Günther Kundt

Skin-Sparing Mastectomy with Conservation of the Nipple–Areola Complex and Autologous Reconstruction is an Oncologically Safe Procedure

Objective Is skin-sparing mastectomy (SSM) with conservation of the Nipple–Areola Complex (NAC) and immediate autologous reconstruction as safe in oncologic terms as SSM with resection of the NAC as modified radical mastectomy (MRM)? Summary Background Data The originally described technique of SSM included the removal of gland, NAC, and biopsy scar. However, the risk of tumor involvement of NAC in patients with breast cancer has been overestimated. Patients and Methods Between 1994 and 2000, 286 selected patients with an indication for MRM and tumor margins of greater than 2 cm from the nipple were presented with the alternative of a SSM. Regular follow-up data were evaluable of 112 patients with SSM and 134 patients with MRM. Immediate reconstruction was achieved by latissimus dorsi flap or TRAM flap. The mean follow-up time was 59 (18 to 92) months. Results Patients with SSM were significantly younger than those with MRM but were comparable regarding clinical data, tumor parameters, adjuvant treatment, and overall complications. After intraoperative frozen sections of the NAC-ground, the NAC could be conserved in 61 (54.5%) but was resected in 51 (45.5%) of the 112 patients with SSM. The aesthetic results after SSM were evaluated as excellent or good in 91.1% (102/112) patients and were significantly better after preservation of the NAC (P = 0.001). Six (5.4%) recurrences occurred in 112 patients with SSM compared with 11 (8.2%) cases after MRM. Only 1 recurrence in a conserved nipple was treated by wide excision of nipple with conservation of the areola. This patient is still free of disease after 52 months. Conclusion In patients who are candidates for a mastectomy and tumors distant from the nipple, SSM with intraoperative frozen section of the NAC ground offers the opportunity of NAC conservation without increasing the risk of local recurrences.

The Oncological Safety of Skin Sparing Mastectomy with Conservation of the Nipple-Areola Complex and Autologous Reconstruction : An Extended Follow-Up Study

Objective:To find out if skin sparing mastectomy (SSM) and nipple sparing mastectomy (NSM) with immediate autologous reconstruction as safe in oncological terms as modified radical mastectomy (MRM). Summary Background:The oncological safety of less radical surgical procedures like SSM and NSM cannot be evaluated by randomized trials. A careful and long lasting follow-up of patients, treated with SSM or NSM, is urgently needed. Patients and Methods:Between 1994–2000, 246 selected patients with an indication for MRM were treated with SSM, NSM, or MRM. Short term results were published in 2003.1 After a mean follow-up of 101 months (range 32–126), 238 evaluable patients with SSM (N = 48), NSM (N = 60), or MRM (N = 130) were analyzed for local and distant recurrences, breast cancer specific death, and esthetic results. Results:Local recurrences occurred in 10.4% (SSM), 11.7% (NSM) and 11.5% (MRM) of all patients (P = 0.974). With regard to isolated DM (25.0%, 23.3%, respectively 26.2%; P = 0.916) and breast cancer specific death (20.8%, 21.7%, respectively 21.5%; P = 0.993), there were no significant differences between subgroups. The re-evaluation of esthetic results by surgeons revealed a significant shift from 78.4% excellent results after 59 months to 47.9% after 101 months follow-up (SSM; P = 0.004) and from 73.8% to 51.7% (NSM; P = 0.025). An important risk factor for decreased cosmetic score was application of adjuvant radiotherapy. Conclusion:In patients who are candidates for a mastectomy, skin sparing mastectomy or nipple sparing mastectomy with immediate autologous reconstruction are oncologically safe techniques. Adjuvant radiotherapy decreases the esthetic results even after a longer period of time.

Impaired Flow-Mediated Vasodilation, Carotid Artery Intima-Media Thickening, and Elevated Endothelial Plasma Markers in Obese Children: The Impact of Cardiovascular Risk Factors

OBJECTIVES. Childhood obesity contributes to the development of adult obesity and subsequent cardiovascular disease. The present study aimed to assess vascular status (flow-mediated vasodilation [FMD], intima-media thickness [IMT]) and to analyze plasma surrogate endothelial markers (von Willebrand factor [vWf], E-selectin, and thrombomodulin) in obese children as compared with controls. Associations between early morphologic and functional vascular changes, surrogate soluble markers of early atherosclerosis, and the cardiovascular risk profile were determined. METHODS. We examined 32 obese children versus 20 control subjects. All of the children underwent identical screening, comprehensive risk factor assessment, and measurements of E-selectin, vWf, thrombomodulin, FMD, and IMT. RESULTS. Compared with controls, obese children demonstrated significantly impaired FMD and increased IMT. Concentrations of soluble E-selectin and thrombomodulin were significantly elevated in obese children, whereas vWf showed no significant differences between obese children and controls. FMD, IMT, E-selectin, and thrombomodulin were significantly associated with various risk factors, including the extent of obesity, arterial hypertension, fibrinogen, C-reactive protein, and low physical fitness. CONCLUSIONS. The present study documented increased IMT, impaired endothelial function, and elevated plasma markers of endothelial activation and injury in obese children. Morbid obesity, arterial hypertension, subclinical inflammation, and low physical fitness formed a risk profile associated with the risk of early atherosclerosis in these children. Sonographic assessment of vascular status and the estimation of soluble endothelial plasma markers, combined with comprehensive risk factor screening, may form a rationale to identify high-risk children susceptible to early atherosclerotic disease and to monitor vascular changes during follow-up studies and therapeutic measures.

Simultaneous Immunohistochemical Detection of Tumor Cells in Lymph Nodes and Bone Marrow Aspirates in Breast Cancer and Its Correlation With Other Prognostic Factors

PURPOSE We studied the prognostic and predictive value of immunohistochemically detected occult tumor cells (OTCs) in lymph nodes and bone marrow aspirates obtained from node-negative breast cancer patients. All were classified as distant metastases-free using conventional staging methods. PATIENTS AND METHODS A total of 484 patients with pT1-2N0M0 breast cancer and 70 with pT1-2N1M0 breast cancer and a single affected lymph node participated in our trial. Ipsilateral axillary lymph nodes and intraoperatively aspirated bone marrow were examined. All samples were examined for OTCs using monoclonal antibodies to cytokeratins 8, 18, 19. Immunohistological findings were correlated with other prognostic factors. The mean follow-up was 54 +/- 24 months. RESULTS OTCs were detected in 180 (37.2%) of 484 pT1-2N0M0 patients: in the bone marrow of 126 patients (26.0%), in the lymph nodes of 31 patients (6.4%), and in bone marrow and lymph nodes of 23 (4.8%) patients. Of the 70 patients with pT1-2N1MO breast cancer and a single involved lymph node, OTCs were identified in the bone marrow of 26 (37.1%). The ability to detect tumor cells increased with the following tumor features: larger size, poor differentiation, and higher proliferation. Tumors of patients with OTCs more frequently demonstrated lymph node invasion, blood vessel invasion, higher urokinase-type plasminogen activator levels, and increased PAI-1 concentrations. Patients with detected OTCs showed reduced disease-free survival (DFS) and overall survival (OAS) rates that were comparable to those observed in patients who had one positive lymph node. Multivariate analysis of prognostic factors revealed that OTCs, histological grading, and tumor size are significant predictors of DFS; OTCs and grading of OAS. CONCLUSION OTCs detected by simultaneous immunohistochemical analysis of axillary lymph nodes and bone marrow demonstrate independent metastatic pathways. Although OTCs were significantly more frequent in patients with other unfavorable prognostic factors, they were confirmed as an independent prognostic factor for pT1-2N0M0, R0 breast cancer patients.

Postoperative Chemotherapy May Not Be Necessary for Patients With ypN0-Category After Neoadjuvant Chemoradiotherapy of Rectal Cancer

PurposeAfter neoadjuvant radiochemotherapy and surgery, there is no general agreement about whether postoperative chemotherapy is necessary. With the help of clinical and pathohistologic data, prognostic factors were determined as a basis for the decision to spare a patient additional chemotherapy or to urgently recommend it.ResultsNinety-five patients treated with neoadjuvant 5-fluorouracil-based radiochemotherapy (November 4, 1997 and June 15, 2004) without distant metastases and an R0 (microscopically complete) resection were evaluated. Adjuvant chemotherapy (5-fluorouracil or 5-fluorouracil/folinic acid) was given to 65 of 95 patients (68.4 percent). The disease-free survival rate after 36 months was chosen as the target parameter (median follow-up, 36 months).MethodsThe five-year survival rate for all patients was 80.3 ± 5.6 percent; the five-year disease-free survival was 78.1 ± 5.1 percent; the five-year local control rate was 94.2 ± 5.1 percent. In the univariate and multivariate analysis of the disease-free survival, the pathohistologic lymph node status after radiochemotherapy (ypN) was the only significant prognostic parameter. Disease-free survival (36 months) for patients without lymph node metastases (ypN0) was excellent, independent of whether they had received postoperative chemotherapy (n = 43; 87.5 ± 6.0 percent) or not (n = 29; 87.7 ± 6.7 percent). Patients with ypN2 status have, despite chemotherapy, a poor disease-free survival at 30 ± 17.6 percent after 36 months.ConclusionsThese retrospective data suggest that, for some patients, postoperative chemotherapy can be spared. For patients with ypN2 status, an intensification of the postoperative chemotherapy should be considered. Further evaluation in prospective studies is urgently recommended.

Ultrasonographic detection of asymptomatic endometrial cancer in postmenopausal patients offers no prognostic advantage over symptomatic disease discovered by uterine bleeding

The aim of this study was to investigate whether endometrial carcinoma (EC) screening by transvaginal sonography (TVS) has a prognostic advantage over symptomatic EC. In a retrospective study, 190 postmenopausal patients with symptomatic EC and 123 asymptomatic patients with suspicious endometrium detected by TVS were analysed regarding clinical, socio-economic and histopathological findings. Total bleeding time and the International Federation of Gynecology and Obstetrics (FIGO) tumour stage were evaluated with respect to their effect on survival. In 123 asymptomatic patients with suspicious endometrium, 16 (13%) EC, 61 (50%) polyps, 21 (17%) hyperplasias, 23 (19%) atrophias, 1 (0.8%) myoma and 1 (0.8%) metastasis were found. TVS findings in asymptomatic patients resulted in unnecessary operations, which were associated with considerable costs totalling at least 116256. Compared with screened asymptomatic patients, symptomatic patients were significantly (P<0.05) older, more frequently obese, and hypertensive, had a larger proportion of cases living in rural areas and visited their gynaecologists rarely. The bleeding time of symptomatic patients strongly correlated with the tumour stage (P<0.0001). Depending on the bleeding time, the 5-year disease-free survival and overall survival rates were 77% and 86% (no bleeding), 83% and 98% (<8 weeks), 74% and 90% (8-16 weeks), and 62% and 69% (>16 weeks), respectively. The corresponding tumour stage-related data for disease-free and overall survival were 100% (Ia; both rates), 87% and 95% (Ib), 66% and 93% (Ic), 63% and 78% (II) and 36% (III/IV; both rates), respectively. Postmenopausal vaginal bleeding represents an early symptom of EC, but it is not always perceived as problematic by the patients. There is no prognostic advantage for screened compared with symptomatic patients, who had bleeding of shorter than 8 weeks. Moreover, patients who are at a high risk for EC tend to avoid TVS screening. Finally, endometrial screening often results in unnecessary operations, which are associated with increased morbidity and costs.

Perioperative screening for metastatic disease is not indicated in patients with primary breast cancer and no clinical signs of tumor spread

AbstractBackground. Is a perioperative metastatic screening program indicated in patients presenting with primary operable breast cancer and no signs of distant metastases? Patients and methods. The impact of staging results (chest X-ray, bone scanning, liver ultrasound) for prognosis, treatment, quality of life and costs was retrospectively analyzed in 1076 patients with an operable breast cancer and no clinical signs of metastases. Results. Staging examinations revealed 30 (2.8%) distant metastases, 130 (12.1%) suspect findings and excluded metastases in 916 (85.1%) patients. Further diagnostic procedures confirmed distant metastases in 7 (5.4%) and excluded them in 123 (94.6%) out of 130 patients with suspect findings. Distant metastases were detected more frequently with increasing pathological tumor size (pT ≤q 2.0 cm: 1.6%, pT 2.1–5.0 cm: 3.0%, respectively pT > 5.0 cm: 15.1%; p < 0.001) and increasing number of involved axillary lymph nodes (pN0: 1.9%, pN1–3+: 1.8%, pN4–9+: 4.0%, pN ≥ 10+: 18.7%; p < 0.001). Due to false positive findings 123 (11.4%) patients had to live for a significant period of time with the psychological distress of suspected metastatic disease. The abandonment of a perioperative screening in 1076 patients saves costs of at least Euro 259,367.68. Conclusions. In breast cancer patients without clinical signs of tumor spread perioperative screening for metastases is not warranted because of low frequency of metastases, false positive findings, missing therapeutic consequences and high costs.

Cell therapy using microencapsulated 293 cells transfected with a gene construct expressing CYP2B1, an ifosfamide converting enzyme, instilled intra-arterially in patients with advanced-stage pancreatic carcinoma: a phase I/II study.

Matthias Lohr (principal investigator) · Zoltan Tibor Bago · Helga Bergmeister · Manfred Ceijna · Mathias Freund · Wolfgang Gelbmann · Walter H. Gunzburg · Ralf Jesnowski · Johannes Hain · Karlheinz Hauenstein Wolfgang Henninger · Anne Hoffmeyer · Peter Karle · Jens-Christian Kroger · Gunther Kundt · Stefan Liebe Udo Losert · Petra Muller · Alexander Probst · Katrin Puschel · Matthias Renner · Renate Renz · Robert Saller Brian Salmons · Maximilian Schuh · Ilse Schwendenwein · Kerstin von Rombs · Thomas Wagner · Ingrid Walter (coinvestigators)

Inhibition of mTOR with sirolimus does not attenuate progression of liver and kidney disease in PCK rats

BACKGROUND Activation of the mTOR pathway has been implicated in the mediation of the progression of polycystic kidney disease (PKD). Whereas targeted inhibition of mTOR has been proven to be effective in various animal models of autosomal dominant PKD, its efficacy in autosomal recessive PKD (ARPKD) remains to be elucidated. We examined the effects of sirolimus in PCK rats, an orthologous animal model of human ARPKD. METHODS Weaned PCK rats (n = 85) and SD-control rats (n = 72) received drinking water without and with sirolimus (corresponding to a daily intake of 2 mg/kg body weight) for 4, 8 and 12 weeks, respectively. The renal and hepatic functions were monitored throughout the treatment periods. Kidneys and livers were harvested and investigated with respect to progression of fibrosis, and number and size of cysts using the QWin image analysis programme. Expression of Akt, mTOR and its downstream target pS6K were assessed by immunohistochemistry. RESULTS Five out of 43 sirolimus-treated PCK rats, but none of the controls, died during the study. Sirolimus treatment resulted in slightly reduced weight gain. In PCK rats, grossly enlarged kidney and livers as well as hepatic fibrosis together with enlarged bile ducts were readily detectable. Whereas activation of Akt/mTOR signalling was hardly detectable in the kidneys of SD rats, strong signals were seen in the kidneys of PCK rats. Despite a significantly reduced relative kidney weight after 12 weeks of treatment (P < 0.05), neither fibrosis and cyst area nor renal function improved during treatment. Sirolimus-treated PCK rats showed only a minor inhibition of renal mTOR-specific phosphorylation of S6K. Male PCK rats on sirolimus presented with increased concentrations of bile acids and bilirubin compared with controls (each P < 0.05 at 12 weeks). Similar, albeit non-significant, effects were noted in female PCK rats. CONCLUSIONS Sirolimus failed to attenuate progression of kidney and liver disease in PCK rats. The lack of a protective effect might be due to intrinsic or acquired rapamycin resistance in this animal model of ARPKD.

Tumour Necrosis Factor-α Promoter Polymorphism in Erythema Nodosum

Erythema nodosum is a common skin disease characterized by erythematous, tender subcutaneous nodules, mostly located on the lower extremities. Little is known about its pathogenesis, although a wide variety of aetiological factors (e.g. bacterial and viral infections, neoplastic diseases and drugs) have been described. Sarcoidosis, a typical granulomatous disease, often occurs in association with erythema nodosum (Loefgren syndrome). Since granulomatous diseases have been closely linked to a deregulated tumour necrosis factor (TNF)-a production, it was tempting to speculate whether TNF-a might play a role in the pathogenesis of erythema nodosum, at least in cases associated with sarcoidosis. A previously described nucleotide exchange, (G→A) at position -308 in the human TNF-α gene promoter, has been shown to be a major cause for enhanced TNF-a production. In the present report, we investigated the genomic TNF-a promoter region in patients suffering from EN with and without underlying sarcoidosis. Our results showed a strong correlation between the uncommon TNF A II allele and sarcoidosis-associated erythema nodosum. Patients with erythema nodosum without underlying sarcoidosis displayed a similar allele frequency compared with controls. Taken together, we provide evidence that erythema nodosum in association with sarcoidosis might be pathogenically linked to altered TNF-α production due to a genetic promoter polymorphism.