CONKO-006: A randomised double-blinded phase IIb-study of additive therapy with gemcitabine + sorafenib/placebo in patients with R1 resection of pancreatic cancer - Final results.

BACKGROUND: CONKO-006 was designed for patients with pancreatic adenocarcinoma with postsurgical R1 residual status to evaluate the efficacy and safety of the combination of gemcitabine and sorafenib (GemSorafenib) compared with those of gemcitabine + placebo (GemP) for 12 cycles. PATIENTS AND METHODS: This randomised, double-blind, placebo-controlled, multicenter study was planned to detect an improvement in recurrence-free survival (RFS) from 42% to 60% after 18 months. Secondary objectives were overall survival (OS), safety and duration of treatment. RESULTS: 122 patients were included between 02/2008 and 09/2013; 57 were randomised to GemSorafenib and 65 to GemP. Patient characteristics were wellbalanced (GemSorafenib/GemP) in terms of median age (63/63 years), tumour size (T3/T4: 97/97%), and nodal positivity (86/85%). Grade 3/4 toxicities comprised diarrhoea (GemSorafenib: 12%; GemP: 2%), elevated gamma-glutamyl transferase (GGT) (19%; 9%), fatigue (5%; 2%) and hypertension (5%; 2%), as well as neutropenia (18%; 25%) and thrombocytopenia (9%; 2%). By August 2017, 118 (97%) RFS event had occurred. There were no difference in RFS (median GemSorafenib: 8.5 versus GemP: 9.4 months; p = 0.730) nor OS (median GemSorafenib: 17.6 versus GemP: 17.5 months; p = 0.481). Landmark analyses suggest that patients who received more than six cycles of postoperative chemotherapy had significantly longer OS (p = 0.021). CONCLUSION: CONKO-006 is the first randomised clinical trial to include exclusively patients with PDAC with postsurgical R1 status thus far. Sorafenib added to gemcitabine did neither improve RFS nor OS. However, postoperative treatment exceeding six months seemed to prolong survival and should be further investigated in these high-risk patients. CLINICAL TRIAL INFORMATION: German Tumor Study Registry (Deutsches Krebsstudienregister), DRKS00000242.

Observational study on preservation of the superior rectal artery in sigmoid resection for diverticular disease.

AIM: Recent investigations have shown improved patient reported outcome after preservation of the inferior mesenteric artery in sigmoid resection for diverticular disease. We report on our experience with preservation of the superior rectal artery (SRA). METHODS: This is an observational single center study in a high-volume, level II inner city hospital from 2006 to 2008. Inclusion criteria were all patients with diverticular disease. Exclusion criteria were stoma formation, cancer, and iatrogenic perforation. Patients were investigated in group A with preservation of the SRA, and group B ligation of the SRA. Outcomes assessed, included incidence of anastomotic breakdown, intraoperative complications, hospital stay, and risk factors. RESULTS: The patient population included 259 patients, 46 patients were excluded, leaving 100 patients in group A and 113 patients in group B. Patients in both groups were comparable regarding age, gender, co-morbidities and stage of disease. Anastomotic breakdown occurred in one patient in group A and in eight patients in group B (p = 0.038). Incidence of intraoperative bleeding, wound dehiscence, and length of stay was increased in group B (p < 0.03; p < 0.04; p = 0.05). Obesity was an independent risk factor for anastomotic dehiscence in group B (p < 0.04). CONCLUSION: Our data comprise the largest patient population reported so far on vascular preservation in surgery for diverticular disease. The results of this study support the establishment of evidence based recommendations on the level of dissection in diverticular disease. Specifically obese patients are at risk of anastomotic breakdown with ligation of the SRA.

[Transvaginal cholecystectomy: results of a randomized study]. / Transvaginale Cholezystektomie: Ergebnisse einer randomisierten Studie.

BACKGROUND: Transvaginal cholecystectomy (TVC) is regarded as a model operation in the newly developed field of natural orifice transluminal endoscopic surgery (NOTES). Randomized, controlled trials to assess TVC as a surgical strategy are largely missing. MATERIALS AND METHODS: The study was a double blind, randomized, controlled, single center trial in female patients > 18 years with symptomatic cholecystolithiasis comparing laparoscopic cholecystectomy (CLC) and TVC. The study investigated pain reduction of ≥ 1 point on a visual-numeric rating scale with a follow-up after 7 days. Secondary endpoints were complications and patient reported outcome. Groups were established using computer-generated randomization and sealed envelopes in the operating theatre. At the end of the surgical procedure all patients received a standard 4-trocar dressing as for CLC and a vaginal tamponade. RESULTS: A total of 426 patients were asked to participate, of which 97 were randomized, 51 in the CLC, 41 in the TVC groups and 5 were excluded from the study. Patients were comparable regarding age, body mass index (BMI) and American Society of Anesthesiologists (ASA) grade. Surgical and anesthesia times were significantly different. There was no difference in postoperative pain. The majority of patients were satisfied with both procedures and TVC was recommended to other patients by 93 % of patients in the TVC group. CONCLUSION: The results did not show superiority of TVC over CLC with regards to postoperative pain. With no differences in postoperative pain and high patient satisfaction, TVC can be recommended to future patients as an alternative method. For confirmation of this evaluation of TVC further randomized trials are needed.

Expanded TCR Vbeta subsets of CD8(+) T-cells in late-onset myasthenia gravis: novel parallels with thymoma patients.

Little is known about pathogenesis -- and especially about involvement of CD8(+) T-cells -- in late-onset myasthenia gravis (LOMG). Remarkably, outstanding CD8(+) TCRVbeta-subset expansions were found in 64% and 72% of recent onset LOMG or thymoma-associated MG (vs. 16% with early-onset MG (p<0.0002); 21% in older controls (p<0.001)). In LOMG, ~25% of the expanded cells initially showed a naïve CD62L(+hi)/CD45RA(+) recent thymic emigrant (RTE)-like phenotype. These expansions associated significantly with IgG antibodies against cytomegalovirus (p<0.036), IL-12 and/ or IFN-alpha2 (p<0.03). The CD8(+) TCRVbeta expansions were stable over 5years, but RTE markers declined.

[Minimal invasive transvaginal right hemicolectomy: report of the first complex NOS (natural orifice surgery) bowels operation using a hybrid approach]. / Minimalinvasive transvaginale Hemikolektomie rechts: Bericht über die erste komplexe NOS (Natural Orifice Surgery)Darmoperation in Hybridtechnik.

BACKGROUND: Laparoscopic surgery has dramatically changed abdominal surgery by reducing the risk of wound infections, incisional hernias and adhesions. The surgical concept using natural orifices (NOS) may be even less traumatic and so less invasive. PATIENT AND METHODS: This operation was performed in a 66-year-old woman with an adenoma in the ascending colon. Through a 5 mm incision at the umbilicus a pneumoperitoneum was created and a trocar inserted. For the operation a 12 mm trocar and a curved grasper have been inserted in the posterior fornix of the vagina. Because of adhesions an additional 5 mm trocar was necessary. Through this incision the laparoscopic right hemicolectomy with an intracorporal anastomosis was performed. RESULTS: The histology showed an adenoma with 21 lymph nodes. The removal of the specimen through the vagina was without any difficulties. The postoperative course was regular. CONCLUSIONS: This operation is to our knowledge the first right hemicolectomy as a NOS/NOTES-operation in a human patient. It shows that with rigid instruments even complex procedures through natural orifices are feasible.

[Pancreatic heterotopia as a rare diagnosis of a size increasing gastric tumor]. / Pankreasheterotopie als seltene Differenzialdiagnose eines grössenprogredienten Magentumors.

A 39 years old woman was noted to have a submucosal gastric tumor during gastroscopy for cholecystectomy. She was asymptomatic regarding this tumor. The patient was primarily observed, but the tumor size increased. The lesion was biopsied with a negative result. A local excision with simultaneous endoscopy was done laparoscopically. Malignancy was excluded by immediate sectioning. Histological examination revealed pancreatic heterotopy Type I by Heinrichs- with exocrine and endocrine cells. The patient had an uneventful postoperative course. Eight months after resection the patient was free from recurrence and symptoms.

[The thoracoscopic thymectomy for myasthenia gravis]. / Die thorakoskopische Thymektomie bei der Myasthenia gravis.

UNLABELLED: Myasthenia gravis (MG) is a chronic autoimmune disease that usually responds positively to treatment with thymectomy. Standard surgical procedures have been shown to result in a favorite outcome. The optimal surgical access, however, is under discussion. PATIENTS AND METHOD: In a prospective study conducted between 8/97 and 4/05, 173 patients with MG underwent thoracoscopic thymectomy, for which a left-sided approach was generally applied. An analysis of the intraoperative and postoperative course was performed in 137 patients (8/97 and 12/03), as well as of the impact of the surgical procedure on further development of the disease. The results obtained were compared with those published in the literature, with particular reference to results obtained with open surgery. In 8 patients, the procedure was converted to an anterolateral thoracotomy or sternotomy, so we examined 129 patients, which were operated thoracoscopically. RESULTS: The patients in this study were 93 females and 36 males, with a mean age of 35.8 (range: 9-83) years. The mean preoperative duration of the disease was 22.9 (range: 1-140) months. The duration of operation was 50 to 85 minutes, the blood loss was lower than 100 ml. The mean follow up was 24.7 (range: 1-57) months. Complete remission was noted in 30 patients (23.3 %), and improvements reflected either in a reduction of the required medication, or a decrease in symptom severity, were seen in a total of 86 patients (66.6 %). CONCLUSION: Complete thoracoscopic thymectomy is a technically feasible operation, and as effective as conventional open surgery. Remissions or symptomatic improvements were observed in more than 89 % of the patients. The low morbidity rate, in combination with excellent cosmetic results, has led to increasing acceptance of the operation both by patients and neurologists. Therefore, thoracoscopic thymectomy represents a new, alternative method for treatment of patients with MG.

[Prospective multicenter trial of gastric cancer surgery--a contribution to clinical research on quality control]. / Prospektive Multizenterstudie zur Chirurgie des Magenkarzinoms--Ein Beitrag zur klinischen Versorgungsforschung.

By the mean of a prospective multicenter observational study (East German Gastric Cancer Study - EGGCS), 1 139 consecutive patients with gastric cancer were enrolled in 80 East German surgical departments from January 1 to December 31, 2002. Out of them, 1,031 (90.5%) underwent surgical intervention. The resection rate was 86.4% (n = 891); the R0 resection rate (n = 726) was 81.5%. Gastrectomy was performed in 79.8 % (n = 649) of subjects with radical resections (n = 813). In approximately 70 % of the interventions with curative intention, lymph node resection of the D2 compartment was carried out. The postoperative hospital mortality was 8.3%. The results were compared with the data obtained in the German Gastric Cancer Study (GGCS 1992); relevant differences and aspects were discussed.

Invasive staging of non-small cell lung cancer--a prospective study.

OBJECTIVES: Clinical prognosis and treatment schedules of non-small cell lung cancer (NSCLC) are dependent on tumor stage. This explains the importance of an exact pretreatment staging of the primary tumor and lymph nodes especially in locally advanced NSCLC, to differentiate between resectable and non-resectable disease. To assess the lymph node status of the upper mediastinum, the diagnostic value of mediastinoscopy is accepted to be superior to radiological methods. In contrast, thoracoscopy is not yet established as a standard staging tool. PATIENTS AND METHODS: Seventy-three consecutive patients with CT-based suspicion of advanced NSCLC have been investigated as part of a phase II study on neoadjuvant treatment of NSCLC. All patients underwent mediastinoscopy and mediastinal lymph node sampling. In the case of a negative result we performed additional thoracoscopy. RESULTS: In 52.1% (n = 38) of the patients the invasive diagnostic methods led to results that were effectively different from those of the radiological findings. In 11 patients (15.1%) CT-assessed lymph node metastases could invasively not be confirmed, whereas nine patients (12.3%) had positive mediastinal lymph nodes but no corresponding CT signs (diameter <1 cm). The results were achieved by mediastinoscopy in 15 (20.5%) and by thoracoscopy in five (6.8.%) patients. A radiologically unexpected T4 stage has been found in four (5.5%) and a M1 stage in four (5.5%) patients by thoracoscopy. On the contrary, in seven patients a suspected infiltration of mediastinum or parietal pleura could be thoracoscopically excluded. Four patients have been in an unexpected high stage of tumor progression at the moment of diagnostic procedures and therefore have been included in palliative therapy schedules. Ten patients have been 'overstaged' by radiological methods and benefited from a primarily curative resection after invasive staging. CONCLUSIONS: Of the 73 prospectively studied patients with locally advanced NSCLC, 12 (16.4%) have been staged too low and 13 (17.8%) too high. If exclusively staged by radiological methods, about 34% of lung cancers have been classified incorrectly. Therefore, these tools are not a sufficient basis for diagnosis of stage III NSCLC disease. Mediastinoscopy with consecutive thoracoscopy is an essential part of the therapeutic planning in locally advanced NSCLC, and results are significantly superior to clinical staging.

Effects of ozone on evaporative water loss and thermoregulatory behavior of marine toads (Bufo marinus).

Ozone (O(3)) is a strong pulmonary irritant and causes a suite of respiratory tract inflammatory responses in humans and other mammals. In addition to lung injury, rodents exposed to O(3) exhibit a pronounced decrease in core body temperature at rest, which may offer a protective effect against O(3) damage. The effects of O(3) on other vertebrates have not been studied. Compared to individuals exposed to air (N=34), Bufo marinus toads exposed to O(3) (N=32) for 4 h lost 3.78 g body mass (adjusted mean from analysis of covariance, body mass mean+/-SD, 90.1+/-21.90 g). We tested the thermoregulatory responses of 22 toads in a thermal gradient 1, 24, and 48 h after 4-h exposure to air (N=11) or 0.8 ppm O(3) (N=11). Individual toad thermal preferences were also significantly repeatable across all trials (intraclass correlation=0.66, P <0.001). We did not observe a direct effect of O(3) exposure on the preferred body temperatures (PBT) of toads. However, O(3) exposure did have an indirect effect on selected temperatures. Ozone-exposed toads with higher evaporative water loss rates, in turn, also selected lower PBT, voluntary minimum, and voluntary maximum temperatures 24 h post-exposure. Ozone exposure may thus alter both water balance and thermal preferences in anuran amphibians.

Chromosomal alterations in the clonal evolution to the metastatic stage of squamous cell carcinomas of the lung.

Comparative genomic hybridization (CGH) was applied to squamous cell carcinomas (SCC) of the lung to define chromosomal imbalances that are associated with the metastatic phenotype. In total, 64 lung SCC from 50 patients were investigated, 25 each with or without evidence of metastasis formation. The chromosomal imbalances summarized by a CGH histogram of the 50 cases revealed deletions most frequently on chromosomes 1p21-p31, 2q34-q36, 3p, 4p, 4q, 5q, 6q14-q24, 8p, 9p, 10q, 11p12-p14, 13q13-qter, 18q12-qter and 21q21. DNA over-representations were most pronounced for chromosomes 1q11-q25, 1q32-q41, 3q, 5p, 8q22-qter, 11q13, 12p, 17q21-q22, 17q24-q25, 19, 20q and 22q. In ten cases, paired samples of primaries and at least one metastasis were analysed. The comparison revealed a considerable chromosomal instability and genetic heterogeneity; however, the CGH pattern indicated a clonal relationship in each case. The difference in histograms from the metastatic and non-metastatic tumour groups was most useful in pinpointing chromosomal imbalances associated with the metastatic phenotype, indicating that the deletions at 3p12-p14, 3p21, 4p15-p16, 6q24-qter, 8p22-p23, 10q21-qter and 21q22, as well as the over-representations at 1q21-q25, 8q, 9q34, 14q12 and 15q12-q15, occurred significantly more often in the metastatic tumour group. The comparison of the paired samples confirmed these findings in individual cases and suggested distinct genetic changes, in particular the extension of small interstitial deletions, during tumour progression. Importantly, metastasis-associated lesions were frequently detectable in the primary tumour providing a method of identifying patients at risk for tumour dissemination. Individual profiles and histograms are accessible at our web site http://amba.charite.de/cgh.

[Askin's tumor--a rare entity. Case report with references to the literature]. / Der Askin-Tumor--eine Rarität. Ein Fallbericht mit Einflüssen der Literatur.

Askin's Tumour (synonym: primitive neuroectodermal tumour) is a rare neoplasm of the chest wall. In 1979 Askin and Rosai described an unique clinicopathological entity, characterised as a malignant small-cell tumour of the soft tissues of the chest wall in childhood and adolescence. We report on a case of a 28-year old male who had a massive tumour in the left thorax with association to the chest wall. The clinical symptoms were dyspnoea and increasing chest pain. The tumour was revealed as a sarcoma of the lung by CT-guided fine needle aspiration. A pneumectomy of the left lung with partial resection of ribs IV. and V. was performed. Postoperative histology revealed an Askin's tumour of the chest wall with infiltration of the lung. After surgical treatment in our hospital we transferred the patient to an oncological centre for adjuvant chemotherapy. As a consequence of aggressive growth of tumour therapy should be performed in oncological centres in clinical studies. The treatment includes radical surgical resection, neoadjuvant and adjuvant chemotherapy plus radiation. In our case the primary resection was performed because of increasing symptoms. It is difficult to establish an accurate preoperative diagnosis of Askin's tumour. Microscopy and immunohistological stain of the specific marker--neuron-specific enolase--are essential. Multimodal treatment allows a long-term survival, but often the prognosis is infaust.

Operative technique for thoracoscopic thymectomy.

In most cases, myasthenia gravis (MG) and thymoma require complete removal of the thymus gland and resection of the pericardial fatty tissue. There is some debate however, over which surgical approach is best for thymectomy. We have developed a new technique for complete thoracoscopic thymectomy. Between October 1994 and February 1998, we performed a prospective observational study of thoracoscopic thymectomy in 19 patients. The results were analyzed with special reference to perioperative morbidity, short- and intermediate-term improvement of MG, and quality of life. This study showed the feasibility of complete thoracoscopic thymectomy. The procedure was successfully applied in 19 of 20 cases. Thoracoscopic thymectomy was accomplished with zero mortality and a very low perioperative morbidity. While the short-term improvement of MG after this procedure was comparable to that seen with conventional surgery, the short- and intermediate-term quality of life was much better. The preliminary results of thoracoscopic thymectomy appear to be excellent for both patients and neurologists. A prospective randomized trial has been designed to compare thoracoscopic thymectomy with the gold standard of median sternotomy for thymectomy.

Pituitary adenylate cyclase activating peptides relax human pulmonary arteries by opening of KATP and KCa channels.

BACKGROUND: Pituitary adenylate cyclase activating peptides (PACAPs) are potent endothelium independent dilators of human coronary arteries; however, their effects on human pulmonary arteries are unknown. METHODS: The vasorelaxant effects of PACAP27 on human pulmonary segmental arteries were studied and the specific potassium (K+) channel regulatory mechanisms in the vasorelaxant effects were tested by means of isometric contraction experiments. RESULTS: PACAP27 produced dose dependent relaxations of 10 microM rings preconstricted with prostaglandin F2 alpha (PGF2 alpha) with half maximal relaxation (IC50) at 17 nM. Pretreatment of the vessels with the ATP sensitive K+ (KATP) channel blocker glibenclamide (1 microM) or with the Ca2+ activated K+ (KCa) channel blocker iberiotoxin (100 nM) inhibited the PACAP27 induced relaxation. CONCLUSIONS: These results provide evidence that PACAPs are potent vasodilators of human pulmonary arteries and that this relaxation might be mediated by opening of KATP and KCa channels.

Distinct regions of allelic imbalance on chromosome 10q22-q26 in squamous cell carcinomas of the lung.

The genetic mechanisms underlying the progression to the metastatic phenotype of lung cancer are poorly understood. We recently showed that small cell lung cancer (SCLC) and metastasizing squamous cell carcinomas are characterized by an increased incidence of allelic loss on chromosome 10q. In the present study we performed a deletion mapping using 24 polymorphic markers on chromosome 10q22-q26 in 39 squamous cell carcinomas (SCC) of the lung identifying 14 metastatic carcinomas (74%) and three non-metastatic SCC (15%) with allelic imbalance. The allelotype analysis indicated three regions of allelic loss that were clustered at the loci Afm086/D10S541, D10S185 and D10S1782/D10S169. A localized microsatellite instability was observed in two carcinomas for the markers D10S1686 and D10S1782. In addition the PTEN/MMAC1 gene was analysed by direct DNA sequencing and Southern blot analysis in 25 and 28 carcinomas, respectively, without detecting any genomic alterations. Similarly, no altered transcript was detected in 15 tumor cell lines and 20 primary tumors by Northern blot analysis or RT-PCR. In summary, three distinct regions of allelic imbalance were identified suggesting that multiple tumor suppressor genes on chromosome 10q contribute to tumor progression and metastases formation of lung cancer.

Allelic loss on chromosome 10q in human lung cancer: association with tumour progression and metastatic phenotype.

We analysed 78 carcinomas of the lung for allelic losses on chromosome 10q. The tumours were of different stage and grade and comprised 22 small-cell lung carcinomas (SCLC), 40 squamous cell carcinomas (SCC), 11 adenocarcinomas, four large-cell carcinomas and one carcinoid. They were investigated by six polymorphic markers located between 10q21 and 10qter. We observed a high incidence of loss of heterozygosity (LOH) in SCLC (91%) and metastatic SCC (56%). Non-metastatic SCC showed deletions in three cases (14%) and no LOH was found in the other types of non-small-cell lung cancer. The statistical analysis indicated that the presence of LOH correlated significantly with advanced tumour stages in the entire collective and in particular within the SCLC and SCC subgroups. For SCC, a positive association was found between LOH and metastases formation, while in SCLC the number of non-metastatic tumours was too small for a final conclusion. Whereas SCLC was frequently characterized by multiple allelic losses, suggesting the deletion of the entire chromosomal arm, SCC showed interstitial imbalances. A high incidence of allelic loss was observed between the markers D10S677 and D10S1223. The analysis of five informative cases suggested the presence of two non-overlapping regions between the loci D10S677/D10S1237 and D10S1213/D10S1223. In SCLC, we did not find mutations in the putative tumour-suppressor gene MXI1. The data indicate that LOH on chromosome 10q is associated with tumour progression in SCC and SCLC. Thus it may become a useful genetic marker in the assessment of the malignant potential of these tumour types.