Long-term prognostic impact of surgical complications in the German Rectal Cancer Trial CAO/ARO/AIO-94.

BACKGROUND: The influence of postoperative complications on survival in patients with locally advanced rectal cancer undergoing combined modality treatment is debatable. This study evaluated the impact of surgical complications on oncological outcomes in patients with locally advanced rectal cancer treated within the randomized CAO/ARO/AIO-94 (Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society) trial. METHODS: Patients were assigned randomly to either preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) or postoperative CRT between 1995 and 2002. Anastomotic leakage and wound healing disorders were evaluated prospectively, and their associations with overall survival, and distant metastasis and local recurrence rates after a long-term follow-up of more than 10 years were determined. Medical complications (such as cardiopulmonary events) were not analysed in this study. RESULTS: A total of 799 patients were included in the analysis. Patients who had anterior or intersphincteric resection had better 10-year overall survival than those treated with abdominoperineal resection (63·1 versus 51·3 per cent; P < 0·001). Anastomotic leakage was associated with worse 10-year overall survival (51 versus 65·2 per cent; P = 0·020). Overall survival was reduced in patients with impaired wound healing (45·7 versus 62·2 per cent; P = 0·009). At 10 years after treatment, patients developing any surgical complication (anastomotic leakage and/or wound healing disorder) had impaired overall survival (46·6 versus 63·8 per cent; P < 0·001), a lower distant metastasis-free survival rate (63·2 versus 72·0 per cent; P = 0·030) and more local recurrences (15·5 versus 6·4 per cent; P < 0·001). In a multivariable Cox regression model, lymph node metastases (P < 0·001) and surgical complications (P = 0·008) were the only independent predictors of reduced overall survival. CONCLUSION: Surgical complications were associated with adverse oncological outcomes in this trial.

Surgical options for locally recurrent rectal cancer--review and update.

Locally recurrent rectal tumours in the pelvis are found in about 6% following treatment for rectal cancer. This type of tumour can cause serious local complications and symptoms. The aim of modern surgical oncology is to offer a curative treatment option embedded in an interdisciplinary network of specialities to the patient. Due to advancements in surgical techniques and procedures, especially regarding surgical reconstruction, the possibilities of a curative treatment regarding recurrent cancers have been expanded and established. To aim for a curative treatment one must introduce a multimodal therapy including radio- and chemotherapy, and a radical oncological surgery with en bloc resection of the tumour and affected surrounding organs to achieve a R0-resection.

[Plastic surgery of extended defects after exenteration of the pelvis]. / Plastische Deckung ausgedehnter Defekte nach exenterativen Eingriffen im Becken.

Extended resections of pelvic malignancies, especially in cases of recurrent malignancies, result in the formation of large tissue defects in the region of the pelvic floor and perineum, which are difficult to deal with. Both after extra levator rectal excision and pelvic exenteration, wound healing deficiencies and local infections of the perineal wound are frequent. Primary closure is often impossible due to a lack of tissue substance after resection and an additional previous radiotherapy in most cases. This can result in poor or non-healing wounds, a consecutive need of complex care and an increased risk of secondary problems including tumour recurrences. A permanent wound closure of good quality can therefore only be achieved by plastic surgery. This can be done by local or distant muscle flaps with or without skin, for example, the gluteus maximus flap, the vertical rectus abdominis muscle flap (VRAM) or free flaps such as the latissimus dorsi flap.

Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study).

BACKGROUND: Initially, unresectable colorectal liver metastases can be resected after response to chemotherapy. While cetuximab has been shown to increase response and resection rates, the survival outcome for this conversion strategy needs further evaluation. PATIENTS AND METHODS: Patients with technically unresectable and/or ≥5 liver metastases were treated with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated with regard to resectability every 2 months. Tumour response and secondary resection data have been reported previously. A final analysis of overall survival (OS) and progression-free survival (PFS) was carried out in December 2012. RESULTS: Between December 2004 and March 2008, 56 patients were randomised to arm A, 55 to arm B. The median OS was 35.7 [95% confidence interval (CI) 27.2-44.2] months [arm A: 35.8 (95% CI 28.1-43.6), arm B: 29.0 (95% CI 16.0-41.9) months, HR 1.03 (95% CI 0.66-1.61), P = 0.9]. The median PFS was 10.8 (95% CI 9.3-12.2) months [arm A: 11.2 (95% CI 7.2-15.3), arm B: 10.5 (95% CI 8.9-12.2) months, HR 1.18 (95% CI 0.79-1.74), P = 0.4]. Patients who underwent R0 resection (n = 36) achieved a better median OS [53.9 (95% CI 35.9-71.9) months] than those who did not [21.9 (95% CI 17.1-26.7) months, P < 0.001]. The median disease-free survival for R0 resected patients was 9.9 (95% CI 5.8-14.0) months, and the 5-year OS rate was 46.2% (95% CI 29.5% to 62.9%). CONCLUSIONS: This study confirms a favourable long-term survival for patients with initially sub-optimal or unresectable colorectal liver metastases who respond to conversion therapy and undergo secondary resection. Both FOLFOX/FOLFIRI plus cetuximab, appear to be appropriate regimens for 'conversion' treatment in patients with K-RAS codon 12/13/61 wild-type tumours. Thus, liver surgery can be considered curative or alternatively as an additional 'line of therapy' in those patients who are not cured. CLINICAL TRIAL NUMBER: NCT00153998, www.clinicaltrials.gov.

[Modified McPeek score in multiple trauma patients. Prospective evaluation of a points system for recording follow-up factors]. / Modifiziertes McPeek-Punkte-System bei Polytraumapatienten. Prospektive Evaluierung eines Punktesystems zur Erfassung von Verlaufsfaktoren.

BACKGROUND: Many commonly available trauma scores predict mortality, but to evaluate the success of a certain therapy or for difficult scientific and epidemiological purposes this may be insufficient in the face of improved survival rates. For outcome analysis of multiple trauma patients, the extent of medical resources needed could be an additional outcome measurement. McPeek et al. developed a potential scoring system for elective surgery patients, which was recently modified for multiple trauma patients. AIM: The current study investigated if the McPeek score could be prospectively used in multiple trauma patients and whether it could become an additional helpful tool in outcome assessment. Applicability was assessed by practical examples. MATERIAL AND METHODS: In this prospective single-centre study at the University Hospital of Innsbruck, Austria, between December 2008 and November 2010 multiple trauma patients (≥ 18 years) with an injury severity score (ISS) ≥ 17 were enrolled. Besides demographic data, prehospital vital parameters and diagnoses, all diagnoses from the trauma, mortality, length of stay in the intensive care unit and the hospital were recorded. The commonly used trauma scores ISS, revised trauma score (RTS), a severity characterization of trauma (ASCOT) and trauma and injury severity score (TRISS) were applied and an observed McPeek score was allocated following end of hospitalization. The McPeek scoring system was used according to the latest modifications. A correlation between trauma scores and the McPeek score was performed. The McPeek score was then predicted by a common trauma score using ordinal regression with the polytomous universal model (PLUM method). By subtracting the predicted from the observed McPeek scores the residual McPeek value was calculated and used for practical examples of outcome analysis with the McPeek scoring system. RESULTS: Out of 406 identified multiple trauma patients during the study phase, 183 had to be excluded due to missing data (mainly prehospital or following transfer). A total of 223 patients (mean ISS 31.2, mean age 47.2 years) were enrolled and assigned to the population-based observed McPeek score (median 4.0). Correlation coefficients were Glasgow coma scale (GCS) 0.59, ISS 0.62, RTS 0.65, TRISS 0.74 and ASCOT 0.77 (p < 0.0001). The TRISS predicted the McPeek score best in ordinal regression (pseudo-R(2) = 0.944, p < 0.0001). The residual McPeek score (observed minus predicted) was used to illustrate the influence of the blood glucose level on admission and the influence of head injury on outcome of multiple injury patients in detail. CONCLUSION: The modified McPeek score is applicable to multiple trauma patients to assess outcome for scientific or epidemiological purposes. Its main advantage is that it quantifies outcome independently of regional or national circumstances.

[Oesophageal perforation: a retrospective analysis of aetiology, diagnosis and therapy]. / Osophagusperforation: Eine retrospektive Analyse über Atiologie, Diagnostik und Therapie.

Oesophageal perforation is commonly a rare diagnosis which is associated with a high mortality rate. Decisive for a good clinical outcome are localisation and depth of the perforation, risk factors, the time until diagnosis and a rapid therapy. The data we collected agree with those in the published papers. In cases of an early diagnosis sometimes an endoscopic therapy is possible. In -cases of surgical therapy the smallest intervention is the most favourable. A resection with the necessity for a later reconstruction is considered as the ultima ratio.

Identification of heregulin, a specific activator of p185erbB2.

The proto-oncogene designated erbB2 or HER2 encodes a 185-kilodalton transmembrane tyrosine kinase (p185erbB2), whose overexpression has been correlated with a poor prognosis in several human malignancies. A 45-kilodalton protein heregulin-alpha (HRG-alpha) that specifically induced phosphorylation of p185erbB2 was purified from the conditioned medium of a human breast tumor cell line. Several complementary DNA clones encoding related HRGs were identified, all of which are similar to proteins in the epidermal growth factor family. Scatchard analysis of the binding of recombinant HRG to a breast tumor cell line expressing p185erbB2 showed a single high affinity binding site [dissociation constant (Kd) = 105 +/- 15 picomolar]. Heregulin transcripts were identified in several normal tissues and cancer cell lines. The HRGs may represent the natural ligands for p185erbB2.

[Treatment of retroperitoneal sarcoma in Germany : Results of a survey of the German Society of General and Visceral Surgery, the German Interdisciplinary Sarcoma Study Group and the advocacy group Das Lebenshaus]. / Behandlung retroperitonealer Sarkome in Deutschland : Eine Umfrage der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie, der Deutschen Interdisziplinären Studiengruppe Sarkome und der Patientenorganisation Das Lebenshaus.

OBJECTIVE: Retroperitoneal sarcomas (RPSs) are rare cancers with some variability in clinical and histopathological presentation. In Germany, general treatment strategies of retroperitoneal sarcoma are unknown since centralized registries do not exist. The objective of this survey was to access the medical care of RPS patients in Germany. METHODS: In cooperation with the German Society of General and Visceral surgery, the German Interdisciplinary Sarcoma Study Group and the patient advocacy group Das Lebenshaus we designed an online survey assessing diagnostic and treatment strategies (e. g. performance of tumor biopsies, administration of multimodal therapies and surgical strategy). All departments for general and visceral surgery in Germany were addressed (n = 976). RESULTS: Responses were received from 191 of 976 departments. Only 11 surgical departments treat more than 10 RPS patients per year. A multidisciplinary sarcoma board exists in 19 hospitals. Staging is generally performed by cross-sectional imaging. In 54% of the departments pretreatment tumor biopsy is a standard procedure. Surgery is performed as compartment resection in 85% of the departments. A systematic lymph node dissection is done in 40%. Adjuvant radio- or chemotherapy is performed as a standard treatment in 27% and 22% departments, respectively. CONCLUSION: The survey demonstrates a large heterogeneity in RPS diagnostic and treatment strategies. Dedicated education programs and centralized treatment strategies are warranted to improve the standard of care.

[R1 resection in rectal cancer]. / Die R1-Resektion beim Rektumkarzinom.

R1 resections in rectal cancer particularly affect the circumferential resection margin (CRM) and lead to increased local recurrence rates, more distant metastases and a poorer prognosis. The proximity of the tumor to the CRM is already sufficient to increases these risks; therefore, according to the guidelines, it is now necessary to distinguish between R0 wide (≥1 mm distance), R0 close (<1 mm) and R1. The surgical technique is decisive for avoiding R1 situations. The preparation follows the boundary layers and envelope fascia in a standardized radical way and if necessary deviates away from these structures and the tumor under en bloc resection of neighboring structures. Neoadjuvant therapy also contributes to the reduction of R1 situations but cannot compensate for inadequate surgical procedures.

[Rare lesion in hepatoduodenal ligament]. / Seltene Raumforderung im Ligamentum hepatoduodenale.

A 60-year-old man was admitted for surgical treatment with a diagnosis of distal oesophageal carcinoma. A lymph node metastasis in the area of the hepatoduodenal ligament was suspected by preoperative CT scan and endosonographic examination. During the course of the oesophagectomy, a saccular tumour encircling the common hepatic artery was shown. The vessel and surrounding tumour were resected en bloc. Histology demonstrated a completely thrombosed true aneurysm of the common hepatic artery.

Treatment of Esophageal Perforation: A Single-Center Expertise.

BACKGROUND AND AIMS: Esophageal perforation is a rare diagnosis, which is associated with a high morbidity and mortality. There is only small scientific background regarding the best choice of treatment. Parameters indicating a good clinical outcome seem to be localization, depth of the defect, pre-existing risk factors, and time interval between the event and start of treatment. MATERIAL AND METHODS: We evaluate retrospective data from 39 patients who were treated with a esophageal perforation in our hospital between 2004 and 2012. RESULTS AND CONCLUSIONS: Our collected data agree with the available published literature. Endoscopic treatment seems to be favorable in early diagnosis.

Validation of the sleep-EVAL system against clinical assessments of sleep disorders and polysomnographic data.

OBJECTIVES: To validate the Sleep-EVAL expert system, a computerized tool designed for the assessment of sleep disorders, against polysomnographic data and clinical assessments by sleep specialists. DESIGN: Patients were interviewed twice, once by a physician using Sleep-EVAL and again by a sleep specialist. Polysomnographic data were also recorded to ascertain diagnoses. Agreement between diagnoses generated by Sleep-EVAL and those formulated by sleep specialists was determined via the kappa statistic. SETTINGS: Sleep disorder centers at Stanford University (USA) and Regensburg University (Germany). PATIENTS: 105 patients aged 18 years or over. INTERVENTIONS: NA. RESULTS: Sleep-EVAL made an average of 1.32 diagnoses per patient, compared with 0.93 for the sleep specialists. Overall agreement on any sleep-breathing disorder was 96.9% (Kappa .94). More than half of the patients were diagnosed with obstructive sleep apnea syndrome (OSAS); the agreement rate for this specific diagnosis was 96.7% (Kappa .93). CONCLUSIONS: The findings indicate that the Sleep-EVAL system is a valid instrument for the recognition of major sleep disorders, particularly insomnia and OSAS.

Effects of sex and estrogen on tyrosine hydroxylase mRNA in cultured embryonic rat mesencephalon.

In order to elucidate cellular events responsible for sex differentiation of the nigro-striatal system, we studied the influence of estrogen on the expression of tyrosine hydroxylase (TH) in sex-specific dissociated cell cultures of embryonic day 14 rat mesencephalon. Cultures were raised in the absence or presence of 17 beta-estradiol (10(-12) M) and hybridized with a [35S]oligonucleotide specific to TH. Cultured cells and tissues were probed for estrogen receptor (ER) transcripts by hemi-nested PCR. More TH mRNA containing cells were present in control cultures from female than from male donors. Estrogen treatment resulted in an up-regulation of TH expression in male cells only and induced a reversal of the sex difference in TH mRNA levels present in early control cultures. ER message was detectable in hypothalamic and uterine tissues but not in mesencephalic tissue or cultured cells. Estrogen exposure failed to induce ER expression in cultured mesencephalic cells. It is concluded that there are sex differences in TH mRNA expression of developing midbrain dopaminergic neurons which are independent of the steroid environment. Estrogen can up-regulate TH mRNA in a sex-specific fashion by modulating signal transduction mechanisms other than the classical nuclear receptor pathway.

Ontogeny of aromatase messenger ribonucleic acid and aromatase activity in the rat midbrain.

Estrogen formation catalyzed by neural aromatase is crucial for the sexual differentiation of the brain. Ontogenic expression of aromatase mRNA and aromatase activity were studied in male and female rat midbrains. Aromatase mRNA was transiently expressed in both sexes showing maximum levels on postnatal day (P)2 and being absent on P20 and in adults. Developmental expression of aromatase mRNA preceded that of aromatase activity. These data demonstrate that the capacity for estrogen formation is present during a distinct phase of midbrain development. Our findings suggest an active role for estrogens in the differentiation of midbrain neurons.

Pituitary adenylate cyclase-activating polypeptide: a potent activator of human intestinal ion transport.

To investigate the effects of PACAP-27 on electrolyte transport across the isolated human intestinal mucosa, changes in short-circuit current (Isc) were measured in Ussing chamber experiments. Serosally added PACAP-27 increased Isc in a concentration-dependent manner, eliciting a similar maximal effect in both the jejunal and the colonic mucosa. Bumetanide inhibited Isc responses, indicating stimulation of Cl- secretion. The potency and efficacy of PACAP-27 were comparable to those of VIP, suggesting that both peptides activate intestinal secretion by way of a common receptor located in the basolateral membrane of the intestinal epithelium.

Surgery as primary treatment in patients with liver metastases from carcinoid tumors: a retrospective, unicentric study over 13 years.

BACKGROUND: The heterogeneous nature of carcinoid tumors makes it difficult to develop a standardized treatment strategy for the primary tumor itself and for probable liver metastases. However, prolongation of the 5-year survival rate (5-ysr) and amelioration of the incapacitating symptoms after resection of the primary tumor and its metastases demonstrate that surgical intervention must be the treatment of choice in these tumors. METHODS: The data of 31 patients (17 patients with midgut carcinoids, 10 patients with an endocrine carcinoma (carcinoid) of the pancreas, and 4 patients with carcinoids of the lung) who underwent liver operation for metastatic carcinoid tumors between 1983 and 1996 were analyzed, with special regard to factors influencing postoperative survival. RESULTS: Ten patients underwent curative resection (5-ysr, 86%), and palliative operations were performed in 21 patients (5-ysr, 26%). The overall 5-ysr was 47%, with a mean postoperative follow-up of 3.5 years (range, 4 months to 10.8 years). Postoperative morbidity rate was 13%. Size of liver metastases, radicality of the operation and localization of the primary tumor were factors influencing postoperative survival. CONCLUSIONS: Surgery for metastatic carcinoid tumors may be curative or palliative, with a potential for cure in some cases and prolongation of survival and amelioration of symptoms in the majority of patients.

The nitura study--effect of nitroglycerin or urapidil on hemodynamic, metabolic and respiratory parameters in hypertensive patients with pulmonary edema.

OBJECTIVE: To assess the effects of nitroglycerin or urapidil on hemodynamic, respiratory and metabolic parameters in hypertensive patients with pulmonary edema. DESIGN: Open, randomized and prospective clinical study. SETTING: Out-of-hospital setting and Emergency Department in a 2000-bed hospital. PATIENTS: Hundred twelve patients with evidence of hypertensive crises with pulmonary edema (systolic blood pressure (SBP) > 200 mmHg and/or diastolic blood pressure (DBP) > 100 mm Hg and rales over both lungs) at the time when the emergency physician arrived. INTERVENTIONS: The out-of-hospital treatment consisted of oxygen via face mask, 80 mg furosemide i.v., 10 mg morphium s.c., and either nitroglycerin sublingually (initial dose: 0.8 mg; repetitive administration of 0.8 mg every 10 min to a cumulative dose of 3.2 mg) or urapidil (initial dose: 12.5 mg i.v.; repetitive administration every 15 min to a cumulative dose of 50 mg). If SBP was more than 180 mm Hg and/or DBP more than 90 mm Hg on admission, antihypertensive treatment was continued with nitroglycerin (0.3-3 mg/h) or urapidil (5-50 mg/h). MEASUREMENTS AND RESULTS: Blood pressure (BP) was measured every 5 min with the use of an automatic oscillometric device. Serum lactate, PO2, pH value, and base excess (BE) were evaluated on admission and 6 h later. Blood pressure, serum lactate and BE on admission were significantly lower (SBP: 155 +/- 30 vs 179 +/- 33 mm Hg; p = 0.0002; DBP: 82 +/- 17 vs 93 +/- 19 mmHg; p = 0.001; lactate: 2.2 +/- 1.6 vs 3.9 +/- 2.7; p = 0.0001; BE: -1.9 +/- 3.9 vs -4.4 +/- 1.7; p = 0.0005) and PO2 and pH values were significantly higher in the urapidil group compared to the nitroglycerin group (PO2: 75 +/- 25 vs 66 +/- 17; p = 0.036; pH: 7.33 +/- 0.08 vs 7.29 +/- 0.09; p = 0.042). After 6 h no differences between the two groups were observed. CONCLUSION: The more pronounced BP reduction in the urapidil group was associated with an improved respiratory and metabolic situation in hypertensive patients with pulmonary edema. Therefore, urapidil is a valuable alternative to nitroglycerin in patients with pulmonary edema and systemic hypertension.

Uroguanylin: gene structure, expression, processing as a peptide hormone, and co-storage with somatostatin in gastrointestinal D-cells.

Guanylin/GCAP-I and uroguanylin/GCAP-II are two structurally related peptides which play an important role in the regulation of water/electrolyte balance within the gut. In order to enable the investigation and comparison of both peptide hormones at the genomic level, we decided to clone the corresponding genes. The human gene for guanylin/GCAP-I and its 5'-flanking region have been described recently. Here, we report the three exon/two intron structure of the human uroguanylin/GCAP-II gene and its localization on chromosome 1 p35-34, as determined by radiation hybrid mapping. Together with data obtained for the guanylin/GCAP-I gene we show that these genes are localized in the same chromosomal area with other guanlyl cyclase-activating peptides like ANP etc. Northern hybridization revealed that the expression of the uroguanylin/GCAP-II gene is highest in the intestinal mucosa, especially in the ileum and colon. By means of polymerase chain reaction (PCR), an expression was also observed in the stomach where no guanylin/GCAP-I expression is detectable. Using immunohistochemical methods, uroguanylin/GCAP-II immunoreactive material was distinctly localized in D-type gastric and intestinal endocrine cells. Although the comparable data on the genomic organisation of both peptide hormones verify their high degree of relationship, this finding indicates a special task of uroguanylin/GCAP-II within the stomach, such as regulatory functions in gastric secretion. The redundant expression of the GCAP/GC-C system in the small and large intestine, however, is as yet unclear.

Ontogenetic expression and splicing of estrogen receptor-alpha and beta mRNA in the rat midbrain.

Several studies have shown that estrogen is important for the differentiation of midbrain dopaminergic neurons. This is supported by the previous demonstration of estrogen synthesis in the perinatal ventral midbrain. The present study attempts to characterize the expression pattern of nuclear estrogen receptors (ER-alpha/beta) mRNAs in the ventral rat midbrain during development. By applying primers specific for the hormone-binding domain, ER-alpha mRNA was detected from embryonic day (E) 14 until postnatal day (P) 20, whereas considerable levels of ER-beta mRNA were found from P3 to P20. In contrast, primers spanning the DNA-binding domain demonstrated the presence of transcripts for ER-alpha as well as ER-beta after birth. These findings indicate that both ERs are expressed in the developing midbrain. The presence of ER-alpha transcripts devoid of the DNA-binding region is discussed in the context of 'non-genomic' estrogen signaling possibly by membrane receptors.