were evaluated. Survival of patients after surgical metastasectomy was compared with that of patients receiving standard chemotherapy by matched-pair analysis. RESULTS: Median survival after pulmonary resection was 35.2 months (confidence interval 27.3-43.2). One-, 3-, and 5-year survival for patients following R0 resection was 88.8, 52.1, and 32.9 % respectively. Complete metastasectomy (R0), UICC stage of the primary tumor, pleural infiltration, and hilar or mediastinal lymph node metastases are independent prognostic factors for survival. Matched-pair analysis confirmed that pulmonary metastasectomy significantly improved survival. Although no difference in survival for patients with pulmonary metastases from lower rectal compared to upper rectal or colon cancer was observed, factors to predict survival are different for patients with lower and middle rectal cancer (R0, mediastinal and/or hilar lymph nodes, gender, UICC stage) compared with patients with upper rectal or colon cancer (R0, number of metastases). CONCLUSIONS: Our results indicate that distinct prognostic factors exist for patients with pulmonary metastases from lower rectal compared with upper rectal or colon cancer. This supports the notion that colorectal cancer should not be considered as a single-tumor entity. Metastasectomy, especially after complete resection resulted in a dramatic improvement of survival compared with patients treated with chemotherapy alone.

Usefulness of exhaled nitric oxide to guide risk stratification for bronchiolitis obliterans syndrome after lung transplantation.

The aim of this study was to assess fractional exhaled nitric oxide (FeNO) for the early diagnosis of bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTX). 611 FeNO measurements in 166 consecutive patients were classified depending on BOS stage at the time of assessment and course during minimum follow-up of 3 months: (1) stable non-BOS, (2) unstable non-BOS, (3) stable BOS and (4) unstable BOS. Unstable course was defined as new onset of BOS≥1 or progression of BOS. FeNO before unstable course was significantly increased in comparison to their stable counterparts (non-BOS: 28.9 ± 1.2 ppb, n = 40 vs. 16.4 ± 0.8 ppb, n = 131 and BOS: 32.5 ± 1.3 ppb, n = 35 vs. 15.3 ± 0.8 ppb, n = 26; p = 0.01 each). Average time from FeNO reading to onset of deterioration was 117 ± 9 days in non-BOS and 136 ± 9 days in BOS patients. The positive and negative predictive value of FeNO >20 ppb for BOS was 69.0% and 96.9%, respectively. Serial measurements demonstrated significantly lower mean individual variation in stable recipients as compared to stable patients switching to unstable course (3.2 ± 0.3 ppb vs. 12.7 ± 1.4 ppb, p = 0.02). In particular, the excellent negative predictive value of persistently low FeNO readings for future BOS make FeNO assessments a useful tool for continuous risk stratification after LTX.

Pre- and post-treatment effect of physostigmine on soman-inhibited human erythrocyte and muscle acetylcholinesterase in vitro.

Standard treatment of organophosphorus (OP) poisoning includes administration of an antimuscarinic (e.g., atropine) and of an oxime-based reactivator. However, successful oxime treatment in soman poisoning is limited due to rapid aging of phosphylated acetylcholinesterase (AChE). Hence, the inability of standard treatment procedures to counteract the effects of soman poisoning resulted in the search for alternative strategies. Recently, results of an in vivo guinea pig study indicated a therapeutic effect of physostigmine given after soman. The present study was performed to investigate a possible pre- and post-treatment effect of physostigmine on soman-inhibited human AChE given at different time intervals before or after perfusion with soman by using a well-established dynamically working in vitro model for real-time analysis of erythrocyte and muscle AChE. The major findings were that prophylactic physostigmine prevented complete inhibition of AChE by soman and resulted in partial spontaneous recovery of the enzyme by de-carbamylation. Physostigmine given as post-treatment resulted in a time-dependent reduction of the protection from soman inhibition and recovery of AChE. Hence, these date indicate that physostigmine given after soman does not protect AChE from irreversible inhibition by the OP and that the observed therapeutic effect of physostigmine in nerve agent poisoning in vivo is probably due to other factors.

[Modern tailored therapy for pleural empyema]. / Stadienadaptierte moderne Therapie des Pleuraempyems.

In spite of the development and widespread avail-ability of modern antibiotics, pleural empyema still represents a serious intrathoracic disease -associated with significant morbidity and mortality. Patients with complicated parapneumonic effusions and empyema have an increased morbidity and mortality due at least in part to inappropriate and delayed management of pleural space infections. Timely diagnosis of pleural empyema and rapid initiation of the appropriate surgical treatment modality represent keystone principles for efficient treatment of thoracic -empyema. Simple drainage, minimally invasive surgical treatment modalities (VATS) and image-guided small-bore catheters in combination with adjunctive fibrinolytic drugs have extended the potential therapeutic arsenal. Individual case management with a flexible selection of the most appropriate treatment modality by experienced thoracic surgeons may lead to improved outcomes. In this context a summary of the most recent opinions and results in thoracic empyema management is outlined in the present review.

[Impact of systematic lymph node dissection in the resection of pulmonary metastases of solid extrapulmonary tumours]. / Bedeutung der systematischen Lymphknotendissektion im Rahmen der Resektion pulmonaler Metastasen solider extrapulmonaler Tumoren.

BACKGROUND: The systematic mediastinal and hilar lymph node dissection for the treatment of pulmonary metastases has, until now, not attracted much attention. A possible advantage of systematic lymph node dissection is an improved staging and a better locoregional tumour control due to resection of tumour micrometastases and the disintegration of lymphatic vessels. Aim of the study was to investigate the impact of mediastinal and hilar lymphnode metastases on the prognosis of the patient. METHODS AND RESULTS: Between 1978 and 2006, 249  patients underwent resection of pulmonary metastases from renal cell (91), colorectal (89), breast (45) and head and neck cancer (24), in combination with a systematic mediastinal and hilar lymphnode dissection. Survival was analysed by the Kaplan-Meier method. Multivariate analysis was performed using Cox regression analysis. Lymph node metastases were histologically demonstrated in 25.3 % of all patients. They did not correlate with the tumour grading and lymph node status of the primary tumour or the number of pulmonary metastases. Patients with lymph node metastases had a significantly shorter median survival than patients without (18 vs. 53  months, p < 0.001). Patients who underwent a systematic mediastinal and hilar lymph node dissection showed a trend to a prolonged survival (39.1 vs. 31.9  months, p = 0.089). CONCLUSION: Mediastinal and hilar lymph node metastases are significantly correlated with decreased survival. Systematic mediastinal and hilar lymphadenectomy provides valuable information for the staging and prognosis of patients with pulmonary metastases of kidney, head and neck, breast and colorectal cancers and may help to distinguish those patients who might profit from a more aggressive surgical therapy or an adjuvant therapy.

The dark side of the moon: impact of moon phases on long-term survival, mortality and morbidity of surgery for lung cancer.

OBJECTIVE: Superstition is common and causes discomfiture or fear, especially in patients who have to undergo surgery for cancer. One superstition is, that moon phases influence surgical outcome. This study was performed to analyse lunar impact on the outcome following lung cancer surgery. METHODS: 2411 patients underwent pulmonary resection for lung cancer in the past 30 years at our institution. Intra- and postoperative complications as well as long-term follow-up data were entered in our lung-cancer database. Factors influencing mortality, morbidity and survival were analyzed. RESULTS: Rate of intra-operative complications as well as rate of post-operative morbidity and mortality was not significantly affected by moon phases. Furthermore, there was no significant impact of the lunar cycle on long-term survival. CONCLUSION: In this study there was no evidence that outcome of surgery for lung cancer is affected by the moon. These results may help the physician to quiet the mind of patients who are somewhat afraid of wrong timing of surgery with respect to the moon phases. However, patients who strongly believe in the impact of moon phase should be taken seriously and correct timing of operations should be conceded to them as long as key-date scheduling doesn't constrict evidence based treatment regimens.

Persistence of de novo donor specific HLA-Antibodies after lung transplantation: a potential marker of decreased patient survival.

The impact of de novo donor-specific anti-HLA antibodies (DSA) on outcomes in lung transplantation is still a matter of debate. We hypothesize that differentiating DSA by persistent and transient appearance may offer an additional risk assessment. The clinical relevance of HLA-antibodies was investigated prospectively in 72 recipients with a median follow-up period of 21 months. The presence of HLA-antibodies was analysed by single antigen bead assay prior to and after (3 weeks, 3, 6, 12 and 18 months) transplantation. In 23 patients (32%) de novo DSA were detected. In 10 of these patients (44%) DSA persisted throughout the follow-up period whereas 13 of these patients (56%) had transient DSA. There was a trend towards lower one-year-survival in DSA positive compared to DSA negative patients (83% versus 94%; p=0.199). Remarkably, patients with persistent DSA had significantly reduced survival (one-year survival 60%) compared with both patients without DSA and those with transient DSA (p=0.005). Persistent DSA represented an independent prognostic factor for reduced overall survival in multivariate analysis (HR 8.3, 95% CI 1.8-37.0; p=0.006). Persistence of DSA during the first year after transplantation seems to be more harmful for lung allograft function than transiently detected DSA at an early stage. This article is protected by copyright. All rights reserved.

The University of Munich lung cancer group database: design, profile of cohort and outcome analysis.

OBJECTIVE: Changes in therapeutic concepts can only be justified by a significant improvement of outcome parameters. Furthermore, detailed statistics of complications are needed to guarantee high quality of treatment. This study describes the new University of Munich Lung Cancer Group Database. METHODS: The MLCG-Database contains all patients who underwent surgery for lung cancer at the Department of Surgery, University of Munich Medical Centre since 1978. Data were database recorded on the patient's ward, or directly imported from other departments performing medical examinations on the patient. Data could be entered online at the time of surgery in the operating room. Relevant information from the Munich Tumour Registry was imported via encrypted data communication. Both epidemiological background and influence of preoperative risk factors on morbidity and mortality as well as on long-term survival were analysed. RESULTS: Median follow-up time was 45 months (1-295 months). Overall 5- and 10-year survival was 36% and 28% respectively. Preoperative risk factors were arterial hypertension in 43% of patients, COPD in 34%, abuse of nicotine in 26% and therapy with corticosteroids in 25%. Surgical procedure consist of lobectomy or bilobectomy in 69%, pneumonectomy in 16% and lesser resections in 15%. Intra- and postoperative complications occurred in 1.4% and 32% of patients, respectively. CONCLUSIONS: This paper provides an overview of our MLCG-Database, which allows performing statistics for outcome analysis and quality management reports as well as medical assessment on a huge collection of patient data on a day-to-day basis. In addition, impact analysis of risk factors on postoperative morbidity and mortality as well as investigation of long-term survival underlines results reported internationally.

Outcome following lung resections for pT1 non-small cell lung cancer.

AIMS: To analyse the outcome of patients with pT1 NSCLC treated at our institution by antero-lateral thoracotomy, anatomical lung resections and mediastinal lymph node dissection between 1980 and 2001. METHODS: Follow-up data were obtained retrospectively from 1980 to 1990 and prospectively after 1990. Survival was analysed using the Kaplan-Meier method. RESULTS: Histopathological examinations revealed mediastinal lymph node infiltration in 27.6% (pN1 17.8% and pN2 9.8%). pN2 was classified in 14.1% of adenocarcinomas compared to 6.2% of squamous cell carcinomas. Median overall survival of patients with pT1 carcinomas was 89+16 months (median+standard error). Histopathological N-classification indicates differential prognostic and therapeutic implications in pT1 adeno- and squamous cell carcinomas. CONCLUSIONS: Complete lymph node dissection is required for all patients with T1 NSCLC treated by either open surgery or VATS resection. Histopathological N-classification indicates differential prognostic and therapeutic implications in pT1 adeno- and squamous cell carcinomas.

No effect of the cyclooxygenase-2 inhibitor etoricoxib on pre-emptive and post-operative analgesia in visceral surgery: results of a randomized controlled trial.

BACKGROUND: Pre-emptive analgesia in perioperative care has potential benefits for patients. The pre-emptive and postoperative analgesic effects of the cyclooxygenase-2 inhibitor etoricoxib have been investigated using a 2 × 2 factorial trial design. METHODS: According to the 2 × 2 factorial study design, 103 patients scheduled for visceral surgery, were randomly allocated to two groups prior to surgery. Patients could receive either etoricoxib or placebo (to investigate pre-emptive analgesia). Subsequent to surgery, patients randomly received either etoricoxib or placebo, again. It follows, that four treatment modalities (continuous or replaced intervention) result, to investigate postoperative analgesia. Main Outcome Measure was the cumulative morphine use 48 h post-surgery. Other outcomes included pain intensities, pain thresholds and sensory detection. RESULTS: Eighty-six patients (female n = 42; mean age 53.82 ± 13.61 years) were evaluated on the basis of an intention to treat analysis. Pre-emptive administration of 120 mg etoricoxib did not significantly reduce the cumulative morphine dose within the first 48 h after surgery, when compared to the administration of placebo. The analysis of the post-operative treatment groups showed a non-significant 8% reduction in morphine dose during the continuous administration of etoricoxib. There were no changes in sensory perception as detected with QST before and after surgery or between groups. CONCLUSIONS: The effect of administering etoricoxib was not superior to placebo in reducing the morphine dose required for postoperative analgesia. The lack of changes in peripheral nociception suggests that central algetic mechanisms are of higher impact in the development of postoperative pain following abdominal or thoracic surgery.

Is the polymerase chain reaction or cure of Helicobacter pylori infection of help in the differential diagnosis of early gastric mucosa-associated lymphatic tissue lymphoma?

PURPOSE: The differential diagnosis of early gastric mucosa-associated lymphatic tissue (MALT) lymphoma based on Helicobacter pylori gastritis may be difficult when lymphoepithelial lesions are not detected. The aim of the present study was to investigate the question whether the polymerase chain reaction (PCR) or cure of H pylori infection may be of help in this respect. PATIENTS AND METHODS: Twenty patients with suspected low-grade gastric MALT lymphomas were treated in a double-blinded, randomized, crossover trial with 2,250 mg of either amoxicillin or placebo, both in combination with omeprazole, for 14 days with the aim to cure H pylori infection. PCR was performed using primers specific for the CDR3 region to detect monoclonal B cells. RESULTS: In five of 20 patients, MALT lymphomas were finally diagnosed. Three of these five patients went into complete remission, while two were referred to surgery. In the 15 patients with gastritis, complete regression was observed in all cases. With respect to PCR, monoclonal bands were detected in all four of the analyzed lymphoma patients before histology showed lymphoma. In addition, monoclonal bands were found in three patients with gastritis. In the patients with gastritis and monoclonal PCR, complete regression took longer as compared with the remaining 12 patients with polyclonal PCR and gastritis (P = .0209). Successful H pylori eradication was associated with earlier diagnosis of the MALT lymphoma (P = .0237). CONCLUSION: CDR3-PCR may be of help in the differential diagnosis of early gastric MALT lymphoma. Furthermore, H pylori eradication may lead to earlier diagnosis.

Technetium-99m pyrophosphate in diagnosis of acute cardiac rejection in the rat with effect of cyclosporine: concise communication.

Tc-99m pyrophosphate (PPi) uptake has been measured in a rat model of heterotopic heart transplant at 5 days after transplantation. comparison of tracer uptake, as a ratio between the heterotopic transplanted heart and the recipient's native heart, was made in four groups of animals. Group 1, with transplants between animals of isogeneic strain showed a lower ratio, significantly different from the ratio in Group 2 in which transplants were between nonisogeneic animals. The ratio of uptake after transplantation between nonisogeneic animals treated with 10 mg/kg-day of cyclosporine (Group 3), was not significantly different from Group 1. In contrast, the ratio of uptake between nonisogeneic animals treated with subtherapeutic doses of cyclosporine (Group 4), was not significantly different from Group 2. In Groups 1, 2, and 3 there was a correlation between the histology of the transplanted hearts, graded 1 to 5 according to the severity of rejection, compared with the uptake of Tc-99m PPi. This agent can therefore be used to diagnose cardiac rejection in a rat model, and the results correlate well with the severity of rejection as assessed histologically.

Importance of microscopic residual disease at the bronchial margin after resection for non-small-cell carcinoma of the lung.

A total of 805 patients underwent lung resection for non-small-cell lung carcinoma at the University of Munich Medical Center, Klinikum Grosshadern, from 1978 through 1988. Microscopic residual disease at the bronchial margin was found in 21 patients (2.6%). The tumor residues showed either a mucosal (1%) or a extramucosal (1.6%) spreading pattern. Patients with extramucosal microscopic residual disease had a poorer prognosis (median survival 10.3 months) than patients with mucosal microscopic residual disease (median survival 25 months). The prognosis was better if the tumor was squamous cell as opposed to adenocarcinoma or large-cell carcinoma. The most important prognostic factor was tumor stage. Patients with microscopic tumor infiltration and stage I or II disease survived longer than the comparable stage III group. We suggest that these patients should undergo reoperation, if possible. Patients with stage III disease, mediastinal lymph node involvement, and microscopic residual disease have the same marked reduction in survival as patients with stage III disease but without microscopic tumor infiltration. We do not recommend a follow-up operation in these patients. Complete histologic examination of mucosal and extramucosal peribronchial tissues at the resection line by frozen section is mandatory to avoid leaving microscopic tumor behind, which may adversely affect patient survival.

Prognostic value of deoxyribonucleic acid aneuploidy in primary non-small-cell lung carcinomas and their metastases.

The ploidy status of the deoxyribonucleic acid of a malignant lung tumor provides additional information besides histologic grading and tumor staging according to lymph node infiltration and tumor metastasis. Ninety-nine surgical specimens from patients with non-small-cell lung carcinoma were investigated by flow cytometry. Deoxyribonucleic acid aneuploidy was found in 48% of the primary tumors. Patients with deoxyribonucleic acid-euploid tumors showed better survival (p < 0.01) than those with deoxyribonucleic acid-aneuploid carcinomas independent of tumor stage. Deoxyribonucleic acid ploidy status of the primary tumor was compared with that of N2 lymph node metastases in 29 cases. Seven samples showed a change from deoxyribonucleic acid aneuploidy in the primary tumor to deoxyribonucleic acid euploidy in the lymph node metastases. Survival was significantly better for patients with euploid primary tumors and lymph node metastases, followed by patients with deoxyribonucleic acid-aneuploid primary tumors and euploid lymph node metastases. Survival was poorest in patients with deoxyribonucleic acid-aneuploid primary tumors and lymph node metastases. It was observed that only the simultaneous determination of deoxyribonucleic acid ploidy of primary tumors and lymph node metastases permits accurate prognostic evaluation in case of lymph node infiltration.

Kinetics and dynamics of acute rejection after heterotopic heart transplantation.

Right cervical, heterotopic heart transplantation was performed in 18 mongrel dogs. Study design was based on three different groups (n = 3 x 6). Standard immunosuppression consisted of triple drug therapy in all dogs. Groups II and III received high dose steroids during acute rejection. In group III the native hearts of previous recipients (groups I and II) were used as donors for heterotopic transplantation ("domino" principle). The hearts were examined by daily transmural biventricular biopsies and graded according to Billingham classification. Cytoimmunologic monitoring (n = 345; activation index from peripheral and coronary sinus blood) and fast Fourier transformation ECG (n = 80; area under the curve; surface recordings) served as daily noninvasive methods. Optionally antimyosin scintigraphy (n = 25; single photon emission computed tomography; heart-to-lung ratio) was performed and immunohistologically confirmed by peroxidase staining of the antibody (n = 61). Kinetics of rejection was not uniform in group I (onset after 5.7 days) and biphasic in group II (clear rejection-free interval: 6.8 days). Group III developed a continuously persisting rejection, despite repeated high-dose steroids, with an early onset (3.2 days). The invasive data, consisting of 587 punch biopsies, showed no significant difference between right and left ventricular rejection. Clearly focal rejection appeared in 51.5% of the cases, with subendocardial involvement in 54%. Cytoimmunologic monitoring significantly (p less than 0.001) correlated with daily biopsies in groups I and II. The activation index from coronary sinus blood was two times higher than in peripheral blood. Fast Fourier transform ECG identified the onset of rejection with great accuracy (p less than 0.01). The heart-to-lung ratio of antimyosin scintigraphy corresponded exactly to the various stages of rejection (p less than 0.001). High-dose steroids led to a clear reduction of the ratio in 26% cases. Peroxidase staining showed typical locations of the antibody, depending on the grade of rejection (p less than 0.001). Considering the results of pathology in this transplantation model, relying on endomyocardial biopsy alone in a clinical setting may not seem advisable. Although the results of this study must be confirmed clinically, the simultaneous use of cytoimmunologic monitoring and fast Fourier transformation ECG may prove to be valuable to day-to-day monitoring for acute rejection in the early postoperative course. If both methods indicate the onset of an acute rejection, antimyosin scintigraphy and endomyocardial biopsy, respectively, should be performed to confirm and grade the suspected diagnosis.