Adjuvant extension of chemotherapy after neoadjuvant therapy may not improve outcome in early-stage breast cancer.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is equivalent to adjuvant therapy (AdC) in terms of survival and disease-free interval. Many institutions add AdC after NAC and surgery. However, such extended chemotherapy (ExC) is not evidence based. Study aim was to investigate if ExC improved disease-free (DFS) and overall survival (OS). PATIENTS AND METHODS: From 1998 to 2006 356 consecutive patients received NAC (45 pts), AdC (221 pts) or ExC (90 pts). We analysed these 3 groups to determine effects of ExC and to identify patients who might benefit. NAC consisted in 93% of 3-6 cycles of epirubicin+docetaxel, AdC comprised EC+/-taxanes in 72%. Median age in the NAC, AdC, and ExC-groups was 54, 56 and 52 years with follow-up of 30, 57, and 55 months. RESULTS: After NAC, 35% achieved downstaging and 10% pathologic complete remission. Surprisingly ExC seemed to result in reduction of 5-year DFS: compared to 85% and 82% after NAC and AdC, DFS was 61% after ExC (p=0.001). OS was not significantly affected (79, 91, and 78% after NAC, AdC and ExC, p=0.13). In multivariate analysis after correction for age, menopausal status, stage, grading, hormone receptors, her2-status, radiotherapy and surgery, ExC seemed to adversely affect DFS (HR 2.15, p=0.008), loco-regional and distant recurrence-rates (HR 3.0, p=0.03 and HR 2.0, p=0.02). DISCUSSION: In this single-center analysis ExC could not show advantages in terms of DFS and OS. Because multivariate analyses of retrospective data cannot account for all potential biases, these data require confirmation in randomized clinical trials. Until then, extended chemotherapy should be considered carefully. As in previous studies, no differences were found between NAC and AdC groups.

Medium-term follow-up data after sentinel node biopsy alone for breast cancer.

AIMS: In patients with early breast cancer sentinel node biopsy (SNB) proved to be an accurate procedure for axillary staging with significantly reduced morbidity. Medium- and long-term observational studies are needed to establish, whether SNB alone is able to prevent locoregional recurrence without impairing long-term survival. METHODS: 298 patients with invasive breast cancer were subjected to SNB in a prospective audit. Lymphatic mapping was performed with blue dye and radiocolloids. 180 patients had SNB alone (group 1), while 118 subsequently underwent axillary dissection (AD; group 2). In ten patients AD was omitted despite the tumor burden in the SN. Clinical follow-up studies were performed at regular intervals. The mean follow-up time was 47months in group 1 (range 7-90) and 46months in group two (range 1-87months). RESULTS: Sentinel nodes were identified in 286 out of 298 patients (96%). One patient in group 1 developed axillary and simultaneous supraclavicular lymph node recurrence. After AD regional relapses have so far not been observed. One ipsilateral local recurrence was detected in each group. Five patients in group 1 and 15 patients in group 2 developed distant metastases. Three out of six and eight out of nine patients, respectively, died of their advanced disease. All patients with SN tumor infiltration not subjected to AD are alive and well. CONCLUSIONS: Axillary recurrence is rare after sentinel node biopsy alone. Its rate is comparable to that after AD, even in patients with SN micrometastases. These conclusions are confirmed by reports in the literature.

Sleeve gastrectomy and gastric banding: effects on plasma ghrelin levels.

BACKGROUND: Different changes of plasma ghrelin levels have been reported following gastric banding, Roux-en-Y gastric bypass, and biliopancreatic diversion. METHODS: This prospective study compares plasma ghrelin levels and weight loss following laparoscopic sleeve gastrectomy (LSG) and laparoscopic adjustable gastric banding (LAGB) in 20 patients. RESULTS: Patients who underwent LSG (n=10) showed a significant decrease of plasma ghrelin at day 1 compared to preoperative values (35.8 +/- 12.3 fmol/ml vs 109.6 +/- 32.6 fmol/ml, P=0.005). Plasma ghrelin remained low and stable at 1 and 6 months postoperatively. In contrast, no change of plasma ghrelin at day 1 (71.8 +/- 35.3 fmol/ml vs 73.7 +/- 24.8 fmol/ml, P=0.441) was found in patients after LAGB (n=10). Increased plasma ghrelin levels compared with the preoperative levels at 1 (101.9 +/- 30.3 fmol/ml vs 73.7 +/- 24.8 fmol/ml, P=0.028) and 6 months (104.9 +/- 51.1 fmol/ml vs 73.7 +/- 24.8 fmol/ml, P=0.012) after surgery were observed. Mean excess weight loss was higher in the LSG group at 1 (30 +/- 13% vs 17 +/- 7%, P=0.005) and 6 months (61 +/- 16% vs 29 +/- 11%, P=0.001) compared with the LAGB group. CONCLUSIONS: As a consequence of resection of the gastric fundus, the predominant area of human ghrelin production, ghrelin is significantly reduced after LSG but not after LAGB. This reduction remains stable at follow-up 6 months postoperatively, which may contribute to the superior weight loss when compared with LAGB.

Treatment and reconstruction after disconnection of the failed cervical esophagogastric anastomosis.

Reconstruction of the esophageal passage after severe complications of the esophagogastric anastomosis (disconnection, long stenosis) remains a surgical challenge. We describe the course of five patients with cervical defects (n = 4) or stenosis (n = 1) after complications of the cervical esophagogastric anastomosis and successful reconstruction by free jejunal transfer. Cause of failure of the anastomosis was ischemia in two, and compression, bleeding and unknown reasons in the other three patients respectively. In four patients, subsequent treatment consisted of disconnection of the anastomosis. In all cases, reconstruction by free jejunal transfer was done between 8 weeks and 12 months after primary surgery. A perforation of the graft was observed in one patient (decubital ulcer from the split sternum). All patients regained normal swallowing function. Free jejunal transfer is a safe method for reconstruction of short defects with a satisfactory functional result and minimal surgical trauma.

Efficacy and safety of splenectomy in adult chronic immune thrombocytopenia.

For patients with adult chronic immune thrombocytopenia (ITP) splenectomy (SE) is a highly effective treatment, but there are still uncertainties regarding the long-term efficacy and safety. We evaluated the long-term efficacy and safety of SE in 48 consecutive adult patients with chronic ITP (26 women, 22 men) who underwent SE between 1990 and 2001 at the General Hospital in Vienna, Austria. All patients had no remission after steroid treatment and were steroid dependent. The median age at the time of SE was 44 years (range: 16-77 years). Of 48 patients, 37 achieved a complete remission (CR, platelet count >100 x 10(9)/l), 8 a partial remission (PR) (platelet count 30-100 x 10(9)/l), and 2 had no response (NR). The probability of the overall survival was 98% at a median postsplenectomy observation time of 3.5 years. Seven patients with CR and four patients with PR relapsed. There were no relapses after 1 year. The probability of continuous complete remission (CCR) at 10 years was 79%. The probability of having a platelet count of >100 x 10(9)/l or >30 x 10(9)/l was 61% and 67%, respectively, at 5 and 10 years after splenectomy. Of the 11 relapsed patients, 5 had a second CR ( n=3) or PR ( n=2). The postoperative platelet count was the best predictor for a long-term remission. All patients with postoperative platelet counts >250 x 10(9)/l remained in CR. Patients aged >45 years had a similar success rate as compared with younger patients. Three patients had infections (one pneumonia and two fever of unknown origin) requiring hospitalization, but none had overwhelming septicemia.

Significant symptomatic relief after transoral endoscopic staple-assisted treatment of Zenker's diverticulum.

BACKGROUND: Zenker's diverticulum is associated with characteristic symptoms of progressive dysphagia and regurgitation. As most patients are elderly, the perioperative risk is usually high. We report our clinical experience with the transoral endoscopic staple-assisted method, including a thorough assessment of the symptomatic relief achieved by the procedure. METHODS: 46 consecutive patients (29 m, 17 f) with a median age of 61 years (range, 37-96 years) were treated between 1997 and 2002. The symptoms and their frequency were registered. The follow-up consisted of clinical and radiographic investigations. RESULTS: The median size of the diverticulum was 4 cm (range, 2-12 cm). Transoral treatment was successful in 39 patients; in 7 cases (15.2%) a switch to open surgery was required. The median operating time was 30 min (range, 10-150 min). Mortality rate was nil, while morbidity was 7.7%. The median duration of the postoperative hospital stay was 5 days (range, 1-65 days). After a median follow-up of 11 months (range, 1-40 months), 5 patients had been reoperated on endoscopically due to clinical recurrence. Clinical symptoms were significantly reduced (dysphagia of liquids p

A magnetic probe to retrieve broken metallic parts of instruments during laparoscopic procedures.

To facilitate retrieval of metallic fragments out of the abdominal cavity during laparoscopic procedures, a semiflexible magnetic probe was devised. Efficacy and safety was demonstrated in two clinical cases without need for additional trocar placement or conversion to laparotomy.

Regulation of human jejunal transmucosal resistance and MLC phosphorylation by Na(+)-glucose cotransport.

Na(+)- nutrient cotransport-dependent regulation of paracellular permeability has been demonstrated in rodent intestine and human intestinal epithelial cell lines. In cell lines this regulation is associated with phosphorylation of myosin II regulatory light chain (MLC). However, the subcellular localization of phosphorylated MLC during this regulation has not been studied and regulation of paracellular permeability and MLC phosphorylation has not been studied in isolated human intestine. To evaluate these events in human jejunum, isolated mucosa was mounted in Ussing chambers, characterized electrophysiologically, and then immunostained using anti-phosphorylated MLC and anti-total MLC antisera. MLC phosphorylation was assessed by calculating the ratio of anti-phosphorylated MLC signal to anti-total MLC signal within defined regions. Transmucosal resistance of mucosae without active Na(+)-glucose cotransport was 37 +/- 3% greater than that of mucosae with active Na(+)-glucose cotransport within 15 min. Quantitative double-label immunofluorescence showed that the phosphorylated MLC-to-total MLC ratio increased by 45 +/- 4% within the perijunctional actomyosin ring when Na(+)-glucose cotransport was active. Thus regulation of transmucosal resistance by Na(+)-glucose cotransport is accompanied by increased MLC phosphorylation within the perijunctional actomyosin ring. These data support the proposed critical role of the perijunctional cytoskeleton in physiological regulation of human small intestinal paracellular permeability.

The differentiation inducers phenylacetate and phenylbutyrate modulate camptothecin sensitivity in colon carcinoma cells in vitro by intracellular acidification.

Aromatic fatty acids such as phenylbutyrate (PB) and its metabolite phenylacetate (PA) induce growth arrest, differentiation and apoptosis in solid tumor cells. Despite their antiproliferative action they were reported to exhibit a synergistic effect in combination with cytotoxic drugs like topotecan, and others. Since the activity of the camptothecines (CPTs) depends on local pH conditions, we investigated, whether PB/PA modulate CPT effects indirectly by affecting intracellular pH in SW620 and SW480 colon cancer cells. The results for the colon carcinoma cells show an antagonistic interaction for the combination of CPT and 0.25-5 mM PA in viability assays, resulting in an approximately 3-fold increase in IC50 (control: 20+/-7 nM). A synergistic effect with significantly increased numbers of late apoptotic/necrotic cancer cells (difference +21+/-4%) and 1.4-fold sensitization were detected upon inclusion of 2.5 mM PA during a 4-h CPT (10 micro;M) loading phase. In response to 0.25-1 mM PA/PB the cells exhibit a reversible decrease of pHi (0.1-0.31 pH units) in HEPES- or bicarbonate-buffered media. Dose-dependent acidification and pHi-recovery occurred following addition of PA and PB after an acid load and inhibition of the Na+/H+-antiporter and bicarbonate exchangers, pointing to a possible intracellular mechanism of cytoplasmic acidification. It is concluded that the synergistic modulation of CPT toxicity by short-term PA/PB treatment in colon carcinoma cells is caused by changes in intracellular pH, possibly affecting quantity and localization of the active closed lactone form of this drug.

[Surgery for non-colorectal and non-neuroendocrine liver metastases]. / Die chirurgische Therapie von nicht-kolorektalen und nicht-neuroendokrinen Lebermetastasen.

INTRODUCTION: Hepatic resection has been shown to prolong survival in selected patients with colorectal liver metastases. Due to slow tumor growth patients with neuroendocrine liver metastases tend to have a good prognosis and benefit from chemo-embolisation and symptomatic treatment. The role of surgery in treating non-neuroendocrine and non-colorectal liver metastases is discussed controversially, due to the limited knowledge on this subject. The aim of our study was, therefore, to evaluate our own experiences with hepatic surgery for non-neuroendocrine, non-colorectal liver metastases. METHODS: A retrospective review of 72 patients (median age 60.9 years) who underwent 73 hepatic resections for non-neuroendocrine, non-colorectal liver metastases between 1980 and 2000 at a single tertial referral center was carried out. RESULTS: Hepatic resection was combined with surgery for the primary tumor in 30 cases (41.1%). Hospital mortality was 4.2%. 35 patients (47.9%) developed complications. The mean hospital stay was 17.5 days. In 64.4% of the cases a potentially curative resection was reached. Overall actuarial survival was 52.1% at 1 year, 25.3% at 3 years and 9.9% at 5 years. The respective median overall survival times were 7.1 months (gastric cancer metastases; n = 15), 4.9 months (cholangiocellular cancer metastases; n = 9), 5.6 months (gall bladder, bile duct cancer metastases; n = 8), 35.4 months (kidney cancer metastases; n = 8), 14.4 months (breast cancer metastases; n = 4), 15.3 months (pancreas and other adenocarcinoma metastases; n = 11), 49.9 months (sarcoma metastases; n = 10) and 32.9 months (other metastases; n = 7). CONCLUSIONS: In isolated hepatic metastases originating from sarcoma and hypernephroma radical resection can prolong survival. However, surgery cannot improve the prognosis in patients with liver metastases originating from the pancreas, gallbladder and the biliary tract. In selected patients with liver metastases from gastric and breast cancer long term survival seems possible after resection.

Neurotensin stimulates Cl(-) secretion in human colonic mucosa In vitro: role of adenosine.

BACKGROUND & AIMS: Previous studies indicated that the peptide neurotensin (NT) stimulates Cl(-) secretion in animal small intestinal mucosa in vitro. In this study, we investigated whether NT causes Cl(-) secretion in human colonic mucosa and examined the mechanism of this response. METHODS: Human mucosal preparations mounted in Ussing chambers were exposed to NT. Drugs for pharmacologic characterization of NT-induced responses were applied 30 minutes before NT. RESULTS: Serosal, but not luminal, administration of NT (10(-8) to 10(-6) mol/L) induced a rapid, monophasic, concentration- and chloride-dependent, bumetanide-sensitive short-circuit current (Isc) increase that was inhibited by the specific nonpeptide NT receptor antagonists SR 48692 and SR 142948A, the neuronal blocker tetrodotoxin, and the prostaglandin synthesis inhibitor indomethacin. The mast cell stabilizer lodoxamide and the histamine 1 and 2 receptor antagonists pyrilamine and ranitidine, respectively, did not significantly alter NT-induced Isc increase. In contrast, the adenosine receptor 1 and 2 antagonists inhibited this secretory response, whereas the adenosine uptake inhibitors S-(4-nitrobenzyl)-6-thioguanosine and S-(4-nitrobenzyl)-6-thioinosine and the adenosine deaminase inhibitor deoxycoformycin potentiated NT-induced Isc increase. Serosal adenosine induced a rapid, monophasic, concentration- and chloride-dependent, bumetanide-sensitive Isc increase. CONCLUSIONS: NT stimulates chloride secretion in human colon by a pathway(s) involving mucosal nerves, adenosine, and prostaglandins.

Primary small bowel malignancies: single-center results of three decades.

We highlight one medical center's experiences with primary malignancies of the small bowel. During a 27-year period, 79 patients were treated for small bowel tumors. Of these, 15 (20%) were lost to follow-up; thus, 64 patients were reviewed retrospectively with emphasis on histological distribution and their topography, perioperative complications, overall survival, and prognostic factors. In our 64-patient series, 33 (51.6%) presented with adenocarcinoma; 10 (15.5%), lymphoma; 8 (12.1%), leiomyosarcoma; 5 (7.6%), neurogenic tumor; 2 (3%), unclassified carcinoma; 5 (7.6%), other types of sarcoma; and 1 patient presented with synchronous adenocarcinoma and lymphoma. Of all patients, 30 (46.9%) were curatively treated, whereas 34 (53.1%) underwent palliative procedures. Hospital lethality was 9.4% and mainly occurred in patients operated on under emergency circumstances. Reoperation rate was 29.7%. The observation period lasted at least five years or until death; three patients were alive less than five years postoperatively. Cumulative five-year survival rate was 22.5% in the adenocarcinoma group, 33.3% in the lymphoma group, 33.3% in the leiomyosarcoma group, and 22.2% in patients with other tumors. The uncharacteristic symptoms presented by patients suffering from small intestinal malignancies make early diagnosis difficult. Therefore, especially in patients with long-standing bowel diseases, malignancy should be considered. Early diagnosis and surgical treatment lead to a good prognosis as shown by our study.

Benefit of interferon-alpha2b in a patient with unresectable hepatoma and chronic infection with hepatitis C virus.

Only in a small proportion of patients is advanced hepatocellular carcinoma (HCC) resectable, so the need for effective non-surgical treatments is obvious. We present details of a 72-year-old woman with inoperable HCC and chronic infection with hepatitis C virus, proved by the presence of antibodies directed against hepatitis C virus and positive polymerase chain reaction. The patient was treated with subcutaneous recombinant human interferon-alpha-2b. Within a few weeks, a partial tumour remission, paralleled by a decrease in serum levels of tumour markers and liver enzymes, was observed. In addition, polymerase chain reaction became negative. This observation facilitates the hypothesis that the anti-viral effects of interferon might have been jointly responsible for the anti-tumour activity observed. Interferon-alpha might serve as a treatment option in patients with unresectable hepatoma and chronic active viral hepatitis, but prospective studies are warranted.

In situ mRNA hybridization analysis and immunolocalization of the vitamin D receptor in normal and carcinomatous human colonic mucosa: relation to epidermal growth factor receptor expression.

There is evidence that vitamin D receptor (VDR)-mediated action of 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25-(OH)2D3) could limit colon cancer cell growth particularly when induced by activation of the epidermal growth factor receptor (EGFR). We therefore wanted to ascertain the relevance of this observation for human colon cancerogenesis. Utilizing in situ mRNA hybridization and immunocytochemical techniques, we analyzed cell-specific expression of VDR and EGFR in normal and malignant human colonic mucosa. In normal mucosa, VDR positivity is weak and observed only in a small number of luminal surface colonocytes. In contrast, EGFR expression at a relatively high level is also found in cells at the crypt base. The number of VDR-positive colonocytes increases remarkably during tumor progression. It reaches its maximum in low grade adenocarcinomas and returns to lower levels in highly malignant cancers. In both low- and high grade carcinomas, the great majority of tumor cells contain the EGFR message. The relative abundance of EGFR over VDR in normal mucosa and in high grade carcinomas would create a situation in which mitogenic effects from EGFR activation are only ineffectively counteracted by signaling from 1 alpha,25-(OH)2D3/VDR. In contrast, in well to moderately differentiated tumors, upregulation of VDR could retard further tumor progression.

[Staging of carcinomas of the upper gastrointestinal tract. The current status of diagnostic imaging]. / Staging von Karzinomen des oberen Gastrointestinaltraktes. Standortbestimmung der Bildgebung.

Esophageal carcinoma: CT and endosonography are complementary and the most important imaging modalities at present for staging. After endoscopic and histological diagnosis, CT of the thorax and the abdomen is used. With the proof of local infiltration of a neighbouring organ or in the presence of distant metastasis, palliative therapy can be started. If CT is not conclusive or no local infiltration or distant metastasis is proven, endosonography should be performed. Gastric carcinoma: At present endosonography shows the highest accuracy for diagnosis of the T stage. For differentiation between T3 and T4 tumors the accuracy of CT is not sufficient to predict resectability. The N stage can be determined at present by no modality with sufficient accuracy. Distant metastasis can be diagnosed by CT with high sensitivity and specificity. Small bowel carcinoma: These rare tumors are diagnosed with high accuracy by enteroclysis, whereby the diagnosis takes place at a late stage due to the nonspecific clinical findings.

Effects of substance P on human colonic mucosa in vitro.

Previous studies indicated that the peptide substance P (SP) causes Cl--dependent secretion in animal colonic mucosa. We investigated the effects of SP in human colonic mucosa mounted in Ussing chamber. Drugs for pharmacological characterization of SP-induced responses were applied 30 min before SP. Serosal, but not luminal, administration of SP (10(-8) to 10(-6) M) induced a rapid, monophasic concentration and Cl--dependent, bumetanide-sensitive short-circuit current (Isc) increase, which was inhibited by the SP neurokinin 1 (NK1)-receptor antagonist CP-96345, the neuronal blocker TTX, the mast cell stabilizer lodoxamide, the histamine 1-receptor antagonist pyrilamine, and the PG synthesis inhibitor indomethacin. SP caused TTX- and lodoxamide-sensitive histamine release from colonic mucosa. Two-photon microscopy revealed NK1 (SP)-receptor immunoreactivity on nerve cells. The tyrosine kinase inhibitor genistein concentration dependently blocked SP-induced Isc increase without impairing forskolin- and carbachol-mediated Isc increase. We conclude that SP stimulates Cl--dependent secretion in human colon by a pathway(s) involving mucosal nerves, mast cells, and the mast cell product histamine. Our results also indicate that tyrosine kinases may be involved in this SP-induced response.

Bacteroides fragilis toxin 2 damages human colonic mucosa in vitro.

BACKGROUND: Strains of Bacteroides fragilis producing a 20 kDa protein toxin (B fragilis toxin (BFT) or fragilysin) are associated with diarrhoea in animals and humans. Although in vitro results indicate that BFT damages intestinal epithelial cells in culture, the effects of BFT on native human colon are not known. AIMS: To examine the electrophysiological and morphological effects of purified BFT-2 on human colonic mucosa in vitro. METHODS: For resistance (R) measurements, colonic mucosa mounted in Ussing chambers was exposed to luminal or serosal BFT-2 (1.25-10 nM) and after four hours morphological damage was measured on haematoxylin and eosin stained sections using morphometry. F actin distribution was assessed using confocal microscopy. RESULTS: Serosal BFT-2 for four hours was four-, two-, seven-, and threefold more potent than luminal BFT-2 in decreasing resistance, increasing epithelial 3H-mannitol permeability, and damaging crypt and surface colonocytes, respectively (p<0.05). Confocal microscopy showed reduced colonocyte F actin staining intensity after exposure to BFT-2. CONCLUSIONS: BFT-2 increases human colonic permeability and damages human colonic epithelial cells in vitro. These effects may be important in the development of diarrhoea and intestinal inflammation caused by B fragilis in vivo.