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.

Patterns of chromosomal imbalances in adenocarcinoma and squamous cell carcinoma of the lung.

Comparative genomic hybridization was used to screen 25 adenocarcinomas and 25 squamous cell carcinomas of the lung for chromosomal imbalances. DNA copy number decreases common to both entities were observed on chromosomes 1p, 3p, 4q, 5q, 6q, 8p, 9p, 13q, 18q, and 21q. Similarly, DNA gains were observed for chromosomes 5p, 8q, 11q13, 16p, 17q, and 19q. Adenocarcinomas showed more frequently DNA overrepresentations of chromosome 1q and DNA losses on chromosomes 3q, 9q, 10p, and 19, whereas squamous cell carcinomas were characterized by increased overrepresentations of chromosome 3q and 12p as well as deletions of 2q. For the first time, we used a histogram representation and statistical analysis to evaluate the differences between both tumor groups. In particular, the overrepresentation of the chromosomal band 1q23 and the deletion at 9q22 were significantly associated with adenoid differentiation, whereas the DNA loss of chromosomal band 2q36-37 and the overrepresentations at 3q21-22 and 3q24-qter were statistically significant markers for the squamous cell type. The study strengthens the notion that different tumor subgroups of the respiratory tract are characterized by distinct patterns of chromosomal alterations.

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.

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.

Preservation damage in liver transplantation. Influence of rapid cooling.

Liver preservation and transplantation was performed in pigs. For flush perfusion cold (2 degrees C) and warm (15 degrees C) lactated Ringer's solution were compared. Administration of cold Ringer's resulted in a severe endothelial damage of sinusoids that was aggravated after recirculation, as shown by electron microscopic examination. Using warm Ringer's solution this alteration was limited. Liver parenchymal cells are impaired mainly during reflow as a consequence of microcirculatory disturbance. After cold flushing animals died within a few hours, whereas after flushing with warm Ringer's solution pigs survived definitively.

Acute right-sided heart failure due to hemorrhage into a pericardial cyst.

This is a description of a rare complication of a pericardial cyst with spontaneous internal hemorrhage and following tamponade. The noninvasive diagnosis was done by transesophageal echocardiography and computed thoracic tomography. The cyst was thoracoscopically removed and pathologically examined. This case demonstrates a rare but important and life-threatening complication of mostly asymptomatic pericardial cysts.

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.

Surgery for carcinoma of the gallbladder.

BACKGROUND/AIMS: Carcinoma of the gallbladder is one of the gastrointestinal malignancies with an extraordinarily poor prognosis. The 5-year survival rate amounts to less than 5 per cent in most series. Our aim was to analyze the experience of a single center with surgery for gallbladder carcinoma with special reference to liver wedge resection. MATERIALS AND METHODS: A retrospective analysis examined all patients of the Clinic of Surgery of the Humboldt University Medical School (Charité) with diagnosed gallbladder carcinoma operated on between January 1981 and August 1993. The analysis was based on patient documentation. Cumulative survival rates were calculated according to the method of Kaplan/Meier. Statistical significances were calculated using logrank and Wilcoxon's tests. RESULTS: Eighty one patients (61 female, 20 male) were included in the study. The preoperative diagnoses were confirmed in 33 patients (40.7%). The stage distribution according to the TNM-system revealed 6, 10, 12, and 53 patients at the stages I-IV, respectively. The curative resection rate was 22.2%. Stage-dependent surgical procedures resulted in cumulative survival rates of 33.3% for stages I and II, 8.3% for stage III and 1.9% for stage IV. The overall prognosis was significantly determined by metastatic spread to the lymph nodes. CONCLUSIONS: Diagnostic efforts should focus on detecting the low stages I and II of gallbladder carcinoma. Our results suggest that aggressive surgical management with second intervention and wedge resection or more extended liver resection is the method of choice for stage T1b or more advanced stages of gallbladder carcinoma.

[Current therapy of bile duct cysts. II. Intrahepatic cysts (Caroli syndrome)]. / Aktuelle Therapie der Gallengangscysten. II. Intrahepatische Cysten (Caroli-Syndrom)

17 patients with a Caroli's syndrome are reviewed with emphasis on clinical features and late results (follow-up: 2-10 years). The group consists of 9 women and 8 men ranging in age from 17 to 80 years (mean of 42.6). 14 patients had a diffuse form, 5 of whom had periportal fibrosis with secondary biliary cirrhosis, which in 3 cases resulted in a portal hypertension with hepatic failure. In only 3 cases the dilatation was limited to the left lobe of the liver. 9 of the patients had previously undergone surgery in the form of cholecystectomy and choledocholithotomy elsewhere. The disease was complicated by lithiasis (14 intrahepatic, 9 extrahepatic). Curative treatment was only possible in the 3 patients with unilobar Caroli's syndrome (partial liver resection). In 5 patients we performed a cholecystectomy and choledocholithotomy combined in 2 cases with a transduodenal sphincterotomy. There was no operative death. Endoscopic treatment consisted in removal of stones and decompression of the biliary tree by sphincterotomy in 9 cases and endoscopic retrograde biliary drainage (endoprosthesis) in 5 cases. Excepting the 3 curative operated patients who are asymptomatic respectively 2, 4 and 5 years after surgery, the remaining cases had repeated bouts of acute pains accompanied by recurrent episodes of cholangitis. A late mortality of 23.5% (4 patients) is proof of the poor prognosis of this disease.

[Surgical therapy of malignant thoracic wall tumors]. / Zur operativen Therapie maligner Brustwandtumoren.

Surgical treatment of primary and secondary malignant chest wall tumors present various difficulties depending on their localisation in the anterior, lateral and posterior thoracic wall. The reconstruction and the flap-plastics have to fulfill the functional and cosmetic demands. We report on 35 patients, 22 female and 13 male, ranging in ages from 19-69 (mean 44.59) years. There were 17 primary and 18 secondary tumors. The operation included excision of the thoracic shield, partial or total breast-bone and clavicle resection. Materials used for reconstruction were PTFE-patches, lyophilized dura and ribs. Soft tissue reconstruction was performed by sliding-flap plastics. The one-year survival rate was 90.6%.

[Cystic tumors of the pancreas]. / Cystische Tumoren des Pankreas.

Cystic neoplasms of the pancreas are rare but in the last years more frequently detected. Within a 10-year-period we treated 30 patients, including 8 serous cystadenomas, 6 mucinous cystadenomas, 12 mucinous cystadenocarcinomas, 2 cystic neuro-endocrine tumors and 1 papillary cystic tumor respectively acinar cell cyst-adenocarcinoma. 80% of the patients had symptoms, experienced abdominal pain, weight loss, weakness or abdominal mass. In eight patients the tumors had been misdiagnosed as a pancreatic pseudocyst. The correct type of cystic tumor was diagnosed by preoperative investigations only a few cases. All patients with serous or mucinous cystadenomas are well and without evident recurrence after resection of the tumor. However the survival time of malignant cystic tumors varied strongly. The curative resection of these tumors give patients the chance of long-term survival.

[Laparoscopic gastrectomy. A case report]. / Laparoskopische Gastrektomie. Eine Fallbeschreibung.

Although laparoscopic techniques in gastric surgery have become an important part of upper gastrointestinal surgery, they are mainly utilized for organ preserving procedures. A standardized technique for laparoscopic gastrectomy has not yet been described in detail. The purpose of this study was to develop a standardized technique for laparoscopic gastrectomy with reconstruction by a stapled termino-lateral esophago-je-junostomy and Roux-en-Y-anastomosis in a cadaver model. The resected stomach was removed through an enlarged trocar incision. The described technique has been successfully performed in one patient with early gastric cancer.

[Current therapy of bile duct cysts. I. Extrahepatic cysts]. / Aktuelle Therapie der Gallengangscysten. I. Extrahepatische Cysten.

A total of 23 patients with extrahepatic biliary cysts (11 type I, 4 type II, 4 type III and 4 type IVa according to the classification by Todani) seen at our institution in a 15-year period were reviewed with emphasis on management and long-term results at follow-up of 3 weeks-12 years. Associated hepatobiliary disease occurred in 4 patients, including one case with malignant degeneration in the cyst 23 years after cystenterostomy, and an association of a gallbladder carcinoma with a choledochocele in the other patient. Radical excision of the dilated bile duct and reconstruction by Roux-en-Y hepatico-jejunostomy was performed in 13 cases (9 type I, 3 type II and 1 type III), combined in 3 cases with an antireflux valve. All 13 operated on patients remained in good health for 6 months to 12 years. These results confirm the need for complete early excision of type I, (II) and IVa cysts at all ages before severe complications can occur. Endoscopic treatment of type III choledochocele should be limited to the management of smaller lesions.

[Diagnosis and therapy of postoperative chyloperitoneum]. / Diagnose und Therapie des postoperativen Chyloperitoneums.

Chyloperitoneum is a rare complication of surgical procedures. We report a case of severe chyloperitoneum after abdominothoracic esophageal resection with two-field lymphadenectomy. After diagnosis was established, the lymph leak was located with oral iodine-marked fatty acids (123I-pentadecanoic acid) showing increased activation in the right middle abdomen. Because conservative treatment with total parenteral nutrition showed no decrease in chyle volume, relaparatomy was performed and the lymphatic fistula was successfully treated with suture ligatures. Pathophysiology and different options for localization and treatment of postoperative chyloperitoneum are discussed.

[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.