A phase II study of retifanlimab, a humanized anti-PD-1 monoclonal antibody, in patients with solid tumors (POD1UM-203).

BACKGROUND: POD1UM-203, an open-label, multicenter, phase II study, evaluated retifanlimab, a humanized monoclonal antibody targeting programmed cell death protein-1 (PD-1) in patients with selected solid tumors where immune checkpoint inhibitor therapies have previously shown efficacy. PATIENTS AND METHODS: Eligible patients (≥18 years) had measurable disease and included unresectable or metastatic melanoma, treatment-naive metastatic non-small-cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression (tumor proportion score ≥50%), cisplatin-ineligible locally advanced/metastatic urothelial carcinoma (UC) with PD-L1 expression (combined positive score ≥10%), or treatment-naive locally advanced/metastatic clear-cell renal cell carcinoma (RCC). Retifanlimab 500 mg was administered intravenously every 4 weeks as a 30-min infusion. The primary endpoint was investigator-assessed overall response rate. RESULTS: Overall, 121 patients (35 melanoma, 23 NSCLC, 29 UC, 34 RCC) were enrolled and treated. The overall response rate [95% confidence interval (CI)] was 40.0% (23.9-57.9) in the melanoma cohort, 34.8% (16.4-57.3) in the NSCLC cohort, 37.9% (20.7-57.7) in the UC cohort, and 23.5% (10.7-41.2) in the RCC cohort. Median duration of response was 11.5 months (95% CI 2.2-not reached) in the UC cohort, and was not reached in the other cohorts. Retifanlimab safety was consistent with previous experience for PD-(L)1 inhibitors. CONCLUSIONS: Retifanlimab demonstrated durable antitumor activity in patients with melanoma, NSCLC, UC, or RCC. The efficacy and safety of retifanlimab were as expected for a PD-(L)1 inhibitor. These data support further study of retifanlimab in solid tumors.

First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update.

BACKGROUND: To further characterize survival benefit with first-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone, we report updated data from the phase III CheckMate 9LA trial with a 2-year minimum follow-up. PATIENTS AND METHODS: Adult patients were treatment naïve, with stage IV/recurrent non-small-cell lung cancer, no known sensitizing EGFR/ALK alterations, and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with two cycles of chemotherapy, or four cycles of chemotherapy. Updated efficacy and safety outcomes are reported, along with progression-free survival (PFS) after next line of treatment (PFS2), treatment-related adverse events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental arm due to TRAEs. RESULTS: With a median follow-up of 30.7 months, nivolumab plus ipilimumab with chemotherapy continued to prolong overall survival (OS) versus chemotherapy. Median OS was 15.8 versus 11.0 months [hazard ratio 0.72 (95% confidence interval 0.61-0.86)]; 2-year OS rate was 38% versus 26%. Two-year PFS rate was 20% versus 8%. ORR was 38% versus 25%, respectively; 34% versus 12% of all responses were ongoing at 2 years. Median PFS2 was 13.9 versus 8.7 months. Improved efficacy outcomes in the experimental versus control arm were observed across most subgroups, including by programmed death-ligand 1 and histology. No new safety signals were observed; onset of grade 3/4 TRAEs was mostly observed during the first two treatment cycles in the experimental arm. In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy treatment due to TRAEs (n = 61) median OS was 27.5 months; 56% of responders had an ongoing response ≥1 year after discontinuation. CONCLUSIONS: With a 2-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy provided durable efficacy benefits over chemotherapy with a manageable safety profile and remains an efficacious first-line treatment of advanced non-small-cell lung cancer.

Knowledge, attitudes and practices related to the COVID-19 outbreak among Romanian adults with cancer: a cross-sectional national survey.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic outbreak forced cancer care providers to face different challenges in terms of prevention and treatment management due to specific precautions implemented for oncological patients. We aimed to describe the level of knowledge, attitude and practices (KAP) among cancer patients, with the purpose to provide an image of the impact of COVID-19 and evaluate the effectiveness of pandemic response measures. PATIENTS AND METHODS: We developed a cross-sectional multicentric study that targeted adults with active cancer during the COVID-19 outbreak, aiming to describe KAP related to COVID-19 among Romanian oncological patients. A questionnaire investigating 64 items on KAP related to the novel coronavirus was designed and applied in seven Romanian hospitals. The group of participants consisted of 1585 oncological patients who completed the questionnaire during the outbreak (April-May 2020). RESULTS: Only 172 patients (10.8%) had very good knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection symptoms, treatment options and incubation period. Only 44.3% of patients identified diarrhoea as a sign of COVID-19. About one-third of patients (32.6%) declared that they are 'very worried' about getting infected with the novel coronavirus. More than two-thirds of participants (68%) considered that having cancer represents an additional risk for infection with SARS-CoV-2, but 27.8% would rather not vaccinate against SARS-CoV-2 should a vaccine be available. A small percentage (8.8%) believed that the risk of infection justifies delaying/stopping oncological treatment until after the pandemic. Around half of the participants (55.5%) declared being compliant with all the protective measures against coronavirus infection listed in the questionnaire. CONCLUSION: Romanian oncological patients have a less than expected knowledge about SARS-CoV-2, appropriate prevention behaviours, with limited trust in their efficacy, optimistic attitudes towards COVID-19 and low level of trust in information sources. Good COVID-19 knowledge was associated with appropriate practices towards COVID-19 and optimistic attitudes.

Molecular Profiling of EGFR Status to Identify Skin Toxicity in Colorectal Cancer: A Clinicopathological Review.

Colorectal cancer (CRC) represents an important health problem, being the third most common type of cancer. In Romania, the CRC incidence has doubled over the years. Both environmental factors and genetic susceptibility are very important for the pathogenesis of CRC. The epidermal growth factor receptor (EGFR) plays an extremely important role in CRC tumorigenesis. Overexpression or dysregulation of EGFR pathway molecules are frequently associated with tumor aggressiveness and patient response to treatment. Based on these considerations, EGFR became one of the first targets of molecular therapies used in CRC. At present, cetuximab and panitumumab are considered to be essential in the treatment of patients with metastatic colorectal cancer expressing the KRAS wild-type gene and EGFR. The main adverse effect for both cetuximab and panitumumab is skin toxicity, present in approximately 80% of patients. The risk of secondary infections, in particular of bacterial infections, is also increased. Cases of staphylococcal infection associated with skin peeling, cellulite, erysipelas, and even Staphylococcus sepsis, were reported. For a long time cutaneous toxicity has been a positive predictor in the efficacy of anti-EGFR treatment, but compliance with treatment and the quality of life of patients with metastatic CRC decreases in the presence of these skin reactions. That is why we emphasize the necessity and importance of using a modern method (molecular analysis of gene polymorphisms possibly supplemented by targeted confocal laser endomicroscopy) to identify a molecular diagnosis, in order to foresee and prevent the appearance of skin reactions and to manage skin toxicity.

Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300.

Background: There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician's choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC. Patients and methods: Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician's choice of chemotherapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 or irinotecan 150 mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Results: A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0 months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9-1.4]; P = 0.81} or the secondary end points of PFS [median, 1.4 versus 2.7 months; HR=1.73 (95% CI 1.4-2.2); P > 0.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm. Conclusions: Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy. Trial registration: ClinicalTrials.gov: NCT02625623.

[Procalcitonin as a tool for the assessment of successful therapy of severe sepsis : An analysis using clinical routine data]. / Procalcitonin als Instrument zur Erfolgsmessung der Therapie einer schweren Sepsis : Eine Untersuchung mit klinischen Routinedaten.

INTRODUCTION: Procalcitonin (PCT) is a well-evaluated biomarker for the detection of severe bacterial infections and monitoring effectiveness of antibiotic therapy. This study aims to evaluate the usefulness of PCT in a clinical routine setting. MATERIALS AND METHODS: Of 358,763 clinical cases from 7 German hospitals in 2012 and 2013, 3854 cases had an ICD-10 code representing sepsis. A total of 1778 cases had pathologic PCT and one episode of infection. Of those, 671 showed a series of measures that was suitable to assess treatment success using PCT reduction. Propensity score matching was used to create two comparable groups with 211 patients in each group. RESULTS: The group with PCT reduction within 12 days showed a highly significant better proportion of survival (146/211 vs. 17/211; p < 0.0001). The odds ratio for death according to PCT reduction vs. nonreduction is 25.64 (p < 0.0001; 95 % CI: 14.49-45.45). PCT was normalized after an average of 6.2 days. DISCUSSION: The difference in survival implicates that PCT reduction is a suitable surrogate parameter to indicate successful antimicrobial therapy. Successful antibiotic therapy is a proven predictor for survival in sepsis. This study also showed concordant results in the group of patients with sepsis after abdominal surgery. Results from subgroup analyses confirm the initial findings. PCT reduction was used as surrogate for therapy success, as the antimicrobial therapy was not electronically available. CONCLUSION: PCT reduction is a strong predictor for survival. However, the data show that overall use of PCT to monitor sepsis therapy is not yet routinely established. Hospitals should establish algorithms for sepsis treatment that include PCT for the assessment of adequacy and the monitoring of success of the antimicrobial therapy.

Correlations between CD34 Immunolabelled Blood Vessels and CD34 mRNA Expression in Colorectal Cancer.

PURPOSE: This study aims to determine the correlation between microvessel density of CD34 immunolabelled blood vessels and CD34 mRNA gene expression in colorectal cancer tissue. MATERIAL/METHODS: Standard immunohistochemistry and gene expression was perform on samples collected from 76 patients with colorectal cancer in order to determinate the number of CD34 immunolabelled blood vessels and the relative quantity of CD34 mRNA. RESULTS: For the study group, the mean CD34 immunolabelled microvascular density (MVD) was of 307/mm2, and the mean CD34 gene expression value for colon cancer was 2.303. The low p value (<0.001) of the Spearman correlation test showed a significant direct correlation between CD34 MVD and CD34 gene expression for the entire study group. CONCLUSIONS: CD34 gene`s expression can be looked at as a prognostic factor in colorectal cancer.

[Endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA) in neoplastic Barrett's esophagus or Barrett early cancer is also economically superior to sole radical endoscopic resection]. / Endoskopische Mukosaresektion (EMR) mit nachfolgender Radiofrequenzablation (RFA) bei neoplastischem Barrett-Ösophagus bzw. Barrett-Frühkarzinom ist der alleinigen radikalen endoskopischen Resektion auch ökonomisch überlegen.

INTRODUCTION: Neoplastic changes (mild or high grade intraepithelial neoplasia (L- or HGIEN) or early cancer) in Barrett esophagus are treated with various methods. This study compares clinical-economical aspects of sole stepwise radical endoscopic resection (SRER) against combination treatment with EMR (Endoscopic mucosal resection) and RFA (radiofrequency ablation). MATERIAL AND METHODS: Based on clinical data from a randomized controlled trial 1 we developed an economic model for costs of treatment according to the German Hospital Remuneration System (G-DRG). Our calculating incorporated initial treatment costs and the cost of treating complications (both paid via G-DRG). RESULTS: Medical and economically, the treatment with EMR + RFA advantages over sole SRER treatment 1. The successful complete resection or destruction of neoplastic intestinal metaplastic tissue is similar in both procedures. Acute complications (24 vs. 13 % in SRER EMR + RFA) and late complications (88 vs. 13 % in SRER EMR + RFA) are significantly more likely in sole SRER than in the EMR + RFA. DISCUSSION: While SRER initially appears more cost-effective as a sole therapy, cost levels move significantly above EMR+RFA due to higher complication rates and following procedures costs. Overall, the costs of treatment was €â€Š13 272.11 in the SRER group and €â€Š11 389.33 in the EMR + RFA group. The EMR + RFA group thus achieved a cost advantage of €â€Š1882.78. The study shows that the treatment of neoplastic Barrett esophagus with EMR + RFA is also appropriate in economic terms.

Autophagy and Neovascularization in Colorectal Cancer.

PURPOSE: This study aims to determinate the microvessel density at the base of the tumor, as well in tumor's mass, in order to determinate the number of neovascularization vessels (marked with CD105) in comparison with presence or absence of autophagy puncta. MATERIAL/METHODS: Standard immunohistochemistry was performed on 38 samples of colorectal adenocarcinoma, in order to determinate the presence of autophagy and neovascularization blood vessels with the help of LC3, CD34, CD31 and CD105 antibodies. RESULTS: The autophagy process was observed in the cancerous cells and was noted as present in both regions of interest from the tumor. The mean number of blood vessels market with CD105 is higher in tumor mass then at its base, p value of the Student t test being highly significant (p<0.0001). CONCLUSIONS: The presence of autophagy puncta was notice in every case, both in the mass of the tumor and at its base. Microvascular density of new-grown blood vessels is higher in the mass of the tumor compared with the base of the tumor.

Correlations between colposcopy and histologic results from colposcopically directed biopsy in cervical precancerous lesions.

INTRODUCTION: Cervical cancer develops from well-defined precursor lesions in a varied period of time. Detected in early or pre-invasive stages, cervical cancer is preventable and curable, so detection of precancerous lesions is very important. Colposcopy with directed biopsy is used in the evaluation and management of patients with cervical lesions, and described as the 'gold standard' for the diagnosis of cervical precancer. AIM: The aim of this study is to assess the accuracy of colposcopic examination and cervical punch biopsy, to determine the correlation between these two methods. MATERIALS AND METHODS: We examined 245 patients who present malignant findings at colposcopy and biopsy. Colposcopic findings in our study group: 28 (11.4%) cases were CIN I, 50 (20.4%) cases were CIN II, 150 (61.2%) cases were CIN III, 13 (5.3%) cases were micro-invasive carcinoma and four (1.6%) cases were CIS. Histological results in the 245 examined cases were: four (1.6%) cases normal, 26 (10.6%) cases CIN I, 55 (22.4%) cases CIN II, 138 (56.3%) cases CIN III, 15 (6.1%) cases micro-invasive carcinoma and seven (2.8%) cases of CIS. RESULTS: The correlation was 78.5% in the CIN I category, 84% in the CIN II category, 88.6% (133 out of 150 patients) in the CIN III category, 46.1% for micro-invasive carcinoma and 50% for CIS. The colposcopy method incurred fewer false negatives (four patients), giving a general accuracy rate of 98.3%. Sensitivity of colposcopic examination was 83.6%. CONCLUSIONS: This study demonstrated high accuracy and correlation between colposcopy and histology, comparable with results from similar studies in the literature. Sensitivity is lower, probably because biopsies were done in all cases, during diagnostic work-up. We also demonstrated the usefulness of these two diagnostic procedures as screening tests in preclinical cervical cancer. In our study, there were cases of under or over diagnose; the benefit of colposcopy and directed biopsy is to avoid over treatment of low-grade lesion, and under treatment of high-grade lesion.

Recent data about the role of human papillomavirus (HPV) in oncogenesis of head and neck cancer.

Human papillomavirus (HPV) is a small circular DNA-virus and the high-risk types 16, 18 is implicated in oncogenesis of head and neck cancer--especially oropharynx (tonsil and base of tongue), poorly differentiated (the basaloid type), locoregional advanced stage, poorly differentiated, at the younger male, non-smokers, non-drinkers, sexual behaviors. The prognostic is favorable of human papillomavirus tumor status for patients with oropharynx squamous cell carcinoma treated with radiotherapy (accelerated fractionation without total dose reduction). The impact of HPV-vaccination (ACIP 2007) decreasing the incidence of oropharyngeal cancer, but that patients HPV-positive, have good prognostic in generally (two-year overall survival: 95%, two-year progression-free survival: 88%), therefore HPV-vaccination in routine practice it is controversy.

Aesthetic surgical training in the UK independent sector--the clients' view: Results of a survey on 155 private patients.

As training opportunities in cosmetic surgery become less frequent in teaching hospitals, this survey set out to examine the attitudes of patients towards extending this training into the independent health sector. We questioned 155 private patients, 95% of who were happy for trainees to sit in during their consultations. Of these, 85% were comfortable with the presence of the trainee throughout their appointments and 92% said they saw advantages in having such trainees present. However, patients were less enthusiastic about trainees carrying out procedures, under consultant supervision and for a reduced fee. The survey found that while 49% felt it was a good idea, only 32% would consider it for themselves. Seventeen percent of patients thought this offer alone was inappropriate. This survey has shown that while the vast majority of private patients supported and were happy to participate in higher surgical training during private consultations, fewer would consider the possibility of cosmetic surgery performed by supervised trainees for reduced fees. The implications of these findings for higher surgical training in Plastic Surgery in the UK are discussed.

Precision grip function after hand replantation and digital nerve injury.

Understanding how the loss of digital sensibility affects manual dexterity could have important implications for rehabilitation after hand injury. We investigated precision grip function during lifting tasks in seven patients after hand replantation, in five after single digital nerve injury and in four volunteers subjected to digital anaesthesia. Using their affected hand, all participants could successfully lift test objects with parallel and vertical grip surfaces and they all reliably increased the grip force with increasing object weight (0.11-0.55 kg). However, the grip forces used were frequently significantly higher than those applied by the unaffected hand. This was partly due to participants compensating for loss of sensibility with high grip force safety margins against slips, and partly related to misalignments of the fingertips on the grasp surfaces. The latter was most prominent after hand replantation. In a second series of lifting experiments we changed the shape of the grip surfaces in order to investigate the participants' ability to adapt grip forces based on tactile recognition of object shape. An important finding from this series was that in patients with poor clinical outcomes, the contralateral unaffected hand tended to mirror the abnormal grasp patterns of the injured hand. This suggests that control strategies developed for the impaired hand can influence the control of the contralateral uninjured hand.

Improved sciatic nerve regeneration by local thyroid hormone treatment in adult rat is accompanied by increased expression of SCG10.

Thyroid hormone plays an important role in regulating the development and regeneration of the nervous system. Our previous work showed that local administration of triiodothyronine (T3) at the level of transected rat sciatic nerve increased the number and diameter of regenerated axons, but the mechanism underlying the improved regeneration is still unclear. Here, we have investigated the effect of T3 on the expression of SCG10, a regulator of microtubule dynamics in growth cones. After transection of adult rat sciatic nerves, silicone tubes were implanted and filled with T3 or phosphate-buffered solution. At various time points following surgery, the expression of SCG10 protein and mRNA was analyzed. Semi-quantitative Western blot analysis revealed that sciatic nerve transection induced a more than 20-fold upregulation of SCG10 protein in proximal nerve segments at 1 day post-lesion, while at this time point, SCG10 mRNA in dorsal root ganglion neurons was not increased yet. The increase in SCG10 protein and mRNA could be observed over 30 days. Local T3 treatment significantly enhanced the increase in SCG10 protein levels about two-fold in the different segments of transected nerve during the regeneration period. Also SCG10 mRNA levels in lumbar ganglia were enhanced. Immunohistochemical analysis showed that T3 treatment not only increased the number of SCG10 positive axons but also the intensity of their staining. These results suggest that SCG10 is involved in the regulation of regeneration. The stimulating effect of T3 on SCG10 expression could provide a mechanism by which T3 enhances peripheral nerve regeneration.

The value of serum and tissular expression of CA 125 antigen, in evaluation of the response to second line chemotherapy for the relapsed ovarian carcinoma.

PURPOSE: The purpose of this study is to compare the predicted value of the blood levels variations of CA 125 antigen and the imunohistochemical expression of CA 125, with imagistic criteria (The Response Evaluation Criteran in Solid Tumor--RECIST) regarding the survival estimation of female patients with relapsed ovarian carcinoma which undergo to second line chemotherapy. MATERIAL AND METHOD: We included in this study 40 female patients diagnosed with ovarian carcinoma in the Oncology Clinic of the Emergency County Hospital Craiova, in a period of two years (from 2000 to 2002), which have fulfilled the following criteria: ovarian carcinoma IC-IV stage, according to FIGO system, first line treatment represented by the association between paclitaxel and a platinum salt, refractory or recurrent disease, indications for beginning the second line chemotherapy represented by topotecan or paclitaxel and carboplatin. The serial CA 125 antigen was determined in all patients before starting the chemotherapy and after each two sequences of chemotherapy, and the imunohistochemical expression of CA 125 was evaluated from surgery extracts before the second line chemotherapy (11 cases). The imagistic evaluation of the treatment response was done after 4 sequences of chemotherapy. RESULTS: All patients had measurable disease according to RECIST criteria and had high values (at least double) of the CA 125 antigen blood level at the time of diagnosis. The imunohistochemically expression of CA 125 was correlated in most cases with the blood level of CA 125. The evaluation criterion of the CA 125 antigen has been shown to be more efficient in estimation the survival rate compared with the RECIST system. In a various analysis, which included numerous potential prognostic factors, only the variation of blood levels of these antigen and the free disease interval from the finalization of the first line chemotherapy have been identified as predictive factors of survival, while the other variables, including the RECIST criteria, had no impact on the prognosis regarding the survival. CONCLUSIONS: The response evaluation criteria based on the blood levels variations of CA 125 antigen are a better instrument for the estimation of the compared prognosis with the RECIST criteria, for patients on second line chemotherapy for relapsed ovarian carcinoma.

[DRG-based cost analysis of inpatient conservative treatment of stage III/IV peripheral arterial occlusive disease]. / DRG-basierte Kostenanalyse zur stationären konservativen Behandlung der PAVK Stadium III/IV.

UNLABELLED: DRG-based cost analysis of inpatient conservative treatment of PAD stage III/IV BACKGROUND: In a prospective study carried out by the German Society of Angiology and the DRG Competence Center, Munich, the question was investigated whether the costs of conservative treatment of patients with PAOD stage III/IV (DRG F65) are adequately represented within the current G-DRG system. METHODS UND PATIENTS: Between September 1 and December 16, 2002, a total of 704 patients with DRG F65 (peripheral vascular diseases) were evaluated at 8 angiologic centers in Germany. Apart from the length of hospital stay, the total costs (cost equivalents) were calculated using a method developed by the DRG Research Group at the University of Münster. Moreover, the study population was compared with a German calculation sample for the DRGs F65A/B, as published by InEK. RESULTS: As it turned out, conservatively treated patients with PAOD stage III or IV (DRGs F65A/B) cause significantly (p < 0.001) higher costs and have significantly (p < 0.001) greater lengths of hospital stay than patients who were also assigned to DRG F65 because of other vascular diseases. At the same time it became clear that angiologic centers treat twice as many patients with critical limb ischemia in comparison with the German average. The reimbursement hitherto estimated by InEK covers not even half the cost actually produced by conservative treatment of PAD stage III/IV. CONCLUSION: To ensure a performance-related reimbursement, a new basis DRG for patients with PAD stage III/IV has to be created, as has ben proposed by the German Society of Angiology. Otherwise, adequate conservative therapy in accordance with existing guidelines, of patients who cannot be treated surgically or interventionally will not be possible any more in the future.

Free hand-to-toe transfer: a method to minimise donor-site morbidity in free joint transfers.

Reconstruction of a congenital hand anomaly in a child using single free vascularised transfer of the proximal interphalangeal joint of a second toe with the simultaneous microvascular reconstruction of the donor toe using the stiff joint and its dorsal skin paddle from the hand is described. This is not the first reported case of a toe-finger switch, but it is the first in a free joint transfer, for which it is especially indicated.

hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan.

hAG-2 and hAG-3 are recently discovered human homologues of the secreted Xenopus laevis proteins XAG-1/2 (AGR-1/2) that are expressed in the cement gland, an ectodermal organ in the head associated with anteroposterior fate determination during early development. Although the roles of hAG-2 and hAG-3 in mammalian cells are unknown, both proteins share a high degree of protein sequence homology and lie adjacent to one another on chromosome 7p21. hAG-2 mRNA expression has previously been demonstrated in oestrogen receptor (ER)-positive cell lines. In this study, we have used real-time quantitative RT - PCR analysis and immunohistochemistry on tissue microarrays to demonstrate concordant expression of hAG-2 and hAG-3 mRNA and protein in breast tumour tissues. Tumour expression of both genes correlated with OR (hAG2, P=0.0002; hAG-3, P=0.0012), and inversely correlated with epidermal growth factor receptor (EGFR) (P=0.003). Yeast two-hybrid cloning identified metastasis-associated GPI-anchored C4.4a protein and extracellular alpha-dystroglycan (DAG-1) as binding partners for both hAG-2 and hAG-3, which if replicated in clinical oncology would demonstrate a potential role in tumour metastasis through the regulation of receptor adhesion and functioning. hAG-2 and hAG-3 may therefore serve as useful molecular markers and/or potential therapeutic targets for hormone-responsive breast tumours.