Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome.

Treatment results of AML in elderly patients are unsatisfactory. In an open label randomized phase II study, we investigated whether addition of the XPO1 inhibitor selinexor to intensive chemotherapy would improve outcome in this population. 102 AML patients > 65 years of age (median 69 (65-80)) were randomly assigned to standard chemotherapy (3 + 7) with or without oral selinexor 60 mg twice weekly (both arms n = 51), days 1-24. In the second cycle, cytarabine 1000 mg/m2 twice daily, days 1-6 with or without selinexor was given. CR/CRi rates were significantly higher in the control arm than in the investigational arm (80% (95% C.I. 69-91%) vs. 59% (45-72%; p = 0.018), respectively). At 18 months, event-free survival was 45% for the control arm versus 26% for the investigational arm (Cox-p = 0.012) and overall survival 58% vs. 33%, respectively (p = 0.009). AML and infectious complications accounted for an increased death rate in the investigational arm. Irrespective of treatment, MRD status after two cycles appeared to be correlated with survival. We conclude that the addition of selinexor to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients. (Netherlands Trial Registry number NL5748 (NTR5902), www.trialregister.nl ).

The B-type natriuretic peptide of the Congo and Timneh grey parrot.

In captivity, cardiovascular diseases are common in grey parrots. The diagnosis of these diseases in living birds is difficult, and new diagnostic possibilities would be desirable. The heart is an important endocrine organ in which cardiomyocytes synthetise B-type natriuretic peptide (BNP) and release it into the bloodstream. This hormone has a significant role in cardiovascular and body fluid regulation. The blood concentration of BNP is used in human medicine and small animal medicine as a diagnostic tool in the identification of heart diseases and as a prognostic marker for the risk of mortality. The nucleotide and amino acid sequence of BNP was described in Congo (n = 4) and Timneh (n = 3) grey parrots by PCR after RNA isolation from the atria and ventricles. The results showed a high similarity between the nucleotide sequences of the grey parrots' BNP and the already known sequence of this hormone in chickens. The amino acid sequence of the mature peptide region is consistent in these three species. BNP plasma concentration could be a possible blood parameter for identifying clinically manifest cardiovascular diseases in grey parrots as it is in other species.

Clinical characteristics and outcome of patients over 60 years with Hodgkin lymphoma treated in Switzerland.

Hodgkin lymphoma (HL) in older patients appears to be a different disease compared with younger patients with historically lower survival rates. This is related to a variety of factors, including increased treatment-related toxicity, the presence of comorbidities, and biologic differences. In order to better assess the clinical characteristics, treatment strategies, and outcome of this particular population, we conducted a population-based, retrospective analysis including 269 patients with HL older than 60 years (median age 71 years, range 60-94), treated between 2000 and 2017 in 15 referral centers across Switzerland. Primary endpoints were overall survival (OS), progression-free survival (PFS), and cause-specific survival (CSS). The vast majority of patients were treated with curative intent, either with a combined modality approach (chemotherapy followed by radiation therapy) or with systemic therapy. At a median follow-up of 6.6 years (95% confidence interval [CI], 6.0-7.6), 5-year PFS was 52.2% (95% CI, 46.0-59.2), 5-year OS was 62.5% (95% CI, 56.4-69.2), and 5-year CSS was 85.1.8% (95% CI, 80.3-90.1) for the entire cohort. A significant difference in terms of CSS was observed for patients older than 71 years in comparison to patients aged 60-70 years (hazard ratio 2.6, 1.3-5.0, p = 0.005). Bleomycin-induced lung toxicity (BLT) was documented in 26 patients (17.7%) out of the 147 patients exposed to this compound and was more frequent in patients older than 71 years (15/60, 25%). Outcome of HL pts older than 71 years appeared to decrease substantially in comparison to the younger counterpart. Treatment-related toxicities appeared to be relevant, in particular, BLT. New, potentially less toxic strategies need to be investigated in prospective clinical trials in this particular frail population.

Correction: Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

More effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might improve their outcome. After establishing a safe lenalidomide, dose elderly patients with AML were randomly assigned in this randomized Phase 2 study (n = 222) to receive standard chemotherapy ("3 + 7") with or without lenalidomide at a dose of 20 mg/day 1-21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without lenalidomide (20 mg/day 1-21). The CR/CRi rates in the two arms were not different (69 vs. 66%). Event-free survival (EFS) at 36 months was 19% for the standard arm versus 21% for the lenalidomide arm and overall survival (OS) 35% vs. 30%, respectively. The frequencies and grade of adverse events were not significantly different between the treatment arms. Cardiovascular toxicities were rare and equally distributed between the arms. The results of the present study show that the addition of lenalidomide to standard remission induction chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR2294 in The NederlandsTrial Register (www.trialregister.nl).

Cervical myelopathy due to complex Atlanto-axial malformation including partial atlantal dorsal arch aplasia in a domestic rabbit.

A 1-year-old dwarf rabbit was presented with sub-acute progressive tetraparesis. Radiography, CT and MRI revealed compressive cervical myelopathy secondary to a complex atlanto-axial malformation including partial aplasia of the atlantal dorsal arch, dens malformation, malarticulation and lateral atlanto-occipital displacement. Owners decided against surgical treatment and elected conservative treatment including analgesia with non-steroidal anti-inflammatory drugs, cage rest and physiotherapy. Within 2 months clinical signs deteriorated and the owner elected euthanasia. Subsequent necropsy confirmed imaging findings. Similar cases described in humans and dogs suggest that partial aplasia of the dorsal arch of the atlas might often be an asymptomatic radiologic finding in these species. In contrast, this first description of a similarly affected rabbit demonstrates that complex atlanto-axial malformations can cause severe clinical signs.

Invasive histiocytic sarcoma of the lumbar spine in a ferret (Mustela putorius furo).

This report describes the history, clinical examination and histopathology of a histiocytic sarcoma in a domestic ferret. Clinical signs were acute paraplegia and dysuria. Physical examination revealed a firm, smooth, touch-sensitive mass in and around the lumbar vertebral column. Neurologic examination was consistent with a lesion between spinal cord segments T3 and L3. Magnetic resonance images revealed bone lesions of L2 and L3 combined with compression of the spinal cord due to a homogenous, isointense mass that was diagnosed as a malignant round cell tumour and the ferret was euthanased. Histopathology confirmed the diagnosis of an infiltrative histiocytic sarcoma.

Textile foreign body in a Green Iguana (Iguana iguana): Diagnostic imaging for localisation.

INTRODUCTION: This case report includes different diagnostic imaging methods for localization of textile foreign bodies in reptiles and shows the limitations and advantages of these methods. A six-year-old, male, green iguana was presented to our clinic after ingesting a sock 5 days earlier. Ultrasound, contrast x-ray, computed tomography and endoscopy were used to locate the foreign body before surgery. Attempts to remove the sock endoscopically failed. The sock was surgically removed via celiotomy and enterotomy.

Indications and Route of Hysterectomy for Benign Diseases. Guideline of the DGGG, OEGGG and SGGG (S3 Level, AWMF Registry No. 015/070, April 2015)

Background: Official guideline "indications and methods of hysterectomy" to assign indications for the different methods published and coordinated by the German Society of Gynecology and Obstetrics (DGGG), the Austrian Society of Gynecology and Obstetrics (OEGGG) and the Swiss Society of Gynecology and Obstetrics (SGGG). Besides vaginal and abdominal hysterectomy, three additional techniques have been implemented due to the introduction of laparoscopy. Organ-sparing alternatives were also integrated. Methods: The guideline group consisted of 26 experts from Germany, Austria and Switzerland. Recommendations were developed using a structured consensus process and independent moderation. A systematic literature search and quality appraisal of benefits and harms of the therapeutic alternatives for symptomatic fibroids, dysfunctional bleeding and adenomyosis was done through MEDLINE up to 6/2014 focusing on systematic reviews and meta-analysis. Results: All types of hysterectomy led in studies to high rates of patient satisfaction. If possible, vaginal instead of abdominal hysterectomy should preferably be done. If a vaginal hysterectomy is not feasible, the possibility of a laparoscopic hysterectomy should be considered. An abdominal hysterectomy should only be done with a special indication. Organ-sparing interventions also led to high patient satisfaction rates, but contain the risk of symptom recurrence. Conclusion: As an aim, patients should be enabled to choose that therapeutic intervention for their benign disease of the uterus that convenes best to them and their personal life situation.

Assessment of wound bio-burden and prevalence of multi-drug resistant bacteria during open wound management.

OBJECTIVE: To describe the bacterial bio-burden of open-treated wounds and make comparisons with bite wounds. DESIGN: Retrospective multicentre study. SAMPLE: Microbial culture between 2011 and 2013 from open-treated wounds in dogs and cats (initiation of therapy n=88, follow-up n=52) were compared to those from bite wounds (n=184). PROCEDURES: Bacteria were identified and tested for antibiotic susceptibility by two accredited laboratories. RESULTS: In total, 77/88 (88%) of open-treated wounds yielded positive bacterial cultures at the beginning of treatment, decreasing to 27/52 (52%) during treatment. Upon initial evaluation, 42/88 (48 %) of open-treated wounds were considered infected with multi-drug-resistant bacteria, with a drop to 22/52 (41%) during therapy. Bite wounds yielded fewer positive cultures 88/184 (48%) with only 11/182 (6%) being affected by multi-drug-resistant bacteria. Bacteria found most commonly in open-treated wounds were Enterococcus subspecies, Escherichia coli, Staphylococcus pseudintermedius and Pseudomonas aeruginosa. CONCLUSION: The bacterial populations of open-treated wounds differed markedly from the bite wounds. The high incidence of multi-drug-resistant strains in open wounds highlights the need for alternatives to antibiotics.

Sensor-controlled scalp cooling to prevent chemotherapy-induced alopecia in female cancer patients.

BACKGROUND: Scalp cooling has been used since the 1970s to prevent chemotherapy-induced alopecia, one of the most common and psychologically troubling side effects of chemotherapy. Currently available scalp cooling systems demonstrate varying results in terms of effectiveness and tolerability. METHODS: For the present prospective study, 55 women receiving neoadjuvant, adjuvant, or palliative chemotherapy were enrolled. The aim was to assess the effectiveness of a sensor-controlled scalp cooling system (DigniCap: Sysmex Europe GmbH, Norderstedt, Germany) to prevent chemotherapy-induced alopecia in breast or gynecologic cancer patients receiving 1 of 7 regimens. Clinical assessments, satisfaction questionnaires, and alopecia evaluations [World Health Organization (who) grading for toxicity] were completed at baseline, at each cycle, and at completion of chemotherapy. RESULTS: Of the 55 patients, 78% underwent scalp cooling until completion of chemotherapy. In multivariate analysis, younger women and those receiving paclitaxel weekly or paclitaxel-carboplatin experienced less alopecia. The compound successful outcome ("no head covering" plus "who grade 0/1") was observed in all patients 50 years of age and younger receiving 4 cycles of docetaxel-cyclophosphamide or 6 cycles of paclitaxel-carboplatin. Conversely, alopecia was experienced by all women receiving triplet polychemotherapy (6 cycles of docetaxel-doxorubicin-cyclophosphamide). For women receiving sequential polychemotherapy regimens (3 cycles of fluorouracil-epirubicin-cyclophosphamide followed by 3 cycles of docetaxel or 4 cycles of doxorubicin-cyclophosphamide followed by 4 cycles of docetaxel), the subgroup 50 years of age and younger experienced a 43% success rate compared with a 10% rate for the subgroup pf older women receiving the same regimens. CONCLUSIONS: The ability of scalp cooling to prevent chemotherapy-induced alopecia varies with the chemotherapy regimen and the age of the patient. Use of a compound endpoint with subjective and objective measures provides insightful and practical information when counselling patients.

CW and pulsed electrically detected magnetic resonance spectroscopy at 263GHz/12T on operating amorphous silicon solar cells.

Here we describe a new high frequency/high field continuous wave and pulsed electrically detected magnetic resonance (CW EDMR and pEDMR) setup, operating at 263GHz and resonance fields between 0 and 12T. Spin dependent transport in illuminated hydrogenated amorphous silicon p-i-n solar cells at 5K and 90K was studied by in operando 263GHz CW and pEDMR alongside complementary X-band CW EDMR. Benefiting from the superior resolution at 263GHz, we were able to better resolve EDMR signals originating from spin dependent hopping and recombination processes. 5K EDMR spectra were found to be dominated by conduction and valence band tail states involved in spin dependent hopping, with additional contributions from triplet exciton states. 90K EDMR spectra could be assigned to spin pair recombination involving conduction band tail states and dangling bonds as the dominating spin dependent transport process, with additional contributions from valence band tail and triplet exciton states.

Contrast echocardiography for analysis of heart anatomy in tortoises.

OBJECTIVE: The cardiac anatomy in tortoises depicted on B-mode and color-Doppler should be better differentiated by additional contrast-echocardiography. MATERIAL AND METHODS: An intravenous contrast agent (INN-sulphur hexafluoride [SonoVue®]) was injected in four tortoises (three Testudo hermanni, one Agrionemys horsfieldii), via the coccygeal vein, with parallel B-mode echocardiographic examination. The results of the contrast-enhanced echocardiography were compared with the contrast-free B-mode recordings and color-Doppler ultrasound. RESULTS: The use of SonoVue® enabled clearer distinction of the cardiac structures, differentiation of the arising major arteries, identification of wash-out-shunts, and visualization of blood flow patterns throughout the tortoise heart. CONCLUSION AND CLINICAL RELEVANCE: This study enables the accurate depiction and differentiation of cardiac anatomy in tortoises through the use of a combination of B-mode, color-Doppler and contrast-echocardiography. Basic knowledge of blood flow in the reptile heart is essential to understand echocardiographic anatomy. Blood-flow-patterns and anatomy of the tortoise heart as found in this study will help to establish a basis for further echocardiographic examinations of these animals.

Treatment outcome and patterns of relapse following adjuvant carboplatin for stage I testicular seminomatous germ-cell tumour: results from a 17-year UK experience.

BACKGROUND: Following inguinal orchidectomy, management options for patients with stage I seminoma include initial surveillance or treatment with adjuvant radiotherapy or chemotherapy. The anticipated relapse rate for patients followed by surveillance alone is ∼15%, with adjuvant treatment this risk is reduced to ∼4%-5% at 5 years. After carboplatin treatment, follow-up strategies vary and there are no validated, predictive markers of relapse. PATIENTS AND METHODS: We conducted a retrospective analysis of all patients presenting with stage I seminoma who received a single cycle of adjuvant carboplatin in South Central England between 1996 and 2013. We report on outcome and the results of univariate and multivariate analysis evaluating possible risk factors for post carboplatin relapse. RESULTS: A total of 517 eligible patients were identified. All underwent nuclear medicine estimation of glomerular filtration rate before treatment with carboplatin (dosed at area under the curve × 7). With a median follow-up of 47.2 months (range 0.4-214 months), 21/517 patients have relapsed resulting in a 5-year estimated relapse-free survival of 95.0% (95% confidence interval 92.8% to 97.3%). Median time to relapse was 22.7 months (range 12.5-109.5 months). Relapse beyond 3 years was rare (4/517; 0.8%). Twenty of 21 (95%) relapsed patients had retroperitoneal lymph node metastases. The majority (16/21; 76%) of patients had elevated tumour markers at relapse. Twenty of 517 (3.9%) patients developed a new contralateral testicular germ-cell cancer. There were no seminoma-related deaths. Tumour size was the only variable significantly associated with an increased risk of relapse. CONCLUSIONS: Overall results for this large cohort of patients confirm an excellent prognosis for these patients with outcomes equivalent to those seen in prospective clinical trials. Increasing tumour size alone appears to be associated with an increased risk of post chemotherapy relapse.

Negative pressure wound therapy, silver coated foam dressing and conventional bandages in open wound treatment in dogs. A retrospective comparison of 50 paired cases.

OBJECTIVES: To evaluate negative pressure wound therapy (NPWT) for treatment of complicated wounds in dogs. STUDY TYPE: Retrospective multicentre study. MATERIALS AND METHODS: Dogs (n = 50) undergoing open wound treatment were classified according to treatment method used: bandage (Group A, n = 7), NPWT (Group B, n = 18), and foam dressing (Group C, n = 25). Pairs of patients matched based on wound conformation, localization, and underlying cause were compared between Group A and C (n = 7 pairs) and between groups B and C (n = 18 pairs) in terms of duration of previous treatment, time to closure, and complications. RESULTS: Signalment, antibiotic medications, antiseptic treatment, and bacterial status of wounds were comparable between groups. The duration of previous treatment was significantly higher in patients assigned to Group B (p = 0.04) compared to Group C, while no significant difference was found between groups A and B. Total time to wound closure was significantly shorter in Group C compared to Group A (p = 0.02) and in Group B compared to Group C (p = 0.003). Wounds treated with NPWT suffered significantly less complications (p = 0.008) and were significantly less septic during treatment (p = 0.016) than wounds treated with a foam dressing. CONCLUSION: This study shows that time to healing was halved in NPWT treated patients compared to foam dressing treated patients, which in turn healed faster than patients treated with conventional bandage, underlining the value of NPWT therapy for the treatment of complicated wounds.

The management challenge for household waste in emerging economies like Brazil: realistic source separation and activation of reverse logistics.

Business opportunities in the household waste sector in emerging economies still evolve around the activities of bulk collection and tipping with an open material balance. This research, conducted in Brazil, pursued the objective of shifting opportunities from tipping to reverse logistics in order to close the balance. To do this, it illustrated how specific knowledge of sorted waste composition and reverse logistics operations can be used to determine realistic temporal and quantitative landfill diversion targets in an emerging economy context. Experimentation constructed and confirmed the recycling trilogy that consists of source separation, collection infrastructure and reverse logistics. The study on source separation demonstrated the vital difference between raw and sorted waste compositions. Raw waste contained 70% biodegradable and 30% inert matter. Source separation produced 47% biodegradable, 20% inert and 33% mixed material. The study on collection infrastructure developed the necessary receiving facilities. The study on reverse logistics identified private operators capable of collecting and processing all separated inert items. Recycling activities for biodegradable material were scarce and erratic. Only farmers would take the material as animal feed. No composting initiatives existed. The management challenge was identified as stimulating these activities in order to complete the trilogy and divert the 47% source-separated biodegradable discards from the landfills.

Metastable defect formation at microvoids identified as a source of light-induced degradation in a-Si:H.

Light-induced degradation of hydrogenated amorphous silicon (a-Si:H), known as the Staebler-Wronski effect, has been studied by time-domain pulsed electron-paramagnetic resonance. Electron-spin echo relaxation measurements in the annealed and light-soaked state revealed two types of defects (termed type I and II), which can be discerned by their electron-spin echo relaxation. Type I exhibits a monoexponential decay related to indirect flip-flop processes between dipolar coupled electron spins in defect clusters, while the phase relaxation of type II is dominated by 1H nuclear spin dynamics and is indicative for isolated spins. We propose that defects are either located at internal surfaces of microvoids (type I) or are isolated and uniformly distributed in the bulk (type II). The concentration of both defect type I and II is significantly higher in the light-soaked state compared to the annealed state. Our results indicate that in addition to isolated defects, defects on internal surfaces of microvoids play a role in light-induced degradation of device-quality a-Si:H.

Relevant risk of carboplatin underdosing in cancer patients with normal renal function using estimated GFR: lessons from a stage I seminoma cohort.

BACKGROUND: Seminoma stage I is the most frequent testis cancer and single-dose carboplatin (AUC7) is an effective and widely used adjuvant treatment. Underdosing of carboplatin by 10% has been shown to almost double the rate of relapse and hence correct dosing based on accurate GFR measurement is crucial. The gold standard of GFR measurement with a radiolabelled isotope is expensive and not readily available. In many institutions, it is replaced by GFR estimation with the Cockcroft-Gault formula, which might lead to significant carboplatin underdosing and potentially inferior clinical outcome. METHODS: Retrospective analysis of all patients with stage I seminoma treated with adjuvant carboplatin between 1999 and 2012. All patients had serum creatinine measured and underwent GFR measurement with a radioisotope ((51)Cr EDTA or (99m)Tc DTPA), which was compared with seven standard GFR estimation formulae (Cockcroft-Gault, CKD-EPI, Jelliffe, Martin, Mayo, MDRD, Wright) and a flat dosing strategy. Bias, precision, rates of under- and overdosing of GFR estimates were compared with measured GFR. Bland-Altman plots were done. RESULTS: A total of 426 consecutive Caucasian male patients were included: median age 39 years (range 19-60 years), median measured GFR 118 ml/min (51-209), median administered carboplatin dose 1000 mg (532-1638). In comparison to isotopic GFR measurement, a relevant proportion of patients would have received ≤ 90% of carboplatin dose through the use of GFR estimation formulae: 4% using Mayo, 9% Martin, 18% Cockcroft-Gault, 24% Wright, 63% Jelliffe, 49% MDRD and 41% using CKD-EPI. The flat dosing strategy, Wright and Cockcroft-Gault formulae, showed the smallest bias with mean percentage error of +1.9, +0.4 and +2.1, respectively. CONCLUSIONS: Using Cockcroft-Gault or any other formula for GFR estimation leads to underdosing of adjuvant carboplatin in a relevant number of patients with Seminoma stage I and should not be regarded as standard of care.

Feline osteochondromatosis in a FELV-negative European shorthair cat.

OBJECTIVE: To report palliative treatment in a case of multifocal feline osteochondromatosis in a feline leukaemia virus (FeLV) negative European shorthair cat. CASE: A 6-year-old spayed female European shorthair cat was presented because of a right forelimb lameness caused by an osteochondromatous lesion which had trapped tendons, vessels and nerves of the antebrachium. Several other lesions were present which did not cause the animal discomfort. The cat was tested negative for FeLV. Palliative surgical removal of the mass was performed, resulting in a marked improvement of mobility with no local recurrence. The cat developed a non-regenerative anaemia after surgery, however the underlying cause was not identified upon request of the owner. Overall survival after surgery was only 2 months. The cat was then euthanised due to severe progression of the anaemia. CONCLUSION: Palliative surgical removal of osteochondromas may result in local improvement. However, owners need to be aware that it does not increase overall survival and that the prognosis is poor. Infection with FeLV is not necessarily associated with such lesions.

Morphometric parameters of peripheral nerves in calves correlated with conduction velocity.

BACKGROUND: Peripheral nerve injuries are the most frequent neurologic disorder in cattle. So far, no physiologic values have been established for the motor nerve conduction velocity (mNCV) in this precocial species. OBJECTIVES: The electrophysiologic and morphometric reference values of peripheral nerves in calves were determined. It was hypothesized that these parameters would correlate to the high degree of maturity in the first days of life in this species compared to other species. ANIMALS: Twenty-six healthy calves were used in this study. METHODS: The mNCV of the radial and the sciatic/common peroneal nerve was measured in all 26 calves. Nerve biopsies from a group of 6 calves were taken to correlate the obtained electrophysiologic data with morphological parameters. RESULTS: The mean mNCV of the radial nerve was 48.3 ± 10.6 m/s, whereas the mean mNCV of the sciatic/peroneal nerve was with 83.8 ± 5.9 m/s significantly faster (P < .0001). The average fiber diameter was 8.40 ± 2.80 µm (range, 1.98-17.90 µm) and the average g-ratio was 0.61 ± 0.04 SD. CONCLUSION AND CLINICAL IMPORTANCE: The established reference values for mNCV in calves correlate well with the evaluated morphometric parameters. Attributable to their comparably fast mNCV and high fiber diameters, juvenile calves appear to be much more mature individuals than other mammals. Electrophysiologic characterization of peripheral nerve injury now is feasible in this species.