Failure Of Conventional Treatment Research Articles

Definitive outcomes of self-expandable metal stents in patients with refractory post-transplant biliary anastomotic stenosis

BackgroundEndoscopic retrograde cholangio-pancreatography is the gold standard of treatment in patients with biliary complications after liver transplantation. The benefits of fully covered self-expandable metal stents (FCSEMS) lie in their relative simplicity and the need for only two procedures, one for insertion, and the other for removal. Several case series have been published on such stents with generally good outcomes. Objective is to analyze definitive long-term outcomes of this treatment. MethodsProspective, observational study in a single, tertiary-care referral centre. All consecutive patients with post-transplant biliary stenosis/leak were treated with FCSEMS after failure of conventional treatment. Recurrence was evaluated after four years. ResultsFrom February 2008 to April 2012, 70 patients were included. In all patients, the metal stent was successfully placed. After a mean of 86.7±38.4 days, the stent was removed. Forty-six patients (65.7%) showed resolution. After a mean of 4±1.2 years, 61% of patients maintained the results, but 39% showed recurrence. On the tested variables the diagnosis of stenosis, the number of previous procedures and plastic stents placed correlate with better long-term results. ConclusionsThis series suggests a lack of long-term advantages of FCSEMS over plastic stents in the management of biliary stenosis after liver transplantation.

Evaluation of Interaction Between NK Cells and Colorectal Carcinoma Cells for Development of NK Cell-Based Immunotherapy in Patients with Refractory Disease

BackgroundThe failure of conventional treatment and target therapies to significantly improve outcomes in metastatic colorectal cancer (mCRC) has prompted the development of immune-based therapies, including natural killer (NK) cells-based strategies. NK cells can kill target cells directly, as well as mediate antibody (Ab)-dependent cellular cytotoxicity (ADCC) via the membrane receptor FcgRIII, which binds to the Fc portion of IgG Ab. This feature makes them of particular importance in the immunotherapy of mCRC patients harboring the KRAS mutation that cannot benefit from administration of anti-epidermal growth factor receptor (EGFR) drugs. In this study we evaluated the capacity of patients derived NK cells, either resting or after cytokine activation, to lyse autologous mCRC cells. mCRC cells were analyzed for expression of ligands for adhesion and triggering NK receptors involved in their recognition and killing. We also evaluated whether KRAS mutated mCRC cells were susceptible to anti-EGFR-induced ADCC mediated by NK cells.Patients and methods. After obtaining informed signed consent, 25 mCRC patients have been enrolled to date. Tumor cells were disaggregated by GentleMACS Dissociator (Miltenyi Biotec,Germany), in vitro expanded and analyzed for the expression of ligands for NK triggering receptors. Ligands expression was evaluated by cytofluorimetric analysis and gene expression by qPCR on mCRC cultured cells and by immunohistochemistry in sections of samples embedded in paraffin. Resting and IL-2- or IL-15-activated NK cells, were analyzed for expression of triggering and inhibitory receptors and for their ability to kill autologous mCRC cells alone or after incubation with anti-EGFR monoclonal antibodies (mAbs) in a 51Cr release cytotoxicity assay.Results. Tumor cells were successfully expanded from 21 of 25 samples. Experiments performed in 10 patients showed the inability of patients resting NK cells to lyse mCRC cells (< 10% at effector:target ratio (E:T) of 20:1. Cytokine overnight (ON) activation resulted in an increased NK cytotoxic activity (IL-2: mean 28%; range:10-71; and IL-15: mean 40%; range 16-76 at E:T ratio of 20:1). Additional days of NK cell activation were able to further enhance their lytic capability. In resting NK cells the mean surface expression of activating receptors DNAM-1 and NKG2D was 79%, (range 75-91) and 39 % (range 29-58), respectively. The latter was up-regulated by ON cytokine activation (IL-2: mean 53%, range 48-70; IL-15: mean 70%, range 63-87). Among activating natural cytotoxicity receptors (NCRs), NKp46 is highly expressed both on resting and activated cells (>90%), while low surface expression of NKp30 and NKp44 was documented on resting NK cells (<10%). Their expression could be slightly up-regulated in particular after IL-15 ON activation (mean: 13%, range 9-30). Molecular analysis demonstrated a sizeable gene expression of NK ligands PVR, Nectin-2 and MICA/B on mCRC cells. Cytofluorimetric analysis showed that PVR and Nectin-2 are expressed in a vast majority of cultured mCRC cells (mean 65%, range 60-76; and mean 78%, range 70-98), respectively, while MICA/B were less expressed (mean 18%, range 15-25). The incubation of mCRC cells with anti-EGFR mAbs increased their susceptibility to NK-mediated lysis irrespective of KRAS status of tumor cells. The average rate of increase was greater using resting NK cells as effectors. The ongoing experiments comparing mCRC ligands expression evaluated on cultured tumor cells versus paraffin embedded sections will clarify whether results obtained in vitrocould be translated to the clinical setting.Conclusions.The evidence that ex vivo activated autologous NK cells are able to lyse patients tumor cells can offer new therapeutic options to a cohort of mCRC patients with a poor prognosis. DisclosuresNo relevant conflicts of interest to declare.

AB0421 Evolution of Fatigue in Rheumatoid Arthritis Treated with Rituximab

BackgroundFatigue is a common symptom of rheumatoid arthritis (RA), it can greatly affect the patient's quality of life. Our study aimed to evaluate fatigue evolution and its correlation with the...

Cogan's Syndrome—Clinical Guidelines and Novel Therapeutic Approaches

Cogan's syndrome (CS) is a rare chronic inflammatory disorder, classically characterized by interstitial keratitis and sensorineural hearing loss. Recurrent episodes of inner ear disease might result in deafness. In some patients, it may also be accompanied by systemic vasculitis. Diagnosis of CS is often missed or delayed due to its rarity, the nonspecific clinical signs at onset, and the lack of a confirmatory diagnostic test. The mechanisms responsible for CS are unknown; however, in the last decade, the pathogenesis has been somewhat elucidated, suggesting that the disease is a result of inner ear autoimmunity. The autoimmune hypothesis postulates the triggering of the disease by a viral infection via a number of mechanisms, which are mainly as follows: antigenic mimicry, self-perpetuating inflammation by cytokine release, and unveiling hidden epitopes. Aside from its clinical resemblance to other autoimmune disorders, some autoantigen has apparently been identified, namely, CD148 and connexine 26. Treatment should begin as early as possible. While treatment is based primarily on glucocorticoids, there is no standard alternative for patients who respond poorly. Failure of conventional treatment could lead to profound sensorineural hearing loss. From the limited data we have, infliximab seems to be the most promising biological remedy, enabling steroid tapering and leading to improvement in auditory/ocular disease, with better results when administered in early stages. Proposed guidelines for the use of infliximab in CS are found in the last table of the review, in an attempt to define the proper timing for initiating infliximab treatment in order to avoid permanent disability.

Ovesco system for treatment of postpolypectomy bleeding after failure of conventional treatment

The clip Ovesco (Ovesco, Tübingen, Germany) is a novel endoscopic method for mechanical compression of tissue in the gastrointestinal tract. The indications for treatment are closure of perforations and fistulas and control of bleeding in which the conventional endoscopic treatment has failed. We report two cases about the use of an Ovesco (over-the-scope clip, OTSC) system to control persistent bleeding postpolypectomy after failure of usual treatment.

Desmopressin for the treatment of female storage lower urinary tract symptoms

Female storage lower urinary tract symptoms are prevalent and bothersome. They are usually attributed to an overactive bladder and treated with antimuscarinics. Nevertheless, failure of conventional treatment to alleviate nocturia in particular and epidemiological data suggesting that nocturnal polyuria is the only or a contributing factor to nocturia, has attracted interest in decreasing nighttime urine production as a method of managing nocturia. A reduction in urine production could also, at least temporarily, delay daytime storage symptoms by delaying bladder filling. Therefore, desmopressin, the synthetic analogue or naturally occurring antidiuretic hormone, could have a role in the management of female frequency, urgency and urgency incontinence. This work aims to review data on the use of desmopressin in females with storage symptoms. Available evidence indicates that desmopressin is effi cacious in reducing nighttime urine production and episodes of nocturia, resulting in fewer sleep interruptions. This translates into improved quality of life. Desmopressin is also effective in postponing micturition, urgency and incontinence for several hours after being taken on demand. The tolerability profile of desmopressin is good and significantly improved compared to historical figures due to the introduction of new oral formulations, tailoring the dose according to gender and age and adhering to instructions for fluid restriction before administration. The incidence of hyponatremia, desmopressin’s most important side-effect, is less than 3% in recent trials. The efficacy of desmopressin, combined with its improved safety profile, makes it an interesting method for treating female storage lower urinary tract symptoms.

AB0522 The use of rituximab in current practice during the rheumatoid arthritis naive of anti-TNF alpha

BackgroundRituximab (RTX) is a biotherapy usually recommended during the rheumatoid arthritis (RA) refractory to at least one anti-TNFα. In our country RTX surpassed the anti TNF α in the treatment...

Mirena as an Alternative to Hysterectomy in Cases of Dub

Abstract Introduction: Dysfunctional uterine bleeding is the leading cause of hysterectomy due to conventional treatment failure. Levonorgestrel releasing intra ute-rine device (Mirena) is found to solve this issue by better control of bleeding and thus reducing hysterec-tomy rate. Objective: To measure the efficacy of Mirena as compared to OCP's in control of DUB and to deter-mine that it is an alternative to hysterectomy. Study Design: It was an interventional (experimental) type of study. Setting: Department of Obstetrics and gynecology Unit 11 Lady Willingdon Hospital, Lahore. Duration with Dates: In a total of 60 patients pre-senting with DUB in out patient department from 7 th April 2004 to 31 st December 2005. Subjects and Methods: In a total of 60 patients sele-cted were randomly allocated to Group A and B to receive Mirena and OCP's respectively. Both groups were followed at 6 months and 1 year of treatment. Main outcome measures were patient satisfaction with current treatment and their decision to continue or opt for hysterectomy. 80.7% women receiving Mirena were satisfied with their treatment, while only 30% in the OCP's group (p-value < 0.05) at the end of study. 7.69% was the discontinuation rate of treatment in Mirena group while it was 50% in the control group (p-value < 0.05). Conclusion: Mirena is a better option in the treatment of DUB and it can prove to be an alternative to hyste-rectomy, while we want a more conservative type of treatment. Keywords: 1. Dysfunctional uterine bleeding. 2. Menorrhagia. 3. Abnormal uterine bleeding. 4. Levonorgestrel. 5. Oral contraceptive pills. 6. Tranexamic acid. 7. Estrogens.

Resistant plantar fasciopathy: shock wave versus endoscopic plantar fascial release

To compare the results of Extracorporeal shock wave (ESWT) with a modified endoscopic plantar fasciotomy technique for the treatment of recalcitrant heel pain. Sixty-five patients suffering from chronic heel pain that failed to respond to standard nonoperative methods were randomized to undergo either high-energy extracorporeal shock wave therapy (group 1), or modified endoscopic plantar fasciotomy (group 2). The primary outcome measure was the reduction of pain in the two groups from base line to month three post intervention at the first few steps in the morning. In addition, patients' functions were assessed using American Orthopedic Foot and Ankle-Hindfoot Scale (AOFAS) at week three, month three, and month 12 post-intervention, and finally, Roles and Maudsley scores were assessed. The primary analysis was intention-to-treat and involved all patients who were randomly assigned. Both groups achieved improvement from the base line at 3 weeks, 3 months and 12 months post-intervention. The success rate (Roles and Maudsley score excellent and good) in the ESWT group at month 12 was 70.6 %, while in the fasciotomy group, the success rate was 77.4 % (p = 0.19). In patients who had experienced failure of conventional treatment of plantar fasciopathy, both endoscopic plantar fasciotomy and shock wave therapy can be potentially helpful lines of management.

Intratympanic Steroid Therapy Using the Silverstein Microwick™ for Refractory Sudden Sensorineural Hearing Loss Increases Speech Intelligibility

Objective:To determine whether delivery of methylprednisolone to the round window (administered for 10 days after the onset of the hearing loss) can improve hearing and, in particular, speech intelligibility, after the failure of conventional treatment for idiopathic sudden sensorineural hearing loss. Results: Of the 26 patients enrolled in this non-randomized retrospective study, 14 patients (54%) showed an improvement in the pure tone average (PTA) and 12 remained unchanged. The topical steroid therapy brought about an overall improvement in PTA of 13.5 ± 7.3 dB for the 26 patients enrolled. The auditory capacity index, defined as the mean speech discrimination score obtained at 40, 55 and 70 dB, improved by 24.2 ± 8.7% in 26 patients. Among the 12 patients with a stable PTA, 9 showed an increase in speech intelligibility. Conclusion: Local administration of steroids to the inner ear through the round window route improves hearing and speech intelligibility in patients after failure of conventional therapy.

Failure of conventional treatment with pyrimethamine and sulfadiazine for secondary prophylaxis of cerebral toxoplasmosis in a patient with AIDS

Failure of conventional treatment with pyrimethamine and sulfadiazine for secondary prophylaxis of cerebral toxoplasmosis in a patient with AIDS

Chronic Recurrent Multifocal Osteomyelitis Primarily Affecting the Spine Treated With Anti-TNF Therapy

A case report describing chronic recurrent multifocal osteomyelitis (CRMO) with initial presentation limited to spine, successfully treated by anti-TNF-alpha therapy after failure of conventional treatment methods. To describe an unusual manifestation and treatment of a rare disease. CRMO is a rare inflammatory bone disease that should be differentiated from bacterial osteomyelitis. Rarely, it can affect the spine and in this case the most important differential diagnosis is infectious spondylodiscitis. The disease has an unpredictable course with exacerbations and spontaneous remissions. Although the majority of cases remit spontaneously (or after the use of nonsteroidal anti-inflammatory drugs [NSAIDs]), some progressive and resistant cases have been reported. We describe a case of CRMO with an unusual clinical presentation emphasizing the importance of this finding as a differential diagnosis of spondylodiscitis and comment on the available treatment alternatives. A 17-year-old man presented with debilitating dorsal spine pain. Magnetic resonance imaging of the spine revealed bone lesions at multiple vertebral levels. After failure of antibiotic treatment, the diagnosis of CRMO was suggested. An initial good response to NSAIDs was followed by a recurrent course and involvement of peripheral joints besides the use of corticosteroids and other drugs. The introduction of infliximab was followed by complete remission of the disease. Our observation highlights the need of awareness for the differential diagnosis in suspected cases of osteomyelitis not responding to antibiotics. Anti-TNF-alpha agents should be considered in CRMO refractory cases.

Advances in the Medical Treatment of Diabetic Retinopathy

Proliferative diabetic retinopathy (PDR) remains the leading cause of blindness among working-age individuals in developed countries (1). Diabetic macular edema (DME), another important event that occurs in diabetic retinopathy, is more frequent in type 2 than type 1 diabetes (2). Whereas PDR is the most common sight-threatening lesion in type 1 diabetes, DME is the primary cause of poor visual acuity in type 2 diabetes. Because of the high prevalence of type 2 diabetes, DME is the main cause of visual impairment for diabetic patients (2). In addition, DME is almost invariably present when PDR is detected in type 2 diabetes (3). Neovascularization caused by severe hypoxia is the hallmark of PDR, whereas vascular leakage caused by the breakdown of the blood retinal barrier (BRB) is the main event involved in the pathogenesis of DME (4,5). Although tight control of both blood glucose levels and hypertension is essential to prevent or arrest progression of the disease, the recommended goals are difficult to achieve in many patients and, consequently, diabetic retinopathy develops during the evolution of the disease. When PDR or clinically significant DME do appear, argon-laser photocoagulation is currently indicated, which the efficacy of has been widely demonstrated (6). However, the optimal period for laser treatment has frequently passed; moreover, it is not uniformly successful in halting visual decline. In addition, argon-laser photocoagulation is associated with moderate visual loss, some diminished visual field, reduced color vision, and reduced contrast sensitivity. The presence of these symptoms led to the prevailing thinking that laser treatment prevents vision loss but rarely results in visual improvement. Intravitreal corticosteroids have been successfully used in the eyes of patients with persistent DME and loss of vision following the failure of conventional treatment (i.e., focal laser treatment and attention to systemic risk factors). However, …

Treatment of Chronic Nonunions of the Humerus with Free Vascularized Fibula Transfer: A Report of Thirteen Cases

Chronic nonunions of the humerus remain a challenging problem. We reviewed 13 cases of chronic nonunion of the humerus resulting from trauma or osteomyelitis treated with vascularized fibula transfer after failure of conventional treatment. Patient averages were 35 years of age, follow-up of 19 months, and 4.2 prior operations. Healing was obtained in 12 of 13 (92%) patients with an average healing time of 18 weeks and graft length of 12.5 cm. In total, 11 of 12 (91%) patients who united had good to excellent range of motion of their shoulder and elbow. There were eight complications in 7 of 13 patients (54%). Two patients developed fractures of the graft, and three had superficial infections at the harvest site requiring operative debridement. Two patients had median neurapraxia that resolved by 4 months. Two patients complained of intermittent pain at the donor site. No significant correlations were found between time to heal and other covariates.

Pleurovenous shunt for treating refractory benign pleural effusion

We report the case of a 63-year-old female with hepatic cirrhosis due to chronic hepatitis C, successfully treated for refractory nonmalignant hepatic hydrothorax by using a long-term pleurovenous shunt (PVS). After failure of conventional treatment by mechanical pleurodesis, a PVS was inserted to drain the pleural fluid into the right subclavian vein. After 8 months of follow-up, the effusion is well controlled, and the shunt remains patent.

Molecular Imaging of bcl-2 Expression in Small Lymphocytic Lymphoma Using 111In-Labeled PNA–Peptide Conjugates

The bcl-2 gene is overexpressed in non-Hodgkin's lymphoma (NHL), such as small lymphocytic lymphoma (SLL), and many other cancers. Noninvasive imaging of bcl-2 expression has the potential to identify patients at risk for relapse or treatment failure. The purpose of this study was to synthesize and evaluate radiolabeled peptide nucleic acid (PNA)-peptide conjugates targeting bcl-2 gene expression. An (111)In-labeled PNA complementary to the translational start site of bcl-2 messenger RNA was attached to Tyr(3)-octreotate for somatostatin receptor-mediated intracellular delivery. DOTA-anti-bcl-2-PNA-Tyr(3)-octreotate (1) and 3 control conjugates (DOTA-nonsense-PNA-Tyr(3)-octreotate (2), DOTA-anti-bcl-2-PNA-Ala[3,4,5,6]-substituted congener (3), and DOTA-Tyr(3)-octreotate (4) [DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid]) were synthesized by standard solid-phase 9-fluorenylmethoxycarbonyl (Fmoc) chemistry. In vitro studies were performed in Mec-1 SLL cells, which express both bcl-2 messenger RNA and somatostatin receptors. Biodistributions and microSPECT/CT studies were performed in Mec-1-bearing SCID (severe combined immunodeficiency) mice, a new animal model of human SLL. (111)In-Labeled conjugate 1 was taken up by Mec-1 cells through a somatostatin receptor-mediated mechanism. Biodistribution studies showed specific tumor uptake of conjugate 1, the somatostatin analog 4, and the PNA nonsense conjugate 2, but not of the mutant peptide conjugate 3. Mec-1 tumors could be detected by microSPECT/CT using (111)In-labeled DOTA-Tyr(3)-octreotate (4) and the targeted anti-bcl-2 conjugate (1), but not using the 2 negative control conjugates 2 and 3. A new (111)In-labeled antisense PNA-peptide conjugate demonstrated proof of principle for molecular imaging of bcl-2 expression in a new mouse model of human SLL. This imaging agent may be useful for identifying NHL patients at risk for relapse and conventional treatment failure.

Surgical treatment of obesity

More than half of the European population are overweight (body mass index (BMI) > 25 and < 30 kg/m2) and up to 30% are obese (BMI > or = 30 kg/m2). Being overweight and obesity are becoming endemic, particularly because of increasing nourishment and a decrease in physical exercise. Insulin resistance, type 2 diabetes, dyslipidemia, hypertension, cholelithiasis, certain forms of cancer, steatosis hepatis, gastroesophageal reflux, obstructive sleep apnea, degenerative joint disease, gout, lower back pain, and polycystic ovary syndrome are all associated with overweight and obesity. The endemic extent of overweight and obesity with its associated comorbidities has led to the development of therapies aimed at weight loss. The long-term effects of diet, exercise, and medical therapy on weight are relatively poor. With respect to durable weight reduction, bariatric surgery is the most effective long-term treatment for obesity with the greatest chances for amelioration and even resolution of obesity-associated complications. Recent evidence shows that bariatric surgery for severe obesity is associated with decreased overall mortality. However, serious complications can occur and therefore a careful selection of patients is of utmost importance. Bariatric surgery should at least be considered for all patients with a BMI of more than 40 kg/m2 and for those with a BMI of more than 35 kg/m2 with concomitant obesity-related conditions after failure of conventional treatment. The importance of weight loss and results of conventional treatment will be discussed first. Currently used operative treatments for obesity and their effectiveness and complications are described. Proposed criteria for bariatric surgery are given. Also, some attention is devoted to more basic insights that bariatric surgery has provided. Finally we deal with unsolved questions and future directions for research.

Investigation on Colchicine for Acute Pericarditis: a multicenter randomized placebo-controlled trial evaluating the clinical benefits of colchicine as adjunct to conventional therapy in the treatment and prevention of pericarditis; study design amd rationale

Colchicine is safe and effective in the treatment and prevention of recurrent pericarditis after failure of conventional treatment. The recent guidelines of the European Society of Cardiology suggest that colchicine might be useful even in the treatment of the first episode. However, the use of the drug is not based on any strong evidence obtained from clinical trials, and no randomized placebo-controlled trial is available to guide the management of acute pericarditis. The Investigation on Colchicine for Acute Pericarditis (ICAP) trial will enroll 240 patients in a prospective, randomized, double-blind, multicenter investigation of colchicine compared to placebo in patients with acute pericarditis. The primary efficacy end point is the recurrence rate at 18 months. The secondary end points are symptom persistence at 72 h, remission rate at 1 week, number of recurrences, time to first recurrence, disease-related hospitalization, cardiac tamponade, and constrictive pericarditis. The ICAP trial will be the first randomized placebo-controlled trial in this area. This trial will provide important evidence regarding the possible benefit of the early use of colchicine in the treatment of acute pericarditis and the primary prevention of recurrences, the most troublesome and commonest complication of pericarditis.

Leukocytapheresis (LCAP) in the Management of Chronic Active Ulcerative Colitis—Results of a Randomized Pilot Trial

Recent studies suggest that leukocytapheresis with Cellsorba is a valuable therapy for ulcerative colitis after failure of conventional treatment. In this study the potential of leukocytapheresis to induce remission in refractory chronic colitis under the conditions of European treatment guidelines was investigated. The therapeutic benefit of leukocytapheresis in the maintenance of remission was additionally elucidated. Twenty patients were treated weekly for 5 weeks. A significant decrease in the activity index was observed. Fourteen patients achieved clinical remission, and mucosal healing was observed endoscopically in six patients. After randomization these 14 patients in remission entered a second period of either monthly leukocytapheresis or no further treatment. In both groups steroids were tapered down. After 6 months, only one patient in the control group remained in remission, in contrast to five of eight patients in the leukocytapheresis group. In conclusion, leukocytapheresis may offer a therapeutic option in the induction and the maintenance of remission in chronic active ulcerative colitis.

Topical steroid therapy using the Silverstein Microwick™ in sudden sensorineural hearing loss after failure of conventional treatment

Conclusions. Local administration of steroids to the inner ear through the round window route improves hearing in patients after failure of conventional therapy. Objectives. To determine if delivery of methylprednisolone to the round window can improve hearing after failure of conventional treatment for sudden sensorineural hearing loss (SSHL) administered for 10days after the onset of the hearing loss. Patients and methods. A Silverstein® microwick was placed in the round window niche under local anesthesia and endoscopic control, allowing self-administration of methylprednisolone twice a day for 3weeks. Treated patients were compared to a control group composed of similar patients, treated with the same systemic regimen but who did not receive local therapy. Results. Of the 12 patients enrolled in this nonrandomized prospective study, 8 patients showed an improvement of the pure tone average (PTA) and 4 remain stable. Of those who responded to perfusion, eight patients demonstrated a significant mean 24.5±12dB improvement in PTA, and seven patients had a mean 17.5±18% improvement in discrimination, with five patients reaching 100% speech discrimination score (SDS). Patients in the control group did not show any improvement of the PTA.