Tourette syndrome (TS) is a chronic neurodevelopmental dis- order characterised by the presence of multiple motor and vo- cal tics, related to dysfunctional fronto-subcortical pathways in- volved in motor generation (Fig. 1). In the majority of patients, tics are associated with specific tic-related symptoms (echo-, pali- and coprophenomena, self-injurious behaviours, non-ob- scene socially inappropriate behaviours) and co-morbid psy- chiatric disorders, including attention deficit-hyperactivity disor- der and obsessive-compulsive disorder (Table I). The presence of these tic-related symptoms and psychiatric co-morbidities is frequently accompanied by social impairment, which in turn reflects poor health-related quality of life. Treatment strategies for TS include pharmacological and behavioural therapy, plus invasive procedures such as deep brain stimulation (DBS) for severe, treatment-refractory cases (Table II, Figs. 2, 3). Despite being central to the eligibility of candidates for functional neu- rosurgery, the concept of “refractory patients” has never been adequately discussed and defined in TS. We set out to 1) review the available literature on the selection of treatment-refractory patients as candidates for DBS and 2) propose a pragmatic ap- proach to the implementation of the concept of treatment re- fractoriness in the treatment algorithm for TS.
Abstract: Giardia is the commonest parasitic diarrheal pathogen affecting humans and a frequent cause of waterborne/foodborne parasitic diseases worldwide. Prevalence of giardiasis is higher in children, living in poor, low hygiene settings in developing countries, and in travel- ers returning from highly endemic areas. The clinical picture of giardiasis is heterogeneous, with high variability in severity of clinical disease. It can become chronic or be followed by post-infectious sequelae. An alarming increase in cases refractory to the conventional treatment with nitroimidazoles (ie, metronidazole) has been reported in low prevalence settings, such as European Union countries, especially in patients returning from Asia. In view of its relevance, we aim in this review to recapitulate present clinical knowledge about Giardia, with a special focus on the challenge of treatment-refractory giardiasis. We propose a working definition of clinically drug-resistant giardiasis, summarize knowledge regarding resistance mechanisms, and discuss its clinical management according to research-based evidence and medical practice. Advances in development and identification of novel drugs and potential non-pharmacological alternatives are also reviewed with the overall aim to define knowledge gaps and suggest future directions for research.
The current prospective study aims to assess the effectiveness of treatment for severe OCD in clinical practice, using cognitive, behavioral and pharmacologic treatments. It examines the outcome of treatment in both inpatient and com- munity settings, using an assortment of com- plementary outcome criteria. The outcomes are then benchmarked against the treatment effects reported in previous efficacy studies. It expands on previous research in three important ways. It is the first study to examine outcome treatment, predominantly using CBT, in a cohort of severe, treatment-refractory patients seen in both inpa- tient and community settings. Second, it reports on routine clinical practice data allowing for examination of the effectiveness (as opposed to the efficacy) of treatment for OCD. Third, it exam- ines the individual outcomes of patients in both treatment settings.
Abstract: High frequency (> 1 Hz) repetitive transcranial magnetic stimulation (rTMS) applied to the left prefrontal cortex and low frequency ( ≤ 1 Hz) rTMS applied to the right prefrontal cortex have shown antidepressant effects. However, the clinical significance of these effects has often been modest. It was hypothesized that a combination of these two techniques might act synergistically and result in more clinically relevant antidepressant effects. Sixty-two subjects with treatment-resistant major depression (an average of 8 failed medication trials) were randomized to receive combination right low frequency (1 Hz)/left high frequency (10 Hz) rTMS over the dorsolateral prefrontal cortex at 110% of the motor threshold vs sham rTMS. Subjects were treated for 2 weeks (10 weekday sessions) and received 1600 stimulations during each treatment session. Subjects receiving combination treatment were further randomized to receive different orders of treatment: right low frequency first (Slow Right) vs left high frequency first (Fast Left). There were no statistical differences in the active vs sham treatment arms in the primary outcome variable, the Hamilton Depression Rating Scale (HDRS). However compared with subjects in the Sham and Slow Right arms, there was a trend for subjects in the Fast Left arm to show improvement in the HDRS, the Beck Depression Inventory, and the Brief Psychotic Rating Scale with increased number of treatments. The Fast Left arm also showed significant improvement in both blinded clinician and self-ratings of global improvement. These differences were hypothesized to be due to the decreased number of failed medication trials for subjects in Fast Left arm. Neuropsychological performance was not significantly different between the sham and active rTMS arms. Future studies should increase the number of treatment sessions and focus on subjects with moderate treatment resistance.
Many AEDs have been approved as monotherapy and/or as adjunctive agents for the treatment of complex partial sei- zures (Table 1). This discussion will focus on the medications according to their FDA-approved indications, although data do exist to support the use of some agents that are approved as adjunctive therapy for use as monotherapies to treat complex partial seizures. Therapeutic plans are often generated based on individual disease and patient factors, and are influenced by the experience of clinicians rather than by following a pro- scribed treatment algorithm. AED activity against complex partial seizures is often studied in populations of treatment- refractory patients, with efficacy measures generally reported as the percentage of patients with a $50% reduction in
Abstract | Recent developments in the treatment of multiple myeloma have led to improvements in response rates and to increased survival; however, relapse is inevitable in almost all patients. Recurrence of myeloma is typically more aggressive with each relapse, leading to the development of treatment-refractory disease, which is associated with a shorter survival. Several phase II and III trials have demonstrated the efficacy of recently approved agents in the setting of relapsed and/or refractory multiple myeloma, including immunomodulatory agents, such as lenalidomide and pomalidomide, and proteasome inhibitors, such as bortezomib and carfilzomib. Currently, however, there is no standard treatment for patients with relapsed and/or refractory disease. This Review discusses the current treatment landscape for patients with relapsed and/or refractory multiple myeloma and highlights disease-related and patient-related factors—such as pre-existing comorbidities or toxicities—that are important considerations for clinicians when selecting an appropriate treatment regimen.
Noradrenaline and adrenaline, particularly at high doses, have potent vasoconstrictive effects that can lead to irreversible tis- sue ischemia [2,26,27]. Similar concerns arise when AVP and TP are considered for reversing severe vasodilation in septic shock [15,21,23]. When TP is used as a last-resource com- passionate therapy, as in the present study, it is added to the previous treatment, which in this case included combinations of catecholamines in high doses. Such a synergy of effects with an increase of previous tissue perfusion insufficiency or its development could therefore be anticipated. In our series, seven patients had signs of ischemia before TP administration; interestingly, while ischemia persisted in three of them, it improved in four children (Figure 1). On the other hand, five out of nine patients without signs of ischemia developed skin and/ or limb ischemia after adding TP to the catecholamine dose (Figure 1).
Cytokine-induced killer (CIK) cell therapy, a novel T-cell adoptive immunotherapy, was first introduced by Schmidt- Wolf et al, in 1991, where CIK cells were developed by growing peripheral blood mononuclear cells in the presence of interferon (IFN)- γ , anti-CD3 mAb, and interleukin (IL)-2 (1). Since then, the development of CIK cell adoptive immu- notherapy for the treatment of malignant diseases has received considerable attention. CIK cells are ex vivo activated and expanded CD8 + natural killer T cells that have been shown
Introduction: Approximately 85% of patients who die from prostate cancer have bone me- tastases. Even though the radiological aspect of such metastases is osteoblastic, we currently know that these lesions are mixed, with coexisting blastic and lytic lesions, always beginning with bone lysis by osteoclast proliferation. Treatment options are palliative and have poor response, and when there is an improvement it is usually short-lived. This work intends to study the effect of clodronate in the treatment of skeletal complications of prostate cancer.
open-label study testing BV at 1.8 mg/kg intravenously every 21 days for a maximum of 16 cycles. The primary endpoint was objective response rate as determined by an independent review facility. The median number of prior therapies exclud- ing ASCT was 3.5 (range one to 13). Seventy-one percent of patients had primary refractory disease and 42% had failed to respond to the most recent treatment. All patients had failed ASCT and 71% had relapsed within 1 year of ASCT. Patients received a median of nine (range one to 16) cycles of therapy. Eighteen patients received all 16 cycles. Tumor reduction was seen in 94% of patients. The objective response rate was 75% with 34% having complete remissions. The median duration of response was 6.7 months for responders and 20.5 months for complete responders. After a median follow-up of 18.5 months, 31 patients were alive and free from disease progression. Median progression-free survival was 5.6 months overall, but in the complete responders it was 21.7 months. The most common adverse events ($10% reports) were peripheral sensory neuropathy (42%), nausea (35%), fatigue (34%), neutropenia (19%), diarrhea (18%), pyrexia (14%), vomiting (13%), arthralgia (12%), pruritus (12%), myalgia (11%), peripheral motor neuropathy (11%), and alopecia (10%). Fifty-five percent of patients experienced grade 3 or higher toxicity: 20% neutropenia events, 8% periph- eral neuropathy events, and 6% anemia events. Neuropathy typically developed after prolonged exposure to BV, with a median onset of grade 2 events at 27.3 weeks, which were found to be reversible in most patients. Twenty patients had adverse events that led to treatment discontinuation, including peripheral sensory neuropathy in six patients and peripheral motor neuropathy in three patients. Adverse events in 47% of patients led to treatment delays, most commonly because of neutropenia (16%) and peripheral sensory neuropathy (13%). The dose was reduced to 1.2 mg/kg every 21 days in eleven patients, ie, ten due to peripheral neuropathy and one due to grade 4 thrombocytopenia.
measured by tumor response rate; secondary objectives were duration of response, progression-free survival (PFS), OS, and treatment-related toxicity. Eligible patients were aged $18 years with a Karnofsky performance status (KPS) $80. Tumor response was assessed after the initial 2 cycles. Nine patients (18%; 95% CI: 8.4%–30.9%) achieved PR and 25 achieved stable disease (SD) for an overall disease control rate of (PR + SD) of 67% (95% CI: 52.1%–79.3%). Addition- ally, objective response was seen in 8 of 34 patients (24%) previously treated for metastatic disease and in 1 of 17 (6%) patients previously treated in the neoadjuvant or adjuvant setting. The median duration of response was 9.1 months (95% CI: 4.2–15.0) and median PFS was 3.0 months (95% CI: 2.4–3.8). Median OS was 6.6 months (95% CI: 4.8–7.6). Significant toxicities included grade 3–4 leukopenia in 45% patients and grade 3–4 neutropenia in 67% patients. Five patients (10%) experienced febrile neutropenia, 2 of whom died of drug related toxicity. Importantly, grade 3–4 sensory neuropathy was not observed, nor was grade 3–4 renal function impairment.
There is a clear need for a new perspective on the treatment of the IIMs. The prognosis is not well known, since long-term outcome and prognostic factors vary widely. Favorable long-term outcome ranges from 18% to 90%. Predictors of poor outcome are the duration at disease onset, the presence of cancer (9,10), and possibly also male sex (9), dysphagia, longstanding symptoms prior to diagnosis or start of therapy, subset of myositis, skin ulcers, delay in diagnosis or in start of therapy, various types of myositis, pulmonary (especially intersti- tial lung disease) and cardiac involvement, the presence of low total protein and albumin levels, and antisynthe- tase or anti–signal recognition particle autoantibodies (10). A monocyclic disease course was seen in 15–48% of patients (9,10). Over the long term, myositis has a chronic continuous or polycyclic disease course, with major effects on perceived disability and quality of life, despite regained muscle strength (9), although other investigators have reported that after a median of 7.5 years of followup, most patients (86%) had no disease activity, and 83% had no disability (10). It is of note that all these outcome studies were performed using the conventional classification criteria for PM and DM.
Over the past decade the treatment of MM in the U.S. has been anchored by the use of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), often given in combination with the steroid dexamethasone as well as other cytotoxic agents. Drugs that have become mainstays of treatment include the PI bortezomib (Velcade®, Takeda Millenium) as well as the second-generation IMiD lenalidomide (Revlimid®, Celgene), which has largely supplanted earlier use of thalidomide. These agents have been used following treatment with autologous stem cell transplant or as first-line treatment in those ineligible for transplant due to age, frailty, and/or organ dysfunction. More recently, newer agents have been approved for treatment in patients who are refractory to first- line treatment or who relapse following such treatment, including newer-generation IMiDs and PIs as well as monoclonal antibodies, immunostimulatory antibodies, and histone deacetylase
ClinicalTrials.gov as NCT00787969, April 2009). This phase I/II trial is planned to evaluate the efficacy and safety of tem- sirolimus when given together with cladribine and rituximab; the treatment is repeated every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. As secondary endpoints, the trial includes the assessment of metabolic markers (hyperglycemia and hyperlipidemia) as markers of mTOR inhibition and correlation of response with serum-free light chains, single-nucleotide polymorphisms in host immune genes, vitamin D metabolites, and PI3K pathway member expression.
in patients with epilepsy, whereas the analysis of human brain specimens from drug-refractory epileptic patients showed strong activation of the IL-1b/IL-1R1 system in brain resident cells, such as in glia and neurons [21,22]. Functional interactions between cytokines and classical neurotransmitters such as glutamate and GABA have been also described, pointing out at novel glio-neuronal communications in epilepsy and suggesting that cyto- kine-mediated changes in neuronal excitability may pro- mote seizures . Innate immune mechanisms such as complement have been also shown to be potentially involved in epilepsy . The role of innate immunity was further supported by a recent study performed in spontaneously epileptic mice and in human TLE show- ing a new proconvulsant pathway involving high-mobi- lity group box-1 (HMGB1) release from neurons and glia and its interaction with Toll-like receptor 4 (TLR4) . TLR4 and HMGB1 blockade by pharmacologic inhibitors or by genetic deficiency, potentially inter- rupted glia-neuron communication and reduced seizure generation in animal models of seizures in this study .
She had been under regular treatment with colchicine 1 mg daily since diagnosis with a good response for 6 years. In 2008, she moved to Italy to continue her educa- tion, and in June 2010, her attacks recurred with different clinical features including predominant articular symptoms, fever, and abdominal crises, despite continued administration of colchicine (1 mg/day).
Abstract: Significant advances in the management of patients with ulcerative colitis (UC) have been made since the introduction of anti-tumor necrosis factor (TNF)-alpha agents, especially for those who fail or do not tolerate conventional therapies. Two drugs, infliximab first, then adalimumab afterward, showed effectiveness in inducing and maintaining long-term remission both in pivotal trials as well as in clinical practice. However, approximately 25% of patients with UC, who fail or do not tolerate all available therapies, require a colectomy for refractory disease. The therapeutic scenario of UC has been recently upgraded by the introduction of golimumab, the latest anti TNF-alpha agent to be approved. Golimumab is a totally humanized monoclonal antibody, administered by a subcutaneous injection every 4 weeks. Treatment with golimumab has shown to be effective to induce sustained clinical benefit in tough-to-treat patients with UC, including steroid and/or immunosuppressive refractory and steroid-dependent patients. In this review, we summarize all available efficacy and safety data of golimumab in UC, analyzing the potential therapeutic position for the treatment of refractory patients with UC.
Eczema is a delayed type of hypersensitivity reaction caused by complex internal and external excitation factors. It runs its course through three distinct phases: acute, sub-acute, and chronic. The prevalence of eczema is been increased two- to threefold in developed and developing countries during the past three decades. Currently in developed countries, an estimated 15% to 30% of children and 2% to 10% of adults are affected[1, 2]. Chronic eczema differs from acute or sub-acute eczema in recurrence. Individuals with lesions developed over three months are referred to as having chronic eczema. Major clinical characteristics of eczema are skin lesions, appearing to be infiltrated and in hypertrophied state with surface having chaff-like scales or moss-like cover; intense itching, often paroxysmal; and quick relapse rate and prolonged healing time. The common sites involved are hands, feet, legs, cubital fossa, cannus, anus etc. The treatment of chronic eczema is difficult and remains a great challenge for the clinician. The first- line therapeutic option includes the use of topical glucocorticoid hormone. Topical tar, salicylic acid, and retinoic acid preparations are also used for treatment. Glucocorticoid hormones in combination with immunomodulators such as tacrolimus[5,6] and pimecrolimus  are available for the treatment of refractory chronic eczema. If topical preparations fail, oral methotrexate, cyclosporine, and other immunosuppressive agents, as well as retinoic acid , light therapy[11,12], and X-ray treatment are common alternative treatment options. However, these treatments often have an unsatisfactory result and are prone to induce side effects. The disease being pruritic dermatitis, its psychological effects can have serious repercussions on the quality of lives of patients. Thus, there is an urgent need of new and more effective therapies.
Abstract: Treatment of refractory and/or relapsed multiple myeloma has been a challenging problem for over 20 years. However, we have made significant progress addressing this disease with the use of bortezomib, the first in class proteasome inhibitor, and the immunomodulatory agents, thalidomide and lenalidomide. Carfilzomib, the second-generation proteasome inhibitor, has also been approved for treatment of relapsed/refractory multiple myeloma. Carfilzomib is a highly selective and potent inhibitor of proteasome chymotrypsin-like activity. Phase I and II clinical trials have reported an acceptable toxicity profile, with manageable thrombocytopenia and anemia being the most common side effects. Peripheral neuropathy, a frequent dose-limiting side effect of bortezomib, was rare. Further, carfilzomib demonstrated encouraging single- agent activity and appeared to be effective even in patients refractory to bortezomib. Based on these promising data, carfilzomib is moving forward into Phase III trials for relapsed multiple myeloma and is also being investigated as front-line combination therapy for patients with newly diagnosed myeloma.