Partial Resolution Of Lesions Research Articles

A Single Dose Oral Azithromycin versus Intramuscular Benzathine Penicillin for the Treatment of Yaws-A Randomized Non Inferiority Trial in Ghana.

BackgroundYaws is a treponemal infection that was almost eradicated fifty years ago; however, the disease has re-emerged in a number of countries including Ghana. A single-dose of intramuscular benzathine penicillin has been the mainstay of treatment for yaws. However, intramuscular injections are painful and pose safety and logistical constraints in the poor areas where yaws occurs. A single center randomized control trial (RCT) carried out in Papua New Guinea in 2012 demonstrated the efficacy of a single-dose of oral azithromycin for the treatment of yaws. In this study, we also compared the efficacy of a single oral dose of azithromycin as an alternative to intramuscular benzathine penicillin for the treatment of the disease in another geographic setting.MethodologyWe conducted an open-label, randomized non-inferiority trial in three neighboring yaws-endemic districts in Southern Ghana. Children aged 1–15 years with yaws lesions were assigned to receive either 30mg/kg of oral azithromycin or 50,000 units/kg of intramuscular benzathine penicillin. The primary end point was clinical cure rate, defined as a complete or partial resolution of lesions 3 weeks after treatment. The secondary endpoint was serological cure, defined as at least a 4-fold decline in baseline RPR titre 6 months after treatment. Non- inferiority of azithromycin treatment was determined if the upper bound limit of a 2 sided 95% CI was less than 10%.FindingsThe mean age of participants was 9.5 years (S.D.3.1, range: 1–15 years), 247(70%) were males. The clinical cure rates were 98.2% (95% CI: 96.2–100) in the azithromycin group and 96.9% (95% CI: 94.1–99.6) in the benzathine penicillin group. The serological cure rates at 6 months were 57.4% (95% CI: 49.9–64.9) in the azithromycin group and 49.1% (95% CI: 41.2–56.9) in the benzathine penicillin group, thus achieving the specified criteria for non-inferiority.ConclusionsA single oral dose of azithromycin, at a dosage of 30mg/kg, was non-inferior to a single dose of intramuscular benzathine penicillin for the treatment of early yaws among Ghanaian patients, and provides additional support for the WHO policy for use of oral azithromycin for the eradication of yaws in resource-poor settings.Trial RegistrationPan African Clinical Trials Registry PACTR2013030005181 http://www.pactr.org/

Pulmonary alveolar proteinosis during a 30-year observation. Diagnosis and treatment.

Pulmonary alveolar proteinosis (PAP) is a rare disease characterised by the abnormal accumulation of surfactant-like material in macrophages within the alveolar spaces and distal bronchioles. The course of the disease is variable and the prognosis is often good. However, progressive disease in some patients can cause respiratory dysfunction and can be life threatening. In this situation, the only effective treatment is whole lung lavage. The objective of the study was to present the characteristics and the course of pulmonary alveolar proteinosis in our own material, the diagnostic methods used, the indications for treatment and the treatment efficacy. Retrospective analysis included 17 patients: 6 women and 11 men, aged from 32 to 56 years, who were observed in the Third Lung Department of Pneumonology at the National Institute of Tuberculosis and Lung Diseases between 1984 and 2013. In all patients chest X-ray, pulmonary function test and blood gases were performed. In 15 patients, high-resolution computed tomography (HRCT) was obtained. Bronchoscopy was performed in all of the patients, and in 7/17, bronchoalveolar lavage (BAL) was carried out. Fourteen patients underwent open lung biopsy. The indications for whole lung lavage (WLL) were progression of dyspnoea with restriction of daily activity and/or hypoxaemia. In most of the patients (13/17) the diagnosis was established outside our institute. Patients were referred to our department to establish further procedures. The criteria of diagnosis of PAP in most patients (16/17) was the histological examination of lung tissue, obtained by open lung biopsy (14 cases) and transbronchial lung biopsy (TBLB) (2 cases). Only in one patient the diagnosis was established on the basis of BAL. HRCT imaging was characteristic of proteinosis in 11/15 patients, and BAL examination in 6/7 patients, in whom BAL was performed. In four patients, who had been exposed to injurious factors for many years, secondary proteinosis was recognised; in other patients, no exposure or no other disease was found, and primary alveolar proteinosis was diagnosed. In one patient granulocyte macrophage colony stimulating factor autoantibody was detected. The majority of patients (10/17) had clinical symptoms at the diagnosis. The most commonly reported was dyspnoea, followed by respiratory tract infections. The most common abnormality (12/17) in pulmonary lung test was a decrease of diffusing capacity of the lung for carbon monoxide (DLCO). Respiratory distress at rest was found in two patients. Patients were observed for the period of 6 months to 19 years. Spontaneous partial remission was observed in 10 out of 13 untreated patients, including one complete remission; in 3 cases stabilisation was found in radiological examinations; and in other 4 patients, whole lung lavagewas used, resulting in clinical improvement with partial resolution of lesions in radiological examinations in 3 patients. In one patient, despite WLL being repeated three times, improvement was not achieved. Pulmonary alveolar proteinosis is a rare interstitial disease with a mild course in most cases. In 13/17 patients diagnosis was based on histological examination of samples from open lung biopsy. The presented patients were observed in the years 1984-2004, and at that time histologic examination was the main diagnostic method. The most common abnormality in pulmonary function tests was decrease of DLCO. In most cases, spontaneous remission of the disease was observed. In four patients with severe course of PAP, WLL was performed with subjective, functional and radiological improvement in 3 of them.

Multicystic demyelinating myelopathy

A 10-year-old girl presented with subacute lower limb weakness and gait ataxia. MRI revealed a large multicystic spinal cord lesion with patchy enhancement (figure 1, A and B) and 3 small (<6 mm) periventricular and deep white matter brain lesions. The presence of serum anti-aquaporin-4 (AQP4) immunoglobulin G (ELISA assay) and compatible neuropathologic features from neurosurgical specimens1 (figure 2) suggested the diagnosis of a neuromyelitis optica spectrum disorder.2 Targeted immunotherapy was started, with partial lesion resolution (figure 1C).

Tau protein concentrations in the cerebrospinal fluid of children with acute disseminated encephalomyelitis

Background: Acute disseminated encephalomyelitis (ADEM) is clinically characterized by the acute onset of neurological symptoms after a viral infection or immunization, and is thought to represent an autoimmune disease directed against myelin. Tau protein is a phosphorylated microtubule-associated protein, primarily located in neuronal axons. Increased levels of tau protein in cerebrospinal fluid (CSF) are found in various pathological conditions. Methods: We used tau protein as a marker of axonal damage and examined its concentration in the CSF of 27 children with ADEM. Results: CSF tau protein concentration in children with ADEM was significantly higher than that in the CSF of control subjects (P=0.008). There were no significant differences in CSF tau protein concentrations in the ADEM patients with and without encephalopathy. The CSF tau protein concentration in patients with partial lesion resolution in follow-up brain MRI was significantly higher than in patients with complete lesion resolution (P=0.014). Conclusions: In conclusion, we demonstrated that CSF tau protein concentration was significantly increased in ADEM patients. Our findings suggest that axonal damage may occur in addition to demyelination in children with ADEM.

Abstract 849: Cabozantinib (XL184) inhibits growth of prostate cancer in the bone and results in an altered bone environment

Abstract There is a critical need for novel effective therapies for advanced prostate cancer (PCa) and associated bone metastases. A great deal of focus is being placed on investigations into the use of small molecule kinase inhibitors. Cabozantinib (XL184) is a small molecule kinase inhibitor which potently inhibits MET and VEGF receptor 2 (VEGFR2). In a phase 2 adaptive randomized discontinuation trial cabozantinib has demonstrated encouraging signs of clinical benefit in patients with metastatic castration-resistant PCa. Complete or partial resolution of lesions was evident in 82 of 110 (76%) patients with bone metastases as assessed by bone scan. The objectives of our preclinical studies were to investigate the efficacy of cabozantinib on growth of androgen-sensitive and castration-resistant PCa in the bone and on the bone itself. For our in vivo studies we used the androgen-sensitive LuCaP 23.1 PCa xenograft that elicits an osteoblastic reaction in the bone, and the castration-resistant C4-2B PCa xenograft that elicits mixed osteolytic/osteoblastic lesions. Cabozantinib inhibited growth of LuCaP 23.1 in the bone as demonstrated by serum PSA levels (control: 20.1± 0.8ng/ml vs. cabozantinib: 1.5 ±0.4ng/ml, P=0.020). Micro-CT analysis of trabecular bone showed that LuCaP 23.1 growth in the bone resulted in significant increases in bone volume (BV: 7.6 fold increase vs non-tumored tibiae; P=0.017). These increases were attenuated by cabozantinib (BV: 1.3 fold increase vs non-tumored tibiae, P=0.0021). Micro-CT analysis also showed that cabozantinib treatment affected normal bone. BV in non-tumored tibiae from mice treated with cabozantinib was 1.8 fold higher than BV of non-tumored tibiae from untreated mice (P=0.013). To evaluate the effects on osteoblasts in vitro we used MC3T3 cells. In concordance with the detected effects on normal bone, cabozantinib increased alkaline phosphatase activity in MC3T3 cells (1-3 μM, 1.5-2.2 fold increases, ANOVA P&amp;lt;0.0001) and their mineralization (3 μM: 2.2 fold increase, P=0.0023). In the castration-resistant model, C4-2B, cabozantinib treatment also significantly decreased tumor growth based on serum PSA (control: 24.93±6.80 ng/ml vs. cabozantinib: 5.77±1.29 ng/ml, P=0.0096). Micro-CT assessment of tibiae from the C4-2B study and further analyses of all generated tissues are ongoing to further investigate the mechanisms underlying cabozantinib efficacy.In summary, our preclinical results show that cabozantinib is an effective inhibitor of androgen-sensitive as well as castration-resistant PCa in the bone. Importantly our data also indicate that cabozantinib treatment results in increases in bone formation which might be particularly beneficial to patients with advanced PCa who are on androgen ablation therapy and experiencing decreases in bone mineral density and increased frequency of skeletal-related events. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 849. doi:1538-7445.AM2012-849

P1-17-10: Cabozantinib (XL184) in Patients with Metastatic Breast Cancer: Results from a Phase 2 Randomized Discontinuation Trial.

Abstract Background: Cabozantinib is an oral, potent inhibitor of MET and VEGFR2. MET overexpression has been observed in metastatic breast cancer (MBC). High levels of VEGF and its receptors are associated with poor prognosis in patients (pts) with breast cancer. Simultaneous targeting of the MET and VEGF signaling pathways with cabozantinib may therefore be a promising treatment strategy. Results of a phase 2 randomized discontinuation trial (RDT) with single-agent cabozantinib have demonstrated clinical activity in a broad range of tumor types. In addition to observed effects on soft tissue lesions, cabozantinib has also been associated with effects on bone metastases as exhibited by partial or complete bone scan resolution, pain relief and/or reduction of narcotic use. Methods: MBC pts (ER [+], triple [-] or inflammatory subtype) with progressive and measurable disease received single-agent cabozantinib at 100 mg qd PO over a 12 week (wk) lead-in period. Up to 4 prior treatment regimens (hormonal excluded) for MBC were allowed. Tumor response was assessed every 6 wks per mRECIST 1.0. Treatment beyond wk 12 was based on response: pts with partial response (PR) continued with open-label cabozantinib, those with stable disease (SD) were randomized to cabozantinib vs. placebo, and those with progressive disease were discontinued. The primary endpoint was objective response rate (ORR) in the lead-in period, and progression free survival in the randomized period. Post-hoc evaluations of bone scans were conducted. Results: 20 MBC pts were enrolled with a median age of 55 years (range: 31–71).19 pts had invasive ductal carcinoma (1 pt with inflammatory MBC), and 1 pt had invasive lobular carcinoma. 75% of pts were ER/PR [+]; 15% were HER2/neu [+]. 85% of pts had visceral disease including 65% with liver metastases; 70% had bone disease. The median number of prior regimens was 3; 45% received prior anti-VEGF therapy. Most common related adverse events ≥ Grade 3 were fatigue/asthenia, 20%; and hand-foot syndrome, 20%. Dose reductions and permanent discontinuations for AEs occurred in 35% and 15% of pts, respectively. Soft tissue effects: At wk 12, ORR per RECIST was 10% and overall disease control rate (PR+SD) was 45%. Notably, tumor shrinkage was observed in 15/16 pts (94%) with ≥1 post-baseline tumor assessment. Bone effects: 2/3 pts evaluable by bone scan at baseline had partial resolution of lesions and one pt had SD on follow-up bone scans as early as Wk 6. Out of 7 pts receiving narcotics for bone pain, 3 pts reported improved pain and 2 pts had decreased narcotic use, per investigator. The majority of pts analyzed had declines in plasma CTx, an osteoclast marker. Additional enrollment and further bone marker analyses are ongoing. Conclusions: Cabozantinib exhibits clinical activity in pts with MBC regardless of receptor and prior treatment status as reflected by high rate of tumor regression and effects on bone metastases. Cabozantinib is generally well tolerated and the safety profile is comparable to that seen with other tyrosine kinase inhibitors. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-10.

Abstract A233: Cabozantinib (XL184), a dual MET-VEGFR2 inhibitor, blocks osteoblastic and osteolytic progression of human prostate cancer xenografts in mouse bone.

Abstract Background: Prostate cancer bone metastases are associated with high levels of MET expression, and both HGF, the only known ligand for MET, and VEGF appear to direct crosstalk between tumor cells, osteoblasts (OBs), and osteoclasts (OCs). Cabozantinib (cabo), a dual MET-VEGFR2 inhibitor, has shown clinical activity in patients with metastatic castration-resistant prostate cancer (CRPC), where a complete or partial resolution of lesions on bone scans, reduced pain, and soft tissue tumor regression were observed in the majority of patients studied. Therefore, the preclinical effects of cabo were studied in the human CRPC bone xenograft model ARCaPM, which expresses both MET and the VEGF co-receptor neuropilin-1. In addition, the effects of cabo on the differentiation and activity of human OCs and mouse OBs were studied in vitro. Methods: ARCaPM cells were injected bilaterally into the tibiae of nude mice on Day 1, and on Day 31 animals received either cabo at 10 or 30 mg/kg (mpk) or vehicle once-daily for 7 weeks (wks). Animals (n=10 for each dose group) were sacrificed at the end of the treatment period and X-ray images of the tibiae were taken. Five representative tibiae per group were also scanned and analyzed by a Scanco 40 micro-CT instrument. In addition, one tibia from each mouse was fixed, decalcified and embedded for histology and histomorphometry analyzes. The OC culture system consisted of CD34+ cells derived from human bone marrow that were cultured on bovine bone slices in the presence of growth factors including M-CSF and RANK-L. The OB culture system used mouse KS483 cells that differentiate into OBs capable of forming mineralized bone nodules. Results: X-ray and micro-CT imaging of tibiae harvested after the 7 wk treatment period indicated that cabo treatment blocked both the osteoblastic and osteolytic progression of ARCaPM xenograft tumors in bone, with concomitant increases in bone mineral density. Histomorphometry data indicated that tumors were present in 70% (7/10) of the tibiae in the control group but only 30% (3/10) and 20% (2/10) in the 10 mpk and 30 mpk cabo groups, respectively. Consistent with its anti-tumor effect in the bone, cabo treatment decreased the ratio of tumor to tissue area and increased the bone area relative to the tissue area in the analyzed tibia sections compared to vehicle. Histological analyzes indicated an increase in the number of OBs and no change in the number of OCs along the trabecular bone perimeter of tibiae from cabo-treated animals relative to vehicle controls. In the in vitro studies, cabo treatment resulted in reduced OC differentiation in a dose dependent manner but did not affect the ability of mature OCs to resorb bone. In contrast, in the OB studies cabo treatment resulted in a biphasic effect inducing OB differentiation and bone forming activity at the lower doses while reducing these parameters at higher doses. Conclusions: Cabo treatment resulted in diverse effects on the differentiation and function of OBs and OCs in vitro, and blocked both osteoblastic and osteolytic progression of ARCaPM xenograft tumors in bone. These data demonstrate a substantial impact of cabo on tumor cells, OBs, and OCs consistent with the observed clinical results in patients with CRPC. Studies to characterize the molecular mechanisms underlying these effects are underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A233.

Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized discontinuation trial.

4516 Background: Cabozantinib (Cabo) is an inhibitor of MET and VEGFR2. MET signaling promotes tumor growth, invasion and metastasis. Methods: mCRPC patients (pts) with progressive measurable disease (mRECIST) received Cabo at 100 mg qd PO over a 12 week (wk) lead-in stage. Response was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label Cabo, pts with SD were randomized to Cabo vs placebo, and pts with PD discontinued. Primary endpoint was objective response rate (ORR) per mRECIST in the lead-in stage. Up to 200 pts could be enrolled to target 70 randomizations. Bone scans (b-scans) were independently reviewed. Results: Accrual was halted at 168 pts based on an observed high rate of clinical activity. 100 pts are currently evaluable for the lead-in stage; median age 68, 47% with visceral disease, 78% with bone metastasis, and 47% docetaxel (D) pretreated. Median f/u was 4 months (range, 1-15); median PFS not yet reached. Most common related Grade 3/4 AEs were fatigue (11%), HTN (7%), and hand-foot syndrome (5%); no related Grade 5 AEs reported. Dose reductions for AEs occurred in 51% of pts, and discontinuations in 10%. Bone effects: 86% (56/65 pts evaluable by b-scan) had complete or partial resolution of lesions on b-scan as early as wk 6. Eight pts (12%) had SD and 1 pt (2%) had PD. In 28 pts receiving narcotics for bone pain, 64% had improved pain and 46% decreased or halted narcotics, per investigator. Median maximum rise in hemoglobin in anemic pts (Hb < 11 g/dL) was 2.2 g/dL (range, 0.6-3.5). Osteoclast and osteoblast effects were observed: 55% had declines of ≥50% in plasma C-Telopeptide; 56% of pts with elevated tALP had declines of ≥50%. Soft tissue effects: Objective tumor shrinkage occurred in 84% of pts. ORR at wk 12 was 5%; 3 additional PRs await confirmation. PSA changes were independent of clinical activity. Overall, wk 12 disease control rate (PR+SD) was 71%. Randomization was halted and pts unblinded due to high rates of b-scan resolution and pain relief. Conclusions: Cabo showed clinical activity regardless of prior D in mCPRC pts, particularly in pts with bone disease, as reflected by high rates of b-scan resolution and pain relief, in addition to improvements in Hb and tumor regression.

Phase II study of XL184 in a cohort of patients (pts) with castration-resistant prostate cancer (CRPC) and measurable soft tissue disease.

127 Background: XL184 is an oral, potent inhibitor of MET and VEGFR2. MET pathway activation promotes tumor growth, invasion and metastasis. Overexpression of MET and/or its ligand HGF are associated with prostate cancer metastasis. In preclinical studies, androgen ablation upregulates MET signaling. Preliminary data from the open label Lead-in Stage of an ongoing adaptive design phase II randomized discontinuation trial are presented. Methods: Eligible pts had CRPC, measurable disease with or without bone metastasis, and disease progression on ≤1 prior non-hormonal systemic treatment. XL184 was administered orally for 12 weeks (wks). Tumor (RECIST) and bone scan response (complete or partial resolution) were assessed every 6 wks. Primary endpoint is objective response rate at wk 12. Pts with SD at wk 12 will enter a placebo-controlled randomized phase. Results: As of 10/4/10, 72 pts have been enrolled. Median time on study was 50 days (range, 6+-350+ days). Median age was 69 yrs; 45% of pts were docetaxel-pretreated. All pts had measurable disease, including 69% with visceral metastases. To date, there are 24 response evaluable pts, defined as enrolled ≥12 wks prior to data cutoff. 5/24 (21%) pts had a partial response (≥30% reduction) in measurable disease with 3 responses confirmed at 12 wks and 2 unconfirmed responses ongoing. 6/24 (25%) had PSA declines of ≥50%. 13 of 15 (87%) pts with known bone metastases had either complete or partial resolution of lesions on bone scan. Bone scan responses were associated with investigator-reported improvement in bone pain in 11/15 (73%) with pain at baseline. Effects on osteoclast and osteoblast activity were observed: plasma C-telopeptide declined ≥50% in 8/12 (66%) pts and serum total alkaline phosphatase (tALP) declined ≥50% in 5/8 (63%) pts with bone metastases and baseline elevated tALP. The most common AEs ≥Grade 3 severity (related) were fatigue (10%), diarrhea (3%) and elevated AST (3%). Conclusions: XL184 results in tumor responses, partial or complete resolution of lesions on bone scan, and symptom relief in pts with metastatic CRPC, including those pretreated with docetaxel. XL184 also decreased biomarkers of both osteoblast and osteoclast activity. [Table: see text]

Acute Disseminated Encephalomyelitis After Liver Transplantation

During the past 10 years, acute disseminated encephalomyelitis has been reported a few times after organ transplantation. To report a case of acute disseminated encephalomyelitis as a complication of liver transplantation. Case report. The University of North Carolina Hospital and Medical Center, Chapel Hill. Patient A 49-year-old woman admitted because of acute onset of paresthesias, sensory loss, and weakness after liver transplantation. Acute clinical presentation, results of imaging studies, and comprehensive laboratory evaluation were consistent with acute disseminated encephalomyelitis. High-dose intravenous corticosteroid therapy followed by maintenance oral dosing. Clinical and magnetic resonance imaging improvement. Corticosteroid therapy halted clinical progression, with partial resolution of lesions on magnetic resonance images of the brain and spinal cord. This is, to our knowledge, the first report of acute disseminated encephalomyelitis after liver transplantation. Possible pathogenic mechanisms include a cross-reactive immune response to foreign antigens present within the transplanted organ, or an inflammatory response triggered by viral infection in an immunocompromised host.

Efficacy of albendazole and short-course dexamethasone treatment in children with 1 or 2 ring-enhancing lesions of neurocysticercosis: a randomized controlled trial

Objective To determine the efficacy of albendazole plus dexamethasone in children with 1 or 2 ring-enhancing lesions (by computed tomography scan) on resolution of lesions and recurrence of seizure.Study design Randomized controlled open trial.Methods Children of either sex, 1 to 14 years of age, with seizures and 1 or 2 ring-enhancing lesions <20 mm in diameter on computed tomography scan, likely to have neurocysticercosis, were assigned to treatment l groups. Children assigned to the treatment group (n=61) were given 0.15 mg/kg per day dexamethasone for 5 days plus 15 mg/kg per day albendazole for 28 days, starting on the third day of dexamethasone. Control group (n=62) children were given neither dexamethasone or albendazole. Anti-epileptic therapy was given to both the study groups.Results The lesions resolved completely or partially in more children in the treated group compared with the control group (79% versus 57%; P=.02). The proportion of children who had seizures was significantly lower in the treated group compared with the control group at 3 months (10% versus 32%; P=.006) and 6 months (13% versus 33%; P=.03).Conclusions Albendazole plus dexamethasone increased complete or partial resolution of lesions and reduced the risk of subsequent recurrence of seizures among children with neurocysticercosis who had with seizures and 1 or 2 ring-enhancing lesions on computed tomography.