Resection and radiochemotherapy of pancreatic cancer – the future?

Background: To improve the surgical outcome after resection of pancreatic adenocarcinomas, multimodal treatment concepts need to be applied and improved. The controversies among those being pro and contra adjuvant treatment need an up-to-date review of the indications and results achievable with various treatment modalities. Patients/Methods: The literature regarding the indications and results of adjuvant/neoadjuvant therapies in pancreatic cancer was reviewed to provide a solid base for current recommendations and future developments. The biology of the disease in the spontaneous course, after surgery and during/after various palliative and adjuvant/neoadjuvant treatment modalities was focussed on, to characterise the disease for an optimally targeted treatment in conjunction with surgical removal of the tumour. The results of systemic and regional chemotherapy and radiotherapy, either alone or in combination, before, during and after surgery were critically analysed with respect to the oncological possibilities and pitfalls of each treatment method. Results: In two randomised trials, one testing postoperative radiochemotherapy (GITSG), and one postoperative chemotherapy, the adjuvant treatment achieved a significant prolongation of the median survival time. The 5-year and 10-year survival rates were improved in the GITSG study. The EORTC-GITCCG trial could not confirm the benefit of adjuvant radiochemotherapy. This study had a different design than the GITSG trial. Several historical control studies supported the beneficial effect of postoperative radiochemotherapy. In three historical control trials using regional chemotherapy, one with intraoperative radiotherapy , the survival times were improved compared with surgery alone. Intraoperative or postoperative radiotherapy as single modalities might reduce local relapses, but a survival advantage is still debated. Preoperative neoadjuvant radiochemotherapy has several advantages (downstaging, devitalising margins and lymph node metastases, compatibility of treatment vs. postoperative radiochemotherapy), and does not seem to increase the postoperative morbidity. Several trials have confirmed the feasibility of this concept, but no survival advantage has yet been proven. Systemic and regional chemotherapy is able to downstage primarily nonresectable pancreatic cancers. Conclusions: Postoperative adjuvant radiochemotherapy with up-to-date protocols can be recommended for routine treatment, if the surgeon or the patient desires to improve the usually remote prognosis after surgery alone. For those being indecisive or against adjuvant therapy, the participation in trials, e.g. the ESPAC 1 and 2 studies, is strongly recommended. Regarding our own positive experience with adjuvant regional chemotherapy and in view of the postresectional progression pattern, we currently favour adjuvant radiochemotherapy, with the chemotherapy delivered regionally via the celiac axis. This concept will be tested against surgery alone in the ESPAC 2 trial. Neoadjuvant therapies have a great potential, but should be conducted within studies, such as pre-, intra-, or postoperative radiotherapy. Received: 13 February 1998     

Carcinoma of the Ampulla of Vater: Determinants of Long-term Survival in 94 Resected Patients

This retrospective study details 94 patients after surgical resection of carcinoma of the ampulla of Vater to determine prognostic factors. The tumour was limited to the ampulla of Vater in 32%, invaded the duodenal wall in 34%, infiltrated 2cm or less into the pancreas in 22%, and invaded more than 2cm into the pancreas and/or other adjacent structures in 11%. Curative resection was accomplished in 97% of cases. After exclusion of perioperative deaths the 1-, 5- and 10-year survival rates were 79.6%, 38.2%, and 31.6%, respectively with a median survival of 3.68 years. 26 patients survived more than five and 15 patients more than ten years. In an univariate analysis advanced tumour size, poor tumour grading, lymph node metastases and advanced UICC stage significantly decreased survival. Comparison of short and long survivors confirmed tumour size, lymph node status and UICC stage as significant prognostic factors. In a multivariate analysis (Cox model), only tumour size was a statistically independent predictor of prognosis. The survival probability increased with each year a patient survived after resection. When a patient had already survived five years after resection, the probability to survive another five years was 83%. Careful clinicopathologic staging is important for the prognosis after resection.     

The efficacy of dietary intervention on urinary risk factors for stone formation in recurrent calcium oxalate stone patients

PURPOSE: Nutrition is suggested to be the major environmental risk factor in idiopathic calcium oxalate stone disease. The study was designed to evaluate the effect of dietary intervention on urinary risk factors for recurrence in calcium oxalate stone formers. MATERIALS AND METHODS: A total of 76 men and 31 women with idiopathic calcium oxalate stone disease collected 24-hour urine on their habitual, self-selected diets and after 7 days on a balanced standardized diet according to the recommendations for calcium oxalate stone formers. RESULTS: On the usual diet, a urine volume of less than 2.0 l per 24 hours was present in 57.9%, hypercalciuria in 25.2%, hypomagnesuria in 18.7%, hyperoxaluria in 14.0%, hyperuricosuria in 41.3% and hypocitraturia in 57.0% of patients. The frequency of metabolic abnormalities and the risk of calcium oxalate stone formation decreased significantly on the ingestion of the balanced diet, due to the significant increase in urinary volume, pH and citrate excretion and the significant decrease in urinary calcium and uric acid excretion. No change occurred in urinary oxalate and magnesium excretion. CONCLUSIONS: The evaluation of urinary risk profiles of the patients on their usual dietary habits revealed a high risk for calcium oxalate stone formation. A low fluid intake and an increased intake of protein and alcohol were identified as the most important dietary risk factors. The shift to a nutritionally balanced diet according to the recommendations for calcium oxalate stone formers significantly reduced the stone forming potential.     

Treatment of painful vertebral fractures by kyphoplasty in patients with primary osteoporosis: a prospective nonrandomized controlled study.

This study investigates the effects of kyphoplasty on pain and mobility in patients with osteoporosis and painful vertebral fractures compared with conventional medical management. INTRODUCTION: Pharmacological treatment of patients with primary osteoporosis does not prevent pain and impaired activity of patients with painful vertebral fractures. Therefore, we evaluated the clinical outcome after kyphoplasty in patients with vertebral fractures and associated chronic pain for >12 months. MATERIALS AND METHODS: Sixty patients with primary osteoporosis and painful vertebral fractures presenting for >12 months were included in this prospective, nonrandomized controlled study. Twenty-four hours before performing kyphoplasty, the patients self-determined their inclusion into the kyphoplasty or control group so that 40 patients were treated with kyphoplasty, whereas 20 served as controls. This study assessed changes in radiomorphology, pain visual analog scale (VAS) score, daily activities (European Vertebral Osteoporosis Study [EVOS] score), number of new vertebral fractures, and health care use. Outcomes were assessed before treatment and at 3 and 6 months of follow-up. All patients received standard medical treatment (1g calcium, 1000 IE vitamin D(3), standard dose of oral aminobisphosphonate, pain medication, physical therapy). RESULTS: Kyphoplasty increased midline vertebral height of the treated vertebral bodies by 12.1%, whereas in the control group, vertebral height decreased by 8.2% (p = 0.001). Augmentation and internal stabilization by kyphoplasty resulted in a reduction of back pain. VAS pain scores improved in the kyphoplasty group from 26.2 +/- 2 to 44.2 +/- 3.3 (SD; p = 0.007) and in the control group from 33.6 +/- 4.1 to 35.6 +/- 4.1 (not significant), whereas the EVOS score increased in the kyphoplasty group from 43.8 +/- 2.4 to 54.5 +/- 2.7 (p = 0.031) and in the control group from 39.8 +/- 4.5 to 43.8 +/- 4.6 (not significant). The number of back pain-related doctor visits within the 6-month follow-up period decreased significantly after kyphoplasty compared with controls: mean of 3.3 visits/patient in the kyphoplasty group and a mean of 8.6 visits/patient in the control group (p = 0.0147). CONCLUSIONS: The results of this study show significantly increased vertebral height, reduced pain, and improved mobility in patients after kyphoplasty. Kyphoplasty performed in appropriately selected osteoporotic patients with painful vertebral fractures is a promising addition to current medical treatment.     

NEPH2 is located at the glomerular slit diaphragm, interacts with nephrin and is cleaved from podocytes by metalloproteinases

The NEPH family comprises three transmembrane proteins of the Ig superfamily interacting with the glomerular slit diaphragm proteins podocin and ZO-1. NEPH1 binds to nephrin, another component of the slit diaphragm, and loss of either partner causes heavy proteinuria. NEPH2, which is strongly conserved among a large number of species, is also expressed in the kidney; however, its function is unknown. The authors raised NEPH2 antisera to demonstrate NEPH2 expression in a variety of mouse tissues, including the kidney and a podocyte cell line. The authors localized the expression of NEPH2 to the glomerular slit diaphragm by electron microscopy and show NEPH2 homodimerization and specific interactions with the extracellular domain of nephrin in vitro and in vivo. NEPH1, however, failed to interact with NEPH2. The authors detected immunoreactive NEPH2 in urine of healthy subjects, suggesting that the extracellular domain is cleaved under physiologic conditions. These findings were confirmed in vitro in podocyte cell culture. Shedding is increased by tyrosine phosphatase inhibitors and diminished by GM6001, an inhibitor of metalloproteinases. Overexpression experiments indicate an involvement of the MT1-matrix metalloproteinase. The results suggest a role for NEPH2 in the organization and/or maintenance of the glomerular slit diaphragm that may differ from the functions of NEPH1 and nephrin.     

War Experiences and General Health Among People in Bosnia‐Herzegovina and Kosovo

War experiences may have an extensive impact on the health status of the exposed populations. This population‐based study aimed to examine the relationship between war experiences and self‐reported general health in representative sample surveys from Bosnia‐Herzegovina (n = 3,313) and Kosovo (n = 1,000). Data were collected with face‐to‐face interviews fielded in the winter of 2003–2004. Logistic regression analysis was used to compute unadjusted and adjusted odds ratios (ORs). The adjusted effects of the extensiveness of war experiences on poor health were positive in both countries, but they were statistically significant only for Bosnia‐Herzegovina: OR = 1.04, 95% CI [1.00, 1.08] for Bosnia‐Herzegovina and OR = 1.03, 95% CI [0.98, 1.09] for Kosovo. The strongest observed effect was found for Kosovo only: The extensiveness of war experiences was relatively strongly related to longstanding health problems, OR = 1.09, 95% CI [1.03, 1.15]. We found that war experiences may contribute to increased poorer health in the exposed populations; however, the effects 4–9 years after the war ended were modest. Hence, war experiences seemed to be more strongly related to war‐related distress and posttraumatic stress disorder than to self‐reported general health.     

Surgery for Gastrointestinal Stromal Tumors of the Stomach

Background  Gastrointestinal stromal tumors (GISTs) are the main mesenchymal neoplasms in the gastrointestinal tract. Tumor size, mitotic rate, and location correlate with potential malignancy and recurrence rate. Results of surgical treatment of gastric GIST are analyzed with emphasis on recurrence of disease after intermediate follow-up. Methods  From 1998 to 2006, a total of 63 patients (median age 62.1 ± 14.1) underwent gastric resection for GIST. Fifty-five patients (93.6%) returned for follow-up investigations, which included computed tomography in 45, gastroscopy in 32, and endosonography in 29. Positron emission tomography was done in five patients. Results  Mean tumor size was 5.3 ± 3.8 cm. Open atypical gastric resection was done in 32, distal gastric resection in five, and remnant gastrectomy in four patients. Laparoscopic gastric resection was initiated in 22 patients; the conversion rate was four of 22 (18.2%). Overall, R0 resection was reached in 61/63 patients (96.8%). According to the Fletcher criteria, 33 tumors (52.4%) were classified as intermediate or high risk GIST. Six patients (9.5%) died of unrelated causes before follow-up. After a median follow-up of 2.5 years, overall recurrence rate was 7.0% after R0 resection. Conclusion  Histologically proven complete resection is an effective treatment for gastric GIST. Laparoscopic procedures were carried out successfully in selected patients. Preliminary data were presented at the annual meeting of the European Association of Endoscopic Surgeons, Berlin 2006. No research grants funded this study.     

Good outcome after liver transplantation for ALD without a 6 months abstinence rule prior to transplantation including post‐transplant CDT monitoring for alcohol relapse assessment – a retrospective study

Alcoholic liver disease (ALD) is the second most common indication for liver transplantation (LT). The utility of fixed intervals of abstinence prior to listing is still a matter of discussion. Furthermore, post‐LT long‐term observation is challenging, and biomarkers as carbohydrate‐deficient transferrin (CDT) may help to identify alcohol relapse. We retrospectively analyzed data from patients receiving LT for ALD from 1996 to 2012. A defined period of alcohol abstinence prior to listing was not a precondition, and abstinence was evaluated using structured psychological interviews. A total of 382 patients received LT for ALD as main (n = 290) or secondary (n = 92) indication; median follow‐up was 73 months (0–213). One‐ and five‐year patient survival and graft survival rates were 82% and 69%, and 80% and 67%, respectively. A total of 62 patients (16%) experienced alcohol relapse. Alcohol relapse did not have a statistically significant effect on patient survival (P = 0.10). Post‐transplant CDT measurements showed a sensitivity and specificity of 84% and 85%, respectively. In conclusion, this large single‐center analysis showed good post‐transplant long‐term results in patients with ALD when applying structured psychological interviews before listing. Relapse rates were lower than those reported in the literature despite using a strict definition of alcohol relapse. Furthermore, post‐LT CDT measurement proved to be a useful supplementary tool for detecting alcohol relapse.     

The Weil osteotomy for treatment of dislocated lesser metatarsophalangeal joints: Good outcome in 21 patients with 42 osteotomies

Hardly any surgical methods are available for metatarsalgia caused by a dislocated lesser metatarsophalangeal joint (MTP) that do not sacrifice the joint. We reviewed retrospectively the outcome of 60 metatarsal Weil osteotomies for correction of dislocated lesser MTP joints in 31 patients. Between 1995 and 1996, 31 consecutive patients were treated with a Weil osteotomy at 2 institutions. The Weil osteotomy is an oblique osteotomy of the metatarsal neck and shaft, parallel to the ground surface, that controls shortening of the metatarsal by internal fixation with screws or pins. At an average final follow-up of 30 (24-44) months, all patients were interviewed, using a standardized questionnaire based on the AOFAS Lesser Metatarsophalangeal-Interphalangeal Scale. Recurrent or transfer metatarsalgia, formation of callus, mobility and dislocation of the MTP were noted on physical examination. Dorsoplantar and lateral weightbearing radiographs taken preoperatively and at the time of final follow-up were examined for alignment of the metatarsal heads, subluxation or dislocation and for evidence of nonunion, or malunion of the metatarsal osteotomy. We had excellent results in 21 patients (42 osteotomies). A major complication was plantar penetrating hardware in 10 cases (3 screws and 7 pins). We conclude that the Weil osteotomy is a good method for correcting metatarsalgia caused by dislocation of the MTP joint.     

Prolonged thromboprophylaxis with Dalteparin during immobilization after ankle fracture surgery: a randomized placebo-controlled, double-blind study

Background Skeletal trauma and immobilization are well-known risk factors for deep vein thrombosis (DVT) and pulmonary embolism (PE). While prophylaxis against thromboembolic complications has become routine after major orthopedic surgery, whether or not prophylaxis after minor surgery and lower limb immobilization is necessary is still under debate.

Methods In a double-blind, placebo-controlled study, 272 consecutive patients were randomized to receive either thromboprophylaxis with Dalteparin (n = 136) or placebo (n = 136) for 5 weeks after ankle fracture surgery. All patients received 1 week of initial treatment with Dalteparin before randomization. A unilateral phlebography was performed when the cast was removed.

Results The overall incidence of DVT was 21% (95% CI: 13-29%) in the Dalteparin group and 28% (CI: 19- 37%) in the placebo group (risk ratio = 0.8, CI: 0.6-1.1; p = 0.3). The incidence of proximal DVTs was 4% and 3%, respectively. No major bleeding occurred.

Interpretation We found no significant difference in the incidence of DVT between the 2 treatment groups and our results do not support prolonged thromboprophylaxis. The overall incidence of DVT was high, reflecting the potential risk of PE and post-thrombotic syndrome after ankle fracture surgery. Most of the DVTs were asymptomatic, however, and were located in distal veins.