Effective anti-programmed death-1 therapy in a SUFU-mutated patient with Gorlin-Goltz syndrome.

We present the case of a 77-year-old male patient with more than 50 basal cell carcinomas on the head and upper trunk. The patient did not respond to several lines of treatment, including surgery, imiquimod, retinoids, itraconazole and therapy with the hedgehog inhibitor vismodegib. The patient responded well to off-label therapy with the anti-programmed death-1 antibody pembrolizumab after four infusions.

Predictive value of PD-L1 based on mRNA level in the treatment of stage IV melanoma with ipilimumab.

INTRODUCTION: PD-L1 is established as a predictive marker for therapy of non-small cell lung cancer with pembrolizumab. Furthermore, PD-L1 positive melanoma has shown more favorable outcomes when treated with anti-PD1 antibodies and dacarbazine compared to PD-L1 negative melanoma. However, the role of PD-L1 expression with regard to response to checkpoint inhibition with anti-CTLA-4 is not clear, yet. In addition, the lack of standardization in the immunohistochemical assessment of PD-L1 makes the comparison of results difficult. In this study, we investigated the PD-L1 gene expression with a new fully automated technique via RT-PCR and correlated the findings with the response to the anti-CTLA-4 antibody ipilimumab. MATERIALS AND METHODS: Within a retrospective multi-center trial, PD-L1 gene expression was evaluated in 78 melanoma patients in a total of 111 pre-treatment tumor samples from 6 skin cancer centers and analyzed with regard to response to ipilimumab. For meaningful statistical analysis, the cohort was enriched for responders with 30 responders and 48 non-responders. Gene expression was assessed by quantitative RT-PCR after extracting mRNA from formalin-fixed paraffin embedded tumor tissue and correlated with results from immunohistochemical (IHC) stainings. RESULTS AND DISCUSSION: The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab. The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab.

Multi-locus sequence data reveal a new species of coral reef goby (Teleostei: Gobiidae: Eviota), and evidence of Pliocene vicariance across the Coral Triangle.

Here, multi-locus sequence data are coupled with observations of live colouration to recognize a new species, Eviota punyit from the Coral Triangle, Indian Ocean and Red Sea. Relaxed molecular clock divergence time estimation indicates a Pliocene origin for the new species, and the current distribution of the new species and its sister species Eviota sebreei supports a scenario of vicariance across the Indo-Pacific Barrier, followed by subsequent range expansion and overlap in the Coral Triangle. These results are consistent with the 'centre of overlap' hypothesis, which states that the increased diversity in the Coral Triangle is due in part to the overlapping ranges of Indian Ocean and Pacific Ocean faunas. These findings are discussed in the context of other geminate pairs of coral reef fishes separated by the Indo-Pacific Barrier.

[Implementation of regularly performed resuscitation training at a hyperbaric treatment center]. / Implementierung eines regelmäßigen Reanimationstrainings an einem Druckkammerzentrum.

BACKGROUND: Medical emergency situations and even cardiac arrest can occur during treatment of patients in therapeutic hyperbaric chambers just as in other clinical departments; therefore, high quality structured management should be implemented for dealing with emergencies in this special working area. To ensure this the emergency medical treatment should not only be performed according to the current state of medical knowledge but needs to take the special features of the hyperbaric environment including safety aspects into account. METHOD: This article presents a description of the implementation and effects of routine emergency and resuscitation training at a center for hyperbaric medicine. RESULTS: By simulation of emergencies in a hyperbaric chamber it rapidly became clear that the treatment of medical emergencies and cardiac arrest under hyperbaric conditions has some special features and due to safety aspects cannot always be performed according to current medical guidelines. At the time of this simulation in a real life working environment, previously unknown structural and logistic problems became obvious whereby the solutions contributed to a significant improvement of structural and process quality and could potentially also improve the outcome quality. Furthermore, a positive and lasting learning effect in the fields of quality of resuscitation measures, organization of the workplace, communication skills, logistics and safety aspects was detectable by analyzing participant performance over a period of 4 years. On the part of the participating staff a positive feedback and high acceptance of emergency simulator training was confirmed. CONCLUSION: Through annual compulsory emergency training of the complete staff of the hyperbaric unit at the actual workplace, a structural and confident approach to dealing with emergencies and resuscitation situations was observed. By the use of on-site simulator training even in specialized hospital units, deficits and tentativeness regarding logistics, course of action, organization and communication in emergency situations can be minimized to provide optimum patient care in a real life emergency situation by focusing on the medical measures.

Buffy coat volume reduction for optimization of leucapheresis harvests produced by the autoMNC program.

BACKGROUND AND OBJECTIVES: Buffy coat (BC) volume reduction was evaluated in leucapheresis (LA) harvests due to the target monocyte yield and the red blood cell (RBC) content. A packed erythrocyte volume (PEV) of 7.5 ml should not be exceeded to avoid RBC debulking with loss of leucocytes (WBCs) and the monocyte fraction during monocyte counterflow elutriation, a next step of monocyte enrichment prior to cell culture. MATERIALS AND METHODS: Two hundred and fifty-three 5-l leucaphereses (autoMNC program) performed in 102 healthy blood donors (24 female and 78 male donors) were retrospectively analysed. Different categories of BC volumes were compared due to the quality of the LA products measured by blood counts and flow cytometry. RESULTS: Collection of maximum BC volume of 10 ml and more each collection cycle (product volume: 169 ± 21 ml) resulted in 1.58 ± 0·41 × 10e9 CD14(+) monocytes and high volume of packed erythrocyte (18.4 ± 8.8 ml). Low BC volume collection below 6 ml each collection cycle produced only 1.07 ± 0.40 × 10e9 CD14(+) monocytes but reduced PEV significantly by 64% (6.7 ± 4.1 ml). CONCLUSION: By reduction of the BC volume, the PEV in LA products could be reduced, which is a precondition for counterflow elutriation of monocytes. A BC volume between 7 and 8 ml per collection cycle should be adjusted to reduce PEV to 7.5 ml without relevant monocyte loss.

Reflex contraction of the levator ani in women symptomatic for pelvic floor disorders.

OBJECTIVE: Stress urinary incontinence (SUI) is a common health problem in women. Reflex activation of muscular pelvic floor structures may play a role in preserving continence. In this study we aimed to analyze reflex pelvic floor activity on coughing in women seen for urodynamic testing. METHODS: In a retrospective cohort study we analyzed the data sets of 191 women who attended a tertiary referral service for multichannel urodynamic testing and four-dimensional pelvic floor ultrasound scan between May 2009 and February 2010. Coughs were registered on volume ultrasound at a minimum of 16 Hz and analyzed by postprocessing at a later date, the operator being blinded against all clinical data. RESULTS: Of 175 analyzable cough volume datasets, a levator reflex was seen in 138 (79%), and clitoral reflex movement in 160 (91%). On multivariable analysis there was a significant relationship between urodynamic stress incontinence (USI) and the absence of a levator reflex (P = 0.045), and a negative relationship with the magnitude of such a reflex (P = 0.046). Reflex timing was not associated with SUI or USI. CONCLUSION: Reflex contraction of the levator ani can be observed on translabial ultrasound during sudden increases in intra-abdominal pressure. These reflex contractions are common, even in women with symptoms and signs of pelvic floor dysfunction. The observation of a levator reflex on coughing, and its magnitude, show a weak inverse association with the presence of USI.

Projection and patient satisfaction using the "Hamburger" nipple reconstruction technique.

Maintaining projection and achieving patient satisfaction are two key challenges in nipple reconstruction. Skin flap techniques such as CV and star flaps are currently favoured. The "Hamburger" technique was described in 2007 using stacked conchal cartilage discs within a skin flap construct, but no longer-term outcomes have been published. We evaluate both projection and patient satisfaction following nipple reconstruction using this technique. Twenty-three nipple reconstructions performed between 2007 and 2009 were reviewed. A standard pre-tattooed cylinder skin pattern was used with 3 punch biopsies of conchal cartilage harvested through a post-auricular incision. At follow up, reconstructed nipples and donor sites were examined. Nipple projection was measured bilaterally. Patients completed a short questionnaire. Mean follow up was 24 months (9-31). Mean projection was 3.3 mm (range 0-5 mm) and was well matched to the contralateral nipple. No donor site keloid scarring was observed, however cartilage defects were easily palpable in all cases. Patients were satisfied or very satisfied with overall cosmesis in 91% of cases. They were satisfied or very satisfied with projection in 57% of cases. All patients found the donor site acceptable. With the "hamburger" technique medium-term projection was maintained in most cases and was comparable to published data for other techniques with or without cartilage. Patient satisfaction was high even when projection was not well maintained. This suggests that patient satisfaction and projection are not necessarily related. Donor site morbidity was low.

Reversed flow lateral circumflex femoral vessels as recipients for free fibular grafting in treatment of femoral head osteonecrosis.

Free fibular bone grafting is an effective treatment for early osteonecrosis of the femoral head in young patients. However, recipient vessels are often small rendering microvascular anastomosis difficult. We have developed a novel technique using retrograde flow through the branches of the lateral circumflex femoral artery to use the proximal end of the artery as the recipient vessel. A vessel diameter of up to 5 mm is obtained providing a good match with the peroneal vessels. We used this technique to perform vascularized bone grafting of the femoral head in 10 patients with Ficat grade 2 and 3 osteonecrosis. Pulsatile retrograde flow from the lateral circumflex femoral artery was observed in each case. Retrospective review gave a median follow up of 52 months (range 17-99). Symptoms improved in all 10 cases. There was no radiological deterioration over the period of follow-up in eight cases. One patient underwent conversion to a total hip replacement 24 months after surgery. These results compare favorably with other studies. The lateral circumflex femoral artery turnover technique is a reliable and useful technique in vascularized bone grafting of the femoral head.

[Hyperbaric oxygen for carbon monoxide poisoning: case report of severe poisoning due to exhaust fumes]. / Hyperbare Oxygenierung bei Kohlenmonoxidintoxikation: Fallbericht einer schweren Intoxikation durch Autoabgase.

After rescue and transport a patient with severe carbon monoxide poisoning (CO-Hb concentration 82%) was treated by hyperbaric oxygen (HBO) therapy in a pressure chamber. During decompression the patient suffered cardiac arrest due to massive acidosis, hyperpotassaemia, haemoconcentration and elevated CO-Hb level. After successful resuscitation and cardiopulmonary diagnostics, HBO therapy was continued for prophylactic treatment of delayed neurological sequelae. Three months after completing treatment and discharge from hospital there were no neurological sequelae.

Dendritic cell vaccines in metastasized malignant melanoma.

Dendritic cells as immunotherapeutic agents against malignancies have been applied for over ten years. Proof of principle studies demonstrated immunogenicity of dendritic cells even in patients suffering from advanced malignancies. Clinicians and immunologists early focused on this innovative immunotherapeutic approach in metastasized malignant melanoma--a malignancy so far resisting most traditional oncologic treatment modalities. In this review we summarize the experience obtained of dendritic cell therapy in patients with malignant melanoma and state past, present and future obstacles. So far over 850 melanoma patients in 51 trials have been reported since 1998. Within these trials there exists a vast heterogeneity concerning type of dendritic cell applied, differentiation and maturation of dendritic cells, type of antigen target and nature, application mode, number of cells applied, vaccination intervals in addition to patients treated at various stages of melanoma. A minority of patients developed anticipated autoimmune adverse events in addition to expected immune system activation symptoms such as fever and local site reaction. As only solitary World Health Organization (WHO) grade III or IV adverse events were reported one can state that dendritic cell therapy is safe. Objective clinical responses have repeatedly been observed in a minority of heavily pretreated and far advanced melanoma patients. Future challenges include optimization and standardization of dendritic cell generation and application, addition of synergistic immunomodulatory agents to enhance immunogenicity and block tumor escape and treatment of patients at earlier stages of disease who will benefit from this innovative therapy.

Crude-oil biodegradation via methanogenesis in subsurface petroleum reservoirs.

Biodegradation of crude oil in subsurface petroleum reservoirs has adversely affected the majority of the world's oil, making recovery and refining of that oil more costly. The prevalent occurrence of biodegradation in shallow subsurface petroleum reservoirs has been attributed to aerobic bacterial hydrocarbon degradation stimulated by surface recharge of oxygen-bearing meteoric waters. This hypothesis is empirically supported by the likelihood of encountering biodegraded oils at higher levels of degradation in reservoirs near the surface. More recent findings, however, suggest that anaerobic degradation processes dominate subsurface sedimentary environments, despite slow reaction kinetics and uncertainty as to the actual degradation pathways occurring in oil reservoirs. Here we use laboratory experiments in microcosms monitoring the hydrocarbon composition of degraded oils and generated gases, together with the carbon isotopic compositions of gas and oil samples taken at wellheads and a Rayleigh isotope fractionation box model, to elucidate the probable mechanisms of hydrocarbon degradation in reservoirs. We find that crude-oil hydrocarbon degradation under methanogenic conditions in the laboratory mimics the characteristic sequential removal of compound classes seen in reservoir-degraded petroleum. The initial preferential removal of n-alkanes generates close to stoichiometric amounts of methane, principally by hydrogenotrophic methanogenesis. Our data imply a common methanogenic biodegradation mechanism in subsurface degraded oil reservoirs, resulting in consistent patterns of hydrocarbon alteration, and the common association of dry gas with severely degraded oils observed worldwide. Energy recovery from oilfields in the form of methane, based on accelerating natural methanogenic biodegradation, may offer a route to economic production of difficult-to-recover energy from oilfields.

Prolonged use of electronic games--a word of caution.

Post-traumatic hyperextension deformity of the thumb due to rupture of volar plate is a rare but clinically important phenomenon. These injuries are usually related to ball sports like basketball and handball. However, we describe an unusual association in an elderly patient with chronic use of an electronic game, which merits a high index of suspicion for early diagnosis and treatment to prevent long-term complications.