Bortezomib-induced hyponatremia: tolvaptan therapy permits continuation of lenalidomide, bortezomib and dexamethasone therapy in relapsed myeloma.

The development of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) is well recognised in multiple myeloma (MM). SIADH, due to either MM or Bortezomib can be hazardous as severe hyponatremia may develop if large volumes of hypotonic intravenous fluid are used as an adjunct to chemotherapy. We report a case of Bortezomib-induced SIADH, in whom the use of tolvaptan, a vasopressin receptor-2 antagonist, permitted the continuation of triple combination anti-MM therapy with lenalidomide, Bortezomib and dexamethasone (RVD) in a female with aggressive disease, without the development of hyponatremia. Our patient had a rapid relapse, in which the use of Bortezomib as part of an RVD regimen was life-saving. The use of tolvaptan allowed continuation of therapy that is usually halted in other similarly reported cases. This case highlights the possible use of vaptans, which allows an aquaresis to occur by blocking the antidiuretic effects of vasopressin, as a treatment for Bortezomib-induced hyponatremia.

Afatinib in advanced pretreated non-small-cell lung cancer- a Canadian experience.

Background: Afatinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitor (egfr tki), is approved for first-line therapy in advanced EGFR mutation-positive non-small-cell lung cancer (nsclc) and has previously demonstrated activity after failure of chemotherapy and reversible egfr tkis, with improved response and progression-free survival, compared with placebo. Outcomes in pretreated patients with advanced nsclc receiving afatinib through a Canadian special access program (sap) are reported here. Methods: Patients with nsclc progressing after at least 1 line of chemotherapy and an egfr tki were eligible to enrol in the sap. Characteristics of patients from the two largest accruing Canadian centres were retrospectively reviewed, including demographics, disease and treatment data, and patient outcomes. Results: The 53 patients who received afatinib (57% women, 51% never-smokers, 26% of East Asian ethnicity, and 66% with adenocarcinoma) had a median age of 59 years. EGFR mutations were documented in 25%, and EGFR wild-type in 8%. All patients had received prior egfr tki treatment, with 42% achieving a response. Patients took afatinib for a median of 2 months (range: 0-26 months); 17% required 1 or more dose reductions. Of 47 evaluable patients receiving afatinib, 10 experienced tumour shrinkage, and 11, stable disease. Median survival from afatinib initiation was 5 months (95% confidence interval: 2 months to 8 months). Grade 3 or greater diarrhea, rash, paronychia, and stomatitis were seen in 9%, 11%, 6%, and 4% of patients respectively. Conclusions: In an unselected population of pretreated patients with advanced nsclc after tki failure, median survival with afatinib therapy was 5 months. Through a sap, afatinib demonstrated activity in clinical practice, with manageable toxicity.

Reasons for lack of referral to medical oncology for systemic therapy in stage IV non-small-cell lung cancer: comparison of 2003-2006 with 2010-2011.

INTRODUCTION: Only approximately 25% of stage iv non-small-cell lung cancer (nsclc) patients receive systemic therapy. For such patients, we examined factors affecting referral to a cancer centre (cc) and to medical oncology (mo), and use of systemic therapy. METHODS: Using the Glans-Look Lung Cancer database, we completed a chart review of stage iv nsclc patients diagnosed in Southern Alberta during 2003-2006 and 2010-2011, comparing median overall survival (mos), referral, and treatment in the two cohorts. RESULTS: Of the 922 patients diagnosed in 2003-2006 and the 560 diagnosed in 2010-2011, 94% and 82% respectively were referred to a cc, with 22% and 23% receiving traditional chemotherapy (tctx). Referral to a cc or mo and use of tctx correlated with survival (p < 0.0001): The mos duration was 11.2 months in those receiving tctx and 1.0 months in those not referred to a cc. The overall mos duration was similar in the two cohorts (4.1 months vs. 3.9 months, p = 0.47). Major reasons for lack of referral to mo included poor functional status, rapid decline, and patient wish, which were similar to the reasons for forgoing tctx. In the two cohorts, 87 (9.4%) and 42 (7.5%) patients received epidermal growth factor inhibitors, with a mos duration of 16.2 months. Multivariable analysis showed that male sex [hazard ratio (hr): 1.16; p = 0.008] and pulmonary embolus (hr: 1.2; p = 0.002) correlated with worse survival. In contrast, receipt of chemotherapy (hr: 0.5; p < 0.001) and enrolment in a clinical trial (hr: 0.76; p = 0.049) correlated with better survival. CONCLUSIONS: Our experience confirms that, over time, uptake of systemic therapy, including tctx and targeted therapy, changed little despite their established efficacy. Most of the factors limiting systemic therapy uptake appear to be non-modifiable at the time of referral. Rapid diagnosis and the availability of well-tolerated drugs for all nsclc patients will likely be the most important factors in increasing systemic therapy uptake in this population.

The prognostic role of microsatellite instability in colorectal cancer patients.

BACKGROUND: Data from the literature regarding the prognostic role of DNA mismatch repair system (MMR) in colorectal cancer are still controversial. AIM: The aim of the study was to identify the prognostic role of different phenotypic, clinical and pathological characteristics in microsatellite unstable vs. microsatellite stable colorectal cancer in terms of survival and disease free interval. METHODS: We conducted a retrospective study that included a total of 103 patients who underwent curative surgery for colorectal cancer. Immunohistochemistry testing revealed MLH1, MLH2, MLH6, PMS2 genes and mutations of the BRAF gene. We identified three groups of patients: patients with colorectal tumors with MSI produced by hypermethylation, (MLH1/BRAF+) group, patients with microsatellite instable tumours produced by genetic mutations MSI groupb(MLH1, MLH2, MLH6, PMS2) and patients with microsatellite stable tumours (MSS). RESULTS: The study shows that: MSI tumours (MLH1/BRAF+) group occur more frequently in women (p=0.05), on the right side of the colon (p=0.001). The 5-year survival rate was higher in patients with MSI tumours (MLH1/BRAF+) group than in those with microsatellite stable tumours, the differences were not statistically significant ; relapse rate was higher in patients with MSI tumors than in those with MSI tumours (MLH1/BRAF+) group (p=0.03) or with MSS tumors (p=0.004). CONCLUSIONS: The identification of microsatellite unstable colorectal tumours is an important molecular marker with role in recognition subgroups of patients with different phenotypic characteristics, survival and relapse rates. KEY WORDS: Colorectal cancer, Mismatch repair genes, Prognostic role.

Oculoleptomeningeal Amyloidosis associated with transthyretin Leu12Pro in an African patient.

Oculoleptomeningeal amyloidosis is a rare manifestation of hereditary transthyretin (TTR) amyloidosis. Here, we present the first case of leptomeningeal amyloidosis associated with the TTR variant Leu12Pro mutation in an African patient. A 43-year-old right-handed Nigerian man was referred to our centre with rapidly progressive neurological decline. He presented initially with weight loss, confusion, fatigue, and urinary and erectile dysfunction. He then suffered recurrent episodes of slurred speech with right-sided weakness. He went on to develop hearing difficulties and painless paraesthesia. Neurological examination revealed horizontal gaze-evoked nystagmus, brisk jaw jerk, increased tone, brisk reflexes throughout and bilateral heel-shin ataxia. Magnetic resonance imaging showed extensive leptomeningeal enhancement. Cerebrospinal fluid analysis showed a raised protein of 6.4 g/dl. Nerve conduction studies showed an axonal neuropathy. Echocardiography was characteristic of cardiac amyloid. TTR gene sequencing showed that he was heterozygous for the leucine 12 proline mutation. Meningeal and brain biopsy confirmed widespread amyloid angiopathy. TTR amyloidosis is a rare cause of leptomeningeal enhancement, but should be considered if there is evidence of peripheral or autonomic neuropathy with cardiac or ocular involvement. The relationship between different TTR mutations and clinical phenotype, disease course, and response to treatment remains unclear.

Polymerase chain reaction in cerebrospinal fluid for the diagnosis of congenital toxoplasmosis.

BACKGROUND: Congenital toxoplasmosis can result in visual impairment, hearing loss, serious neurologic sequelae and death in the infant. We studied the potential of the polymerase chain reaction (PCR) in cerebrospinal fluid (CSF) for diagnosis of congenital toxoplasmosis. METHODS: For this purpose, we studied both congenitally infected (diagnosed clinically and serologically) and noninfected infants born to untreated mothers. RESULTS: The infants ranged in age from 0 to 180 days. CSF PCR was positive in 27 of the 58 (46.5%) congenitally infected infants and was negative in each of the 103 infants without congenital toxoplasmosis. The frequency of positive CSF PCR varied according to whether infants had major clinical signs of the disease; PCR was positive in 70.9%, 53.3% and 50.9% of those with hydrocephalus, cerebral calcifications and/or eye disease, respectively. Of 6 infants who were negative for both IgM and IgA antibodies, 3 had a positive PCR in their CSF as the confirmatory test for diagnosis of congenital toxoplasmosis. IgM and IgA antibodies and CSF PCR, when combined, yielded a higher sensitivity for diagnosis of congenital toxoplasmosis when compared with the performance of each test alone. CONCLUSIONS: Our findings reveal that in infants with clinical and serologic findings suggestive of congenital toxoplasmosis and born to untreated mothers, CSF PCR has the potential to increase the frequency of cases in which the diagnosis is confirmed.

Correction of moderate and severe acquired flexible flatfoot with medializing calcaneal osteotomy and flexor digitorum longus transfer.

BACKGROUND: Acquired flexible flatfoot encompasses a wide spectrum of disease, and there is no validated treatment protocol. We hypothesized that a medializing calcaneal osteotomy with a flexor digitorum longus transfer is adequate to correct a less severe acquired flexible flatfoot but not a more severe flatfoot. We also hypothesized that use of an additional procedure would further correct the flatfoot. METHODS: The study included seven pairs of cadaver specimens, with one side randomly selected for the creation of a mild flatfoot deformity and the other, for the creation of a severe flatfoot deformity. Cyclic axial load was applied to the intact foot, to the flatfoot, after correction with a medializing calcaneal osteotomy and a flexor digitorum longus transfer, and after the addition of a subtalar arthroereisis. Radiographic and pedobarographic data were obtained at each stage. A repeated-measures analysis of variance with post hoc analysis was used to compare all parameters in the intact foot with those in the flatfoot and corrected specimens. A Student t test was used to compare flatfoot severity between the mild and severe models. RESULTS: Compared with the intact foot, the mild and severe flatfoot models showed a significant change in the talar-first metatarsal angle (p = 0.01 and 0.03, respectively), talonavicular angle (p = 0.04 and 0.04), and medial cuneiform height (p = 0.03 and 0.05). The mild and severe models were significantly different from each other with regard to the talar-first metatarsal angle (p = 0.003) and talonavicular angle (p = 0.002). After the osteotomy and tendon transfer in the mild-flatfoot model, the talar-first metatarsal angle and talonavicular angle were not significantly different from those in the intact state. In the severe-flatfoot model, the talar-first metatarsal angle, talonavicular angle, and medial cuneiform height remained significantly undercorrected after the osteotomy and tendon transfer. After the arthroereisis, the talonavicular angle and medial cuneiform height were not significantly different from the values for the intact foot. CONCLUSIONS: In a cadaver model, the effectiveness of different procedures on radiographic and pedobarographic parameters varies with the severity of an acquired flatfoot deformity.

Plantar pressures in the forefoot after lateral column lengthening: a cadaver study comparing the Evans osteotomy and calcaneocuboid fusion.

BACKGROUND: Excessive varus alignment of the forefoot after lateral column lengthening has been reported to lead to overloading of the lateral foot. The purpose of this study was to investigate whether there is a difference between the Evans opening wedge calcaneal osteotomy (Evans) and the calcaneocuboid distraction arthrodesis (CCDA) with respect to lateral forefoot loading. METHODS: In each of 12 matched pairs of cadaver feet, plantar pressure measurements of the intact specimens were obtained during simulated foot-flat and early heel-rise phases of gait and again after randomly performing the Evans procedure on one foot and the CCDA on the other foot. Cervical plate fixation was used for immediate stability. RESULTS: Both procedures resulted in statistically significant increased loading of the lateral forefoot and decreased loading of the medial forefoot compared with the preoperative status. The relative increase in lateral pressures was statistically greater with the CCDA than with the Evans. The average increase in pressure under the fifth metatarsal head in the foot-flat phase was 46% +/- 42% (range-4% to 141%) with the Evans and 104% +/- 58% (range 9% to 216%) with the CCDA (p = 0.003). In the early heel-rise phase, the increase in pressure was 50% +/- 43% (range 2% to 108%) and 96% +/- 65% (range 12% to 263%), respectively (p = 0.02). CONCLUSION: The experimental data suggest that lateral column overload may be more likely with the CCDA than with the Evans. Physicians should be aware of the likelihood of increasing lateral column loads with both the CCDA and the Evans procedure. It may be possible to avoid this problem by using less lateral column lengthening than the 1 cm used in this study or by considering a medial column arthrodesis or plantarflexion osteotomy to balance forefoot loading.

Zinc in health and chronic disease.

Zinc is a trace element essential for the optimal function of a variety of biochemical and physiological processes. Its role in healthy aging is particularly important as it prevents neo plastic cell growth, is involved in mitotic cell division, DNA and RNA repair. Although zinc is widely available in food, the daily intake in many persons may be suboptimal. Other causes of low zinc concentrations may be due to small bowel conditions that cause mucosal damage and thus decrease absorption. Chronic diseases associated with alterations in zinc status are bronchial asthma, rheumatoid arthritis and Alzheimer disease. At present it is uncertain if therapy with zinc would assist in the management of these chronic diseases. In view of the important cellular functions of zinc in the human body, a diet with an adequate zinc content is beneficial in promoting healthy aging and maintaining good health.

Drug disposition and dosage determination of once daily administration of gentamicin sulfate in horses after abdominal surgery.

OBJECTIVE: To evaluate pharmacokinetics of once daily i.v. administration of gentamicin sulfate to adult horses that had abdominal surgery. DESIGN: Prospective study. ANIMALS: 28 adult horses that underwent abdominal surgery for colic. PROCEDURE: 14 horses were treated with each dosage of gentamicin (i.e., 6.6 or 4 mg/kg, i.v., q 24 h) and blood samples were collected for pharmacokinetic analysis. Plasma gentamicin concentrations were measured by use of a fluorescence polarization immunoassay. Pharmacokinetic analysis measured the elimination half-life, volume of distribution, and gentamicin total systemic clearance. Treatment outcome, CBC, and serum creatinine concentrations were recorded. RESULTS: 1 horse in the high-dosage group died. All other horses successfully recovered, and did not develop bacterial infection or have evidence of drug toxicosis resulting in renal injury. Mean pharmacokinetic variables for gentamicin administration at a high or low dosage (i.e., 6.6 or 4 mg/kg, i.v., q 24 h) were half-life of 1.47 and 1.61 hours, volume of distribution of 0.17 and 0.17 L/kg, and systemic clearance of 1.27 and 1.2 ml/kg/min, respectively. Mean serum creatinine concentration was 1.74 and 1.71 for the high and low dosages, respectively, and serum creatinine concentration was not correlated with gentamicin clearance. CONCLUSIONS AND CLINICAL RELEVANCE: Gentamicin administration at a dosage of 4 mg/kg, i.v., every 24 hours, will result in plasma concentrations that are adequate against susceptible bacteria with a minimum inhibitory concentration (MIC) of < or = 2.0 micrograms/ml. Gentamicin administration at a calculated dosage of 6.8 mg/kg, i.v., every 24 hours will result in optimum plasma concentrations against susceptible bacteria with a MIC of < or = 4.0 micrograms/ml.

A congenital malformation of the maxilla of a horse.

A 1-month-old male American Paint Horse was evaluated for a hard swelling on the right side of the maxillary region. On radiographs there was a large, expansile outpouching of the right maxillary bone between the second and third premolar teeth. Computed tomography further characterized the expansile lesion to have a soft tissue component and to originate in the region of a caudal maxillary tooth. Surgical reconstruction of the defect was unsuccessful and the animal was euthanetized. Based on failure to find histopathologic evidence of a neoplasm or cyst, the diagnosis was a congenital malformation.

Fusarium sp. growth inhibition by wheat germ agglutinin.

The antifungal role of wheat germ agglutinin (WGA) isolated from a Romanian dihaploid variety of wheat against two pathogenic fungal species of Fusarium, F. graminearum and F. oxysporum, is demonstrated. WGA was prepared from unprocessed wheat germs by a new purification procedure using chitin and fetuin-Sepharose as affinity chromatography supports. SDS-PAGE and chitinase assay showed that the WGA preparation migrated as a single protein band and was devoid of any contaminating enzyme chitinase, well known for its antifungal effects. Based on its affinity for N-acetylglucosamine residues, WGA binding to the chitin-containing walls of the fungi was detected by fluorescence microscopy using WGA coupled with fluorescein isothiocyanate (FITC). In vitro testing of WGA action on early developmental stages of both fungal strains resulted in various modifications of the germ tubes, visualised by light microscopy: swelling, vacuolation of the cellular content and lysis of cell walls. Viability tests performed on potato tuber slices showed that the microbial infection was prevented from spreading by pretreatment of the fungal suspension with WGA.

Dynamic updating in DIAS-NIDDM and DIAS causal probabilistic networks.

Diabetes advisory system (DIAS) is a decision support system, which has been developed to provide advice on the amount of insulin injected by subjects with insulin-dependent diabetes mellitus (IDDM). DIAS employs a temporal causal probabilistic network (CPN) to implement a stochastic model of carbohydrate metabolism. The CPN network has recently been extended to provide also advice to subjects with noninsulin-dependent diabetes mellitus (NIDDM). However, due to increased complexity and size of the extended CPN the calculations became unfeasible. The CPN network was, therefore, simplified and a novel approach employed to generate conditional probability tables. The principles of dynamic CPN's were adopted and, in combination with the method of conditioning, learning, and forecasting, were implemented in a time- and memory-efficient way. An evaluation using experimental data was carried out to compare the original and revised DIAS implementations employing data collected by patients with IDDM, and to assess the a posteriori identifiability of model parameters in patients with NIDDM.

Transendoscopic laser treatment of rostral displacement of the palatopharyngeal arch in four horses.

OBJECTIVE: To document the use and clinical outcome of transendoscopic laser techniques for treatment of rostral displacement of the palatopharyngeal arch (RDPA) in horses. SUMMARY BACKGROUND DATA: Rostral displacement of the palatopharyngeal arch is a rare cause of upper respiratory noise and exercise intolerance in horses, and may be associated with abnormal laryngeal anatomy. There are few reports of successful treatment of this condition, and no reports of the treatment of RDPA using laser techniques. METHODS: The diagnosis of RDPA was based on the presence of palatal tissue covering the dorsal aspect of the arytenoid cartilages on endoscopic examination. Either a neodymium:yttrium aluminum garnet (Nd:YAG) laser noncontact technique (1060 nm, 100 W continuous mode) or a diode laser contact technique (808 nm, 14 W, continuous mode) was used. RESULTS: In 3 horses in which the Nd:YAG laser was used, displaced palatal tissue was not fully divided at surgery, but separated after latent thermal necrosis within 3 days. In the horse in which the diode laser was used, tissues were fully divided at the time of surgery. Two horses had abnormal laryngeal anatomy and laryngeal hemiplegia. One of these 2 horses was subjected to arytenoidectomy, and had limited success as a race-horse, while the other was retired as a broodmare. One of 2 horses with no other laryngeal abnormalities raced once unsuccessfully, while the other horse was never raced. CONCLUSIONS: Rostral displacement of the palatopharyngeal arch may be corrected in standing horses using transendoscopic surgery, but despite successful ablation of displaced tissue the prognosis for athletic performance is poor.

Using mand training to establish an echoic repertoire in young children with autism.

This research describes a method that initially establishes a mand repertoire as the first component in producing echoic and tact repertoires in young children with limited verbal repertoires. The subjects were 3 nonverbal children with autism, aged 2.5 to 3.5 years. The results indicated that establishing a mand repertoire as the starting point for echoic training produced the acquisition of an initial echoic repertoire in all 3 children within the first 10 sessions. Two of the children also began tacting during the same period. A mand repertoire was acquired by all subjects by the sixth session. Negative vocal behavior was rapidly reduced without the use of aversive contingencies by shaping inapproapriate vocalizations into acceptable vocal mands. Our discussion analyzes those contingencies that contribute to the effectiveness of the manding procedure and compares this procedure with the conventional vocal imitation model. We also discuss variables that may contribute to the long-term success of language training programs and describe strategies for preventing language delay in typical infants and children.

Endoscopic treatment of suspected infectious intertubercular bursitis in a horse.

A 9-year-old gelding was evaluated because of a 30-day history of mild intermittent left forelimb lameness. The only detectable abnormality was mild atrophy of the musculature of the proximal portion of the left forelimb. The cause of the lameness could not be determined. The horse was discharged from the hospital, but was reexamined 6 weeks later because of worsening of the lameness. At that time, the horse resisted flexion and extension of the left shoulder joint, and results of evaluation of an ultrasound-guided aspirate of fluid from the intertubercular bursa were suggestive of infection. Endoscopic examination of the bicipital bursa revealed synovial hypertrophy, particularly in the distal aspect of the bursa. The bursa was lavaged, and a synovial resector was used to remove inflamed synovium. The horse recovered and was healthy 4 months later. In this horse, endoscopy allowed adequate examination of the intertubercular bursa and was not technically difficult.

DIAS-NIDDM--a model-based decision support system for insulin dose adjustment in insulin-treated subjects with NIDDM.

A decision support system has been developed, Diabetes Insulin Advisory System for patients with non-insulin dependent diabetes mellitus (DIAS-NIDDM), assisting in the adjustment of insulin doses in insulin-treated subjects. DIAS-NIDDM uses a causal probabilistic network (CPN) model of carbohydrate metabolism to make stochastic predictions of blood glucose (BG) excursions. The CPN model is an extension of an existing model with an added component representing endogenous insulin secretion. A linear relationship between BG and insulin concentration due to BG stimulated insulin secretion is assumed. Model parameters (pancreatic sensitivity, insulin sensitivity, and time-to-peak of NPH insulin) are estimated by Bayesian probability updating from patient's specific data (food intake, insulin doses, BG measurements) recorded over a period of 4 days. The estimated parameters allow the system to be potentially used as a diagnostic tool to identify abnormalities of carbohydrate metabolism: impaired insulin secretion, insulin resistance and the severity of the impairments. DIAS-NIDDM was used to predict patient-specific BG profiles and advise on insulin doses during a pilot study in eight patients with NIDDM of whom five were treated with insulin. Compared to the administered insulin amount, daily insulin amount advised by DIAS-NIDDM was similar (within 4 U) in three patients, higher by 20% (19 U) in one patient and lower by 40% (18 U) and 50% (11 U) in two patients, respectively. The inter-day coefficient of variation of the daily insulin advice suggests that, at least according to DIAS-NIDDM criteria, day-to-day adjustment of insulin doses is necessary to maintain optimum control.

Saquinavir-mediated inhibition of human immunodeficiency virus (HIV) infection in SCID mice implanted with human fetal thymus and liver tissue: an in vivo model for evaluating the effect of drug therapy on HIV infection in lymphoid tissues.

Treatment with protease inhibitors alone or in combination with inhibitors of reverse transcriptase potently suppresses levels of human immunodeficiency virus (HIV) RNA in plasma and thereby may significantly delay the progression of HIV-mediated disease. To investigate the effect of treatment with the protease inhibitor saquinavir on HIV replication in the lymphoid tissues, we used a SCID-hu mouse model that we developed, in which human thymic and liver tissues (hu-thy/liv) were implanted under both kidney capsules in SCID mice (thy/liv-SCID-hu mice). These mice are populated in the periphery with large numbers of human T cells and develop disseminated HIV infection after intraimplant injection. thy/liv-SCID-hu mice with established HIV infection that were treated for 1 month with saquinavir had a significantly lower viral load present in the implanted hu-thy/liv and mouse spleen than did the untreated HIV-infected thy/liv-SCID-hu mice. To examine the capacity of acute treatment with saquinavir to prevent HIV infection, some thy/liv-SCID-hu mice were inoculated with HIV and then immediately started on saquinavir. Although treated mice had markedly lower viral loads in the thy/liv implants and spleens, HIV infection was not completely prevented. Thus, the effect of antiviral therapy on HIV infection in the major site of HIV replication, the lymphoid tissues, can be readily evaluated in our thy/liv-SCID-hu mice. These mice should prove to be a useful model for determining the in vivo effectiveness of different therapeutic interventions on acute and chronic HIV infection.