Months Of Stopping Research Articles

Reserve drug as first-line management: Topical interferon α-2b for vernal keratoconjunctivitis.

To elucidate the efficacy and safety profile of interferon α-2b in vernal keratoconjunctivitis (VKC). In this prospective interventional study, VKC patients fulfilling the inclusion and exclusion criteria were included and their signs and symptoms were scored based on the Clinical Scoring System. Patients were treated with topical interferon α-2b eye drop (1 MIU/ml) QID dosing for 6 weeks. Changes in symptoms and signs were evaluated at 2, 4, 8 weeks and 6 months after initiating treatment. A higher score meant severe disease, and a decline in score meant improvement in clinical signs and symptoms. Categorical variables were presented in number and percentage (%) and continuous variables as mean ± standard deviation (SD). Post-medication total subjective symptom score (TSSS) and total objective sign score (TOSS) were compared with baseline, and a P- value of <0.05 was considered significant. Possible ocular and systemic complications were evaluated. The study included 40 patients (32 male and eight female) with a mean age of 8.05 ± 2.33 years. Mean baseline TSSS and TOSS were 6.71 ± 0.564 and 6.59 ± 0.262, respectively, which reduced to 2.71 ± 0.011 ( P = 0.040) and 2.96 ± 0.210 ( P = 0.032), respectively, at 4 weeks and further reduced to 0.42 ± 0.552 and 0.47 ± 0.434, respectively, at 8 weeks. After 6 months of stopping the drug, mean TSSS and TOSS did increase to 2.80 ± 0.820 ( P = 0.044) and 2.50 ± 0.520 ( P = 0.030), respectively, but was still statistically significant improvement compared to the baseline. Also, no ocular or systemic side effects were observed anytime during the study period. Eye drop interferon α-2b (1 million IU/ml) is a safe and effective option as first-line monotherapy for VKC. No side effects and recurrence were observed for 6 months.

Leflunomide-induced collagenous colitis: a case report and literature review

We describe a patient with rheumatoid arthritis and Hashimoto’s thyroiditis who developed chronic diarrhea and subsequently diagnosed with collagenous colitis (CC) 5 years after leflunomide initiation. Cessation of leflunomide resulted in complete resolution of diarrhea within 2 months. Although rare, leflunomide-induced colitis should be considered in patients with otherwise unexplained chronic diarrhea. Diagnosis is challenging as symptom onset can occur many years after leflunomide initiation, but diarrheal symptoms typically resolve within weeks to months of stopping the instigating drug.

Tofacitinib in the treatment of recalcitrant cases of psoriasis vulgaris

Treatment of recalcitrant cases of psoriasis vulgaris can pose a major challenge to dermatologists. Despite the availability of various drugs and treatment modalities, these cases often either show unsatisfactory response to these treatments or may have to be discontinued due to development of adverse effects or may be contraindicated due to underlying morbidities. After exhausting the conventional modalities such as methotrexate, cyclosporine, acitretin, apremilast, and phototherapy, the next line of management involves usage of biologicals. Biologicals, although efficacious in most cases, come with their own set of drawbacks including cost, availability, and risk of development of anti-drug antibodies, rendering them ineffective. Furthermore, some patients have found to relapse within a few months of stopping them. We present a case series of five patients of refractory psoriasis vulgaris who had exhausted all conventional modalities (including biologicals in three of the patients) who were successfully treated with tofacitinib, a small molecule inhibiting Janus kinase 1/3 enzyme. Our patients have reported no side effects with tofacitinib till date and are continuing to maintain the results. From this series, we conclude that tofacitinib may be an effective therapy for the management of recalcitrant psoriasis.

Retrospective Study of Treatment Free Remission in Patients with Chronic Myeloid Leukaemia(CML) Treated at Tertiary Care Oncology Centre from India

Background Tyrosine kinase inhibitors (TKI) have dramatically improved outcomes in Chronic Myeloid Leukemia(CML) patients, but lifelong TKI therapy can negatively impact patients' quality of life due to chronic adverse events. Treatment free remission(TFR) is now the new goal of CML therapy. Studies have shown this is feasible in developed countries. Literature on discontinuation of TKI therapy in resource limited countries such as India is scarce. The purpose of this study was to investigate whether some chronic myeloid leukemia patients with excellent and sustained molecular responses to tyrosine kinase inhibitor treatment can gradually de-escalate TKI therapy and stop therapy in Indian setting. Methods We included all patients above the age of 18years with diagnosis of CML in first Chronic Phase (CP) on TKI therapy of minimum 3 years duration with major molecular response (MMR i.e., <0.1% BCR-ABL1 transcript) of minimum of 2 years duration, enrolled for treatment free remission between January 2018 to December 2021. Starting dose of imatinib was 400mg once daily, dasatinib 100mg once daily and nilotinib 300mg twice a day. In this study the dose of these drugs was reduced by 25% every 6 months . This dose reduction was done with 2 monthly outpatient clinic visits and 2 monthly BCR-ABL1 quantitative PCR monitoring. Patients who maintained MMR during 6 months of dose de-escalation qualified for next level of dose de-escalation. Eventually treatment was stopped completely and monitoring continued. This was retrospective medical record based study done at a tertiary care centre in North India. Results Between Jan 2018 to Dec 2021, 29 patients were enrolled for dose de-escalation and treatment cessation. Among these 29 patients, 19 were on imatinib, 2 on dasatinib and 8 patients on nilotinib. Median age was 39 years( range 21 years to 67 years). Twelve patients were male and 17 female. Median duration of TKI therapy prior to de-escalation was 8 years (range 4years-14 years). Median duration of major molecular response prior to dose reduction was 6 years( range 3years-12 years). In our study 17 of 29 patients had an outcome, while 12 patients are still on de-escalation phase with maintained MMR and are not included in the outcome analysis. Eight patient had loss of MMR(47.05%), 6 while on dose de-escalation and 2 after cessation of TKI. All eight patients achieved MMR after re-initiation of the prior dose, out of these 6 patients had sustained MMR(>6months) at reduced TKI dosing compared to conventional dose. Nine patients (52.9%) have successfully stopped TKI for median duration of 11months (range 6 to 19 months). Conclusion TKI de-escalation was safe for most patients with excellent prior response to TKI therapy. This way of dose reduction , ensured motivation and commitment of patients by doing regular OPD follow ups and BCR-ABL1 PCR testing. In our study 52.9% patient could successfully maintain TFR at a median follow up of 11 months of stopping the drug. We also identified that a subgroup of patients(35.29%) who were unsuccessful in complete cessation of therapy but maintained their molecular response at reduce dose of TKI . These findings show that lower TKI doses might maintain molecular responses in these patients, implying that such patients could be overtreated with routine dosing. More studies of dose de-escalation are warranted.

Spectrum of drug-induced liver injury in a tertiary hospital in southern India.

Background Anti-tuberculosis drugs are thought to account for about 50% of drugs that cause liver injury in India. We show that the spectrum of drugs is much wider than previously reported. Methods We evaluated all patients with unexplained acute liver injury presenting during 2006-2016 using a structured proforma for drug-induced liver injury (DILI). The Roussel Uclaf Causality Assessment Method was used to assess causality. Results DILI was found in 143 of 2534 patients with acute liver injury. Nineteen patients had probable ayurvedic DILI. The other common causes of DILI were statins (16 patients) and anti-tuberculosis drugs (11 patients). Eight patients had DILI post-liver transplant. Fluconazole was the most common cause of post-liver transplant DILI. Chronic DILI (abnormal liver function test after 12 months of stopping the suspected drug) was found in 2 patients. Conclusion In otherwise unexplained acute liver injury, DILI due to ayurvedic drugs should be sought. DILI should be considered in post-liver transplant patients. Patients with DILI should be monitored for at least 12 months to exclude progression to chronic DILI.

Effectiveness, safety, and drug sustainability of biologics in elderly patients with inflammatory bowel disease: A retrospective study.

BACKGROUNDBiologic therapy resulted in a significant positive impact on the management of inflammatory bowel disease (IBD) however data on the efficacy and side effects of these therapies in the elderly is scant.AIMTo evaluate retrospectively the drug sustainability, effectiveness, and safety of the biologic therapies in the elderly IBD population.METHODSConsecutive elderly (≥ 60 years old) IBD patients, treated with biologics [infliximab (IFX), adalimumab (ADAL), vedolizumab (VDZ), ustekinumab (UST)] followed at the McGill University Inflammatory Bowel Diseases Center were included between January 2000 and 2020. Efficacy was measured by clinical scores at 3, 6-9 and 12-18 mo after initiation of the biologic therapy. Patients completing induction therapy were included. Adverse events (AEs) or serious AE were collected during and within three months of stopping of the biologic therapy.RESULTSWe identified a total of 147 elderly patients with IBD treated with biologicals during the study period, including 109 with Crohn’s disease and 38 with ulcerative colitis. Patients received the following biologicals: IFX (28.5%), ADAL (38.7%), VDZ (15.6%), UST (17%). The mean duration of biologic treatment was 157.5 (SD = 148) wk. Parallel steroid therapy was given in 34% at baseline, 19% at 3 mo, 16.3% at 6-9 mo and 6.5% at 12-18 mo. The remission rates at 3, 6-9 and 12-18 mo were not significantly different among biological therapies. Kaplan-Meyer analysis did not show statistical difference for drug sustainability (P = 0.195), time to adverse event (P = 0.158) or infection rates (P = 0.973) between the four biologics studied. The most common AEs that led to drug discontinuation were loss of response, infusion/injection reaction and infection.CONCLUSIONCurrent biologics were not different regarding drug sustainability, effectiveness, and safety in the elderly IBD population. Therefore, we are not able to suggest a preferred sequencing order among biologicals.

PB1897: DISCONTINUATION OF IMATINIB IN PATIENTS FOLLOWED FOR CHRONIC MYELOID LEUKEMIA IN DEEP MOLECULAR RESPONSE

Background: Treatment-free remission (TFR) in CML is defined as achieving a deep molecular remission (DMR) corresponding to molecular remissions of grade 4 or >4. Classically, Imatinib allows it to be achieved in nearly 20% of cases. Aims: We present our experience of stopping Imatib (IMc) (a copy of Imatinib) Methods: Methods and patients This was a study of 25 patients (pts): median age at diagnosis 40 years (9-62) including 2 children and 23 adults, at the time of discontinuation 50 years (18- 73), sex ratio M/F=0.92 (12H/13F); the sokal: 11 pts are intermediate risk, 8 low risk and 6 high risk. According to ELTS, 10 pts low-risk, 10 intermediate-risk, and 5 high-risk, all in chronic phase, all Mbcr/abl and received IMc at 400 mg/day, the first since June 2007 and the last in October 2013. The pts were followed by GeneXpert automated PCR, until deep MR [MMR4 and MMR4.5](Xpert BCR-ABL Ultra test) was achieved and maintained for more than 24 months with a hindsight of more than 5 years. Follow-up of discontinuation was done by PCR every month (2 to 3 months during covid-19); resumption of IMc if BCR/ABL transcript > 0.1% and maintenance of IMc discontinuation, if transcript ≤ 0.1% with monitoring. Deep MR (DMR) was completed at a mean of 70 months; 2 pts (8.3%) were in MMR4 and 23 pts (91.7%) in MMR4.5. with a median follow-up of 8.5 years (6 - 12 years). Imatib discontinuation was started in January 2019 Results: Results of discontinuation CHR was maintained in 24 pts, relapse at 6 months in one pt. TFR was lost in 9 pts (36%): [2 pts (20%) at 1 month, 3 pts (30%) at 2 months, 5 pts (50%) at 6 months]. The median duration of TFR was 23.5 months, 16 pts (64%) remained in DMR (2 children and 14 adults), no progression, withdrawal syndrome noted in 36% (9pts) at one month of stopping, mainly musculoskeletal pain in 28% (7pts), skin rash with pruritus in 12% (3 pts), asthenia in12%, palpebral myositis; among patients who presented these events 66.6% (6 pts) are still in TFR. For relapsed patients, the resumption of IMc was effective in 9 patients, with MMR4 and MMR4.5 achieved on average at 6 months, Summary/Conclusion: Comments: the FIT rate is 64% in our cohort, the relapses (9/25) occurred very quickly, during the first 6 months, the duration of impregnation in our patients who lost their TFR was on average 9 years (6-12 years), without difference with the patients who maintained the FIT which is 8.7 years (6- 13). Sokal and ELTS scores had no influence on FIT since 44.4% (4pts) of intermediate, 33.3% (3pts) of low and 2 of high risk relapsed vs 37.5% (6pts) of intermediate, 25% (4pts) of low and 4 of high risk in FIT, an influence of gender since 77.7% of relapses were men, age and even depth of MMR are all potential factors for cessation but the results in our cohort. The results in our cohort do not confirm their influence since 88.8% of our relapses were in MMR4.5 with a median age of 45 years (42-69) Conclusion: The A-STIM and EURO-SKI studies demonstrate that the depth of response before stopping does not play a prognostic factor for a good FIT, which is confirmed by our study; therapeutic impregnation is the only factor ensuring the maintenance of the FIT found in the studies less in our cohort, hence the factors ensuring the maintenance of the FIT in CML are still to be determined, in order to select the eligible patients.

Dipeptidyl peptidase-4 inhibitor-associated cutaneous eruptions: a retrospective observational study.

Dipeptidyl peptidase (DPP)-4 plays a complex role in immune regulation and its inhibition can have effects on the pathogenesis of various skin diseases. Studies have shown that DPP-4 inhibitors are associated with an increased risk of bullous pemphigoid (BP). To analyse the clinical and histopathological features of cutaneous adverse events in patients on DPP-4 inhibitors. We performed a retrospective review of patients with suspected DPP-4 inhibitor-associated cutaneous adverse events, at a tertiary teaching hospital from 1 January 2017 to 31 December 2020. Exclusion criteria included previous history of chronic skin disease and lack of histopathological reports or follow-up records. The clinical characteristics, latency period, Naranjo Adverse Drug Reaction Probability Scale and clinical outcomes were evaluated. In total, 18 patients (10 men, 8 women; mean age 68.6 years, range 38-89 years) were included. The DPP-4 inhibitors used were teneligliptin (n = 6), vildagliptin (n = 6), sitagliptin (n = 4), linagliptin (n = 1) and saxagliptin (n = 1). The mean interval between therapy initiation and lesion onset was 8.8 months (range 1-24 months). The dermatoses noted were BP (n = 12; 66.6%), lichenoid dermatitis (n = 4; 22.2%), psoriasiform dermatitis (n = 1; 5.6%) and spongiotic dermatitis (n = 1; 5.6%). Eight patients (44.4%) had necrotic keratinocytes as one of the distinct histological features. Causality assessment using the Naranjo scale rated the causative role of DPP-4 inhibitors as 'possible' in all patients. Of the 18 patients, 11 (61.1%) noted improvement in their condition following discontinuation of DPP-4 inhibitors, with 5 having complete remission within 6 months of stopping the drug. DPP-4 inhibitor-associated dermatoses are not necessarily limited to BP. It is necessary to recognize the possibility of other dermatoses in patients on DPP-4 inhibitors as drug substitution/cessation may improve disease morbidity.

Antifungal Drug Resistance of Dermatophytes Causing Superficial Fungal Infections

Background: Superficial fungal infections (SFI) are common skin diseases that were largely simple to treat. However, due to increasing antimicrobial resistance (AMR) of dermatophytes to antifungal drugs, treatment of SFI has become difficult. This study aims to analyze the AMR of dermatophytes and to correlate with the clinical response of antifungal drugs. Methods: A cross‑sectional evaluation was undertaken of 570 consecutive patients with SFI such as tinea corporis, tinea cruris, tinea faciei, and tinea pedis, who were treated with any of the oral antifungal drugs fluconazole, itraconazole and terbinafine. Clinical response was taken within 1 month of stopping the therapy. Microscopic as well as culture and antimicrobial sensitivity analysis were done to characterize and determine the susceptibility of dermatophytes to antifungal drugs aforementioned. Results: Among the 570 patients with SFI, the ratio of male (n=360, 63.16%) to female (n=210, 36.84%) was 1.7:1. The common age group affected by SFI was 31-40 years (27.71%, n=158). The tinea corporis was the most predominant (51.05%) followed by tinea cruris (13.68%). Clinical response analysis showed that the percentage of relapse of SFI after completion of treatment with fluconazole, itraconazole and terbinafine was about 55, 45 and 19, respectively. Culture and antimicrobial sensitivity analysis revealed that the percentage of resistance of dermatophytes from patients of SFI to fluconazole, itraconozole and terbinafine was approximately 70, 55 and 20, respectively. Conclusion: Results reported herein support the notion that the antifungal resistance is evolving in dermatophytes causing SFI, and about 20% dermatophytes are multidrug resistant.

First Report of Reversible Macrocytic Anemia with Dysplastic Features Associated with Palbociclib Use in Patients with Metastatic Breast Cancer

Palbociclib is a reversible cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor that is approved for the treatment of hormone-receptor positive metastatic breast cancer (ER+/HER2- MBC). CDK4/6 inhibitors exert their anti-tumor effect by preventing the G1 to S phase cell cycle transition, resulting in G1 cell cycle arrest. The most commonly reported hematologic side effect of palbociclib is neutropenia. Here we report 3 cases of reversible macrocytic anemia with dysplastic changes as a result of palbociclib use. Next, we present a retrospective study of 32 patients treated with palbociclib. Finally, CDK4 and CDK6 levels were measured in CD34+ stem/progenitor cells (HSPC) from myelodysplastic syndrome (MDS) patients and compared to healthy controls.Methods & ResultsFour months into starting treatment with palbociclib plus an aromatase inhibitor for refractory ER+/HER2- MBC, 3 female patients developed macrocytic anemia, with a mean corpuscular volume (MCV) of >100 femtoliters per cell (fL) and a decrease in hemoglobin (Hb) by 2 grams per deciliter (g/dL). Work-up for macrocytosis was unrevealing except for peripheral blood smears showing dysplastic changes including pseudo-Pelger-Huёt anomaly, suggestive of MDS (see Figure (Fig) 1). Bone marrow aspirates were obtained, which also showed morphology similar to MDS including hypocellular marrow (10% cellularity), dysplastic erythroid forms including binucleated forms and nuclear budding, and small hypolobated megakaryocytes (see Fig 2). Cytogenetic, molecular, and flow analyses were normal. Patients were managed expectantly, and when palbociclib was discontinued for breast cancer progression, the macrocytic anemia resolved to baseline Hb and MCV values within 4 months of stopping therapy.A retrospective study to assess hematological characteristics of 32 patients with ER+/HER2- MBC treated with palbociclib for more than 3 months between 1/1/2015 to 3/1/2017 was performed. Statistical analysis included Wilcoxon signed-rank test and Kaplan Meier estimator. Median age was 65 years and 10 (31%) patients had received prior chemotherapy (see Table 1). Median baseline MCV was 89.75 fL compared to 100.5 fL post palbociclib (p <0.0001), and 16 (52%) patients developed macrocytosis (MCV >100 fL). The median progression-free-survival (PFS) for patients who developed a significant MCV increase (highest MCV >10 fL from baseline MCV) was 422 days compared to 216 days for those without a significant MCV increase (highest MCV ≤10 fL from baseline MCV) (HR 0.29, p=0.035). However, this PFS difference was not seen when the change in MCV was analyzed as a time-dependent variable.As palbociclib treatment appears to induce hematologic and bone marrow changes phenotypically similar to MDS, we examined whether alterations in CDK4/6 expression is observed in human MDS. We evaluated CDK4 and CDK6 expression by qRT-PCR in 183 samples from MDS patient-derived HSPC and 17 healthy marrow control HSPC and found that CDK6, but not CDK4, expression was significantly decreased in MDS HSPC when compared to healthy HSPC (p=0.04) (see Fig 3). We then evaluated MDS phenotype by high (>median) and low (≤median) CDK6 expression, and found that patients with low CDK6 expression had a 1 g/dL lower Hb at presentation when compared to those with high CDK6 expression (p=0.001). Further, when healthy marrow HSPC were treated with palbociclib in vitro, we observed a dose dependent decrease in erythroid colony formation and maturation, replicating the anemia phenotype seen in patients.In conclusion, palbociclib treatment can cause a reversible macrocytic and dysplastic anemia. Macrocytosis is a potential indicator of in vivo CDK4/6 inhibition that could be associated with increased PFS in patients with ER+/HER2- MBC who are treated with palbociclib. Low CDK6 expression in MDS correlates with a worsened anemia phenotype. Further clinical studies with larger sample sizes are needed. Continued safety monitoring of patients on palbociclib is suggested. [Display omitted] DisclosuresSteidl:Aileron Therapeutics: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding; Celgene: Consultancy; Bayer Healthcare: Consultancy.

Treatment Free Remission for Chronic Phase Chronic Myelogenous Leukemia Patients Who Stopped Tyrosine Kinase Inhibitor Therapy Due to Intolerance

Introduction: Chronic Myelogenous Leukemia (CML) is a myeloproliferative neoplasm that is often diagnosed in adults between the ages of 25-60. The outcome of the chronic phase CML has dramatically changed due to Tyrosine Kinase Inhibitor (TKI) therapy. There are well established guidelines from NCCN and ESMO on stopping TKI for patients achieving prolonged remissions with TKIs. We report clinical outcomes from a single tertiary care center in patients who stopped TKI therapy for reasons other than prolonged remission status. Methods: We retrospectively reviewed all the CML patients who were treated at our institution in the past 10 years (January 1st,2009 - December 31st,2018). We excluded patients who had accelerated or blast phase CML, atypical CML, patients on non-TKI therapy, and patients who received an allogeneic stem cell transplant. Results: A total of 117 patients were diagnosed with chronic phase CML at our institution in the past 10 years. Among the 117 patients, 12 of these discontinued TKI therapy. Six patients stopped TKI after achieving prolonged remission with TKI therapy and the remaining patients discontinued due to intolerance to treatment, fear of side effects, and loss of insurance. The median age of the whole cohort is 66 years (range 42-85). Six patients were male and 6 were females. Six patients were diagnosed with CML prior to year 2009 and rest after 2009. Prior to stopping, six patients received only 1 kind of TKI, 2 patients were treated with 2 types of TKIs, 2 patients received 3 types of TKIs, and 2 patients had 4 lines of TKIs (See Table). Cohort 1: 6 patients who stopped due to prolonged remission, median major molecular remission - MMR4 (BCR-ABL &amp;lt;0.01% IS by RT-PCR testing) prior to stopping TKI is 6 years (range 3-13 years). Of the six, only 1 relapsed (within 1 month of stopping) and was initiated back on the same TKI (imatinib). The relapsed patient has not achieved MMR4 level remission to date. Median treatment free remission for this cohort is 13 months (range 1-24 months). Cohort 2: Of those 6 patients who stopped TKI for other reasons: 4 stopped due to side effects/intolerance, 1 stopped due to fear of side effects after FDA label was updated, and 1 patient discontinued due to a loss of insurance. Median duration of MMR4 prior to stopping is 4 years (range 1-11 years). 5 of these 6 patients relapsed in the median time of 6 months (range 3-16 months). Of these 5, 4 were started back on the TKI therapy (three on the same TKI and one on a different TKI). Median treatment free remission for this cohort is 4 months (range 2-16 months). Conclusion: In this small cohort from a single institution's experience, CML patients who discontinued TKI therapy after achieving MMR4 for reasons other than prolonged remission have experienced poor outcomes including a higher rate of relapse and a shorter treatment free remission. We need studies with larger samples sizes and longer follow up to assess outcomes in patients stopping TKI therapy for various reasons. Disclosures No relevant conflicts of interest to declare.

Prognosis Following Discontinuation of OnabotulinumA Therapy in “Super‐responding” Chronic Migraine Patients

To determine whether the successful treatment of chronic migraine (CM) with onabotulinumA (BotoxA) may be followed by a continued respite from headache once therapy has been discontinued. The optimal duration of prophylactic therapy for migraine generally and for CM treated with BotoxA specifically is unknown. We conducted a prospective cohort study evaluating a series of patients with CM at a university-affiliated headache subspecialty clinic in Reno, Nevada, all of whom were treated according to a uniform protocol involving serial injections of BotoxA. We followed all positively responding patients who met our stopping rule for a minimum of 6 months after discontinuation of BotoxA, and we assessed the incidence of clinical worsening in that group. A total of 105/131 patients (80%) for whom complete follow-up was available reported no clinical worsening or need to resume prophylactic therapy over the 6 months following discontinuation of BotoxA therapy. Patients with pre-treatment baseline chronic daily headache (CDH) of greater than 6 months duration were more likely to report clinical deterioration within 6 months of stopping treatment, as compared to patients with CDH of less than 6 months. A greater number of BotoxA treatments required to achieve our stopping rule correlated with clinical deterioration within 6 months of stopping treatment. In many CM patients who experience an especially positive response to serial BotoxA injection therapy, clinical improvement may be sustained for a period of at least 6 months following discontinuation of prophylactic therapy.

Safety of anti-rheumatic drugs in men trying to conceive: A systematic review and analysis of published evidence

There is limited evidence relating to the impact of disease modifying anti-rheumatic drugs (DMARDs) upon male fertility and peri-conception paternal exposure in men with rheumatic disease. Therefore, we conducted a systematic review of available evidence to update information on this subject and guide paternal counselling. A systematic search of PubMed and Embase was carried out up to September 2017, to find relevant peer-reviewed papers, using keywords for fertility/spermatogenesis/conception, men, and disease modifying or biologic drugs commonly prescribed in patients with rheumatic disease. The search yielded 724 papers, and the titles/abstracts were screened independently by 2 authors, duplicates removed and 233 potentially relevant papers selected for full text review. A total of 84 papers were included in the final analysis which covered the impact on fertility of over 611 male exposures to relevant drugs, and over 5986 pregnancies conceived during paternal exposure to (or within 3 months of stopping) these drugs. Aside from the known adverse impact of cyclophosphamide and sulfasalazine on spermatogenesis, overall there was no firm evidence of harm to fertility or pregnancy outcomes with paternal exposure to anti-TNF therapies, abatacept, rituximab, azathioprine, cyclosporine A, hydroxychloroquine, leflunomide, methotrexate or mycophenolate mofetil. There was no evidence found pertaining to the effects of male exposure to IVIG, tacrolimus, golimumab, anakinra or belimumab on fertility or pregnancy outcomes. These results provide further reassurance as to the safety of many DMARDs for men trying to conceive and will be useful when counselling men about risks of anti-rheumatic drugs to fertility and pregnancies, and following accidental conception.

Effects of iron supplementation and nutrition education on haemoglobin, ferritin and oxidative stress in iron-deficient female adolescents in Palestine: randomized control trial.

Iron deficiency and iron-deficiency anaemia are associated with oxidative stress, but their role is largely unclear. Information is scarce on the effects of iron supplementation on biomarkers of oxidative stress in humans. This study evaluated the effectiveness of iron supplementation and nutrition education on improving the levels of haemoglobin and ferritin, and decreasing oxidative stress among iron-deficient female adolescents in Gaza, Palestine. A total 131 iron-deficient female adolescents were recruited and allocated randomly into 3 different groups. The iron supplementation group (A) received 200 mg of ferrous fumarate weekly during the 3-month intervention, the iron supplementation with nutrition education group (B) received iron supplements with nutrition education sessions, and the control group (C) did not receive any intervention. The levels of haemoglobin, ferritin and malonyl dialdehyde were measured at baseline, after 3 months (at which point the intervention was stopped), and then 3 months later. Trial registration number: ACTRN12618000960257. Haemoglobin levels increased significantly after supplementation in both groups A and B. At the follow-up stage (3 months after stopping the intervention), iron and haemoglobin levels in group B continued to increase and malonyl dialdehyde decreased. In Group A, haemoglobin, ferritin and malonyl dialdehyde levels decreased after 3 months of stopping the intervention. No changes were seen in Group C. A nutrition programme should be adopted and integrated into comprehensive intervention programmes to target iron-deficiency anaemia among female adolescents in Palestine.

Immune effects of combinatorial repurposing drugs in refractory ovarian and colorectal cancer patients.

Abstract Background Some refractory cancer patients have a good Karnofsky despite refractory disease. We studied the potential immunomodulatory properties of approved drugs. We used fresh PBMC from refractory patients to study the immune effects of several drugs such as metformin, pidotimod, erdostein, esomeprazole, colchicine, bortezomib, gemcitabine, zoledronic acid and naproxen. Methods 25 high-grade serous ovarian cancer (HGSOC) and 25 colorectal cancer (CRC) subjects were included after approved protocol. The inclusion criteria include Karnofsky 80–100%, complete CT scan, acute phase proteins, granzyme B ELISPOT and antigen-specific ELISA. Results We found after 24 months of treatment in HGSOC 80% of complete response (CR), 15% of stable disease (SD) and 5 % of pseudo-progressive disease (PPD). In CRC we had 50% of CR, 30% of SD and 20% of PPD. In the patients with CR there was an immunological correlation of CD8 persistent immune response by granzyme B ELISPOT in HGSOC and CRC (p=0.0001) and PR (p=0.001), respectively. The combination was well tolerated and after 10 months of stopping the treatment some patients have persistent CD8 specific immune response by ELISPOT and ELISA. Discussion The combination of daily oral metformin, colchicine, pidotimod, erdostein, and naproxen plus weekly low dose of intravenous (IV) esomeprazole (80 mg), bortezomib (0.5 mg/m2), gemcitabine (0.5 mg/m2) and zoledronic acid (100 mg) is clinically feasible, with limited clinical toxicity. We now understand the importance of preserving the CD8 immune response and the use of immune biomarkers such as antigen specific ELISA to improve the rational and generate new combinations to improve clinical outcomes in patients with refractory HGSOC and CRC.

Is Antifungal Resistance a Cause for Treatment Failure in Dermatophytosis: A Study Focused on Tinea Corporis and Cruris from a Tertiary Centre?

Background:Dermatophytoses are one of the most common skin diseases that have been largely simple to treat. However, in recent years, these infections have become recalcitrant to treatment which can possibly be due to antifungal resistance.Aim:To analyze the resistance pattern of patients with recalcitrant dermatophytoses.Materials and Methods:A cross-sectional evaluation was undertaken of 40 consecutive patients with recalcitrant tinea corporis/cruris/both who had taken systemic antifungal treatment and did not respond completely to therapy or had recurrent lesion within 1 month of stopping the therapy. Terbinafine, fluconazole, itraconazole, ketoconazole, amphotericin B, and voriconazole were the antifungals tested using broth microdilution assay for antifungal susceptibility testing of dermatophytes, and MIC50, 90 values were recorded.Results:KOH mount was positive in 18 (45%) patients, culture was positive in 28 (70%) patients. Trichophyton mentagrophytes (35%) and T. rubrum (27.5%) were the predominant isolates. Overall, activity of terbinafine and itraconazole were significantly higher than the other drugs tested. For terbinafine, both T. mentagrophytes and T. rubrum were inhibited at MIC90 of 0.125 μg/ml. Itraconazole-inhibited T. mentagrophytes and T. rubrum at MIC90 of 0.0625 and 0.25 μg/ml, respectively. All isolates had reduced susceptibility to fluconazole.Conclusion:While MIC seen were higher than western data, in-vitro resistance (>1 μg/ml) to antifungals was not seen and probably may not be a cause of treatment failure. Possibly, treatment failure lies in the intricate host fungal interaction and virulence of species which help it to evade host immune response.

Optimizing therapy in inflammatory arthritis: prediction of relapse after tapering or stopping treatment for rheumatoid arthritis patients achieving clinical and radiological remission.

This study aims to assess clinical, lab/immunological or imaging (joint ultrasonography) markers able to predict disease relapse in RA patients in sustained remission when tapering or stopping their treatment. One hundred fifty-seven RA patients in clinical remission (DAS-28 <2.6 for >6months), receiving treatment with sDMARDs and bDMARD therapy, were randomly allocated into any of five groups: Group 1: continue full dose DMARDs and taper biologic therapy by 50% (31 patients); Group 2: taper both DMARDs and biologic therapy dose by 50% (32 patients); Group 3: taper DMARDs by 50% and stop biologic therapy (31 patients); Group 4: stop both DMARDs and biologic therapy (31 patients); Group 5: continue medications without change (31 patients). Forty joints were assessed ultrasonographically (DAS-28 joints+ankles+metatarsophalangeal joints) and prospectively monitored for 12months. The primary endpoint was sustained remission for 12months. Patients were considered as having a relapse when the DAS-28 score was >3.2 and anti-rheumatic treatment was escalated. The frequency of relapse was 41.9% in Group 1, 59.3% in Group 2, 67.7% in Group 3, 77.4% in Group 4 and 6.5% in Group 5. Relapse rates were significantly higher in patients whose ultrasound scores raised within 3months of stopping their medications (P<0.001 for both GS and PD scores). Cox regression identified ACPA positivity (at baseline) and progression of functional disability (at 2months) as predictors for relapse. Tapering therapy is feasible in RA patients. Tailored dynamic approach is advised. Joint ultrasonographic assessment, ACPA positivity and worsening functional disability predicted relapse within a short term after discontinuation of the treatment. RA patients whose DAS-28 score was <2 were more likely to remain in remission.

Comparison between the effects of Propranolol vs Prednisolone vs Prednisolone with Propranolol in the management of infantile hemangioma

Background: Infantile hemangiomas are the most common soft tissue tumors in infancy, Systemic pharmacologic intervention is necessary for endangering, ulcerating, problematic, or life-threatening IHs . These include oral corticosteroid therapy as first-line treatment and interferon - alfa or vincristine as second- or third-line therapeutic agents. Since 2008, use of propranolol has come to the forefront because of its efficacy &amp; minimal side effects.Aims and Objectives: The purpose of this study was to compare the efficacy of orally administered propranolol versus prednisolone versus both in the treatment of potentially disfiguring or functionally threatening infantile hemangiomas.Material and Methods: A prospective study of 24 patients aged 1 week to 12 years child with infantile hemangiomas was randomized into three equal groups. These were as follows: A, Propranolol (1–2 mg/kg/d); B, Prednisolone (1–2 mg/kg/d); and C, receiving both for a minimum duration of 3 months. Dimensions, color, consistency, ultrasonography, photographic documentation based on Visual Analogue Scale (VAS) were recorded before and periodically after starting treatment. A minimum 75% improvement was considered as success with no regrowth up to 1 month of stopping treatment.Results: Mean initial response time (days) in A (4.0 ± 3.3 SD) and C (4.5 ± 3.4SD) was significantly lower than B (8.79 ± 7.8SD) Significant change in consistency was noted very early in A (24 hours) compared to B (8days) and C (6 days). VAS results are as follows: (a) color fading—significant reduction in A within 48 hours compared to B and C (b) flattening— more significant and earlier in A and C than B ,and (c) mean reduction in size: significant in A and C at 3 months), 6 months whereas in B, it was seen only at 6 months.Conclusions: Though it’s a ongoing study, only result of 24 patient had been analysed. Propranolol had a consistent, rapid therapeutic effect compared to prednisolone. A combination of the two had a comparable but not higher efficacy than propranolol alone. Prednisolone was associated with a higher number of complications, thereby decreasing patient compliance.J. Paediatr. Surg. Bangladesh 5(2): 41-44, 2014 (July)

Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial

Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as second-line treatment in patients with metastatic renal cell carcinoma. We did a randomised, phase 2, open-label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT01136733. Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14·6 months [95% CI 5·9-20·1] vs 5·5 months [3·5-7·1]; hazard ratio [HR] 0·40, 95% CI 0·24-0·68; p=0·0005), but not compared with lenvatinib alone (7·4 months [95% CI 5·6-10·2]; HR 0·66, 95% CI 0·30-1·10; p=0·12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0·61, 95% CI 0·38-0·98; p=0·048). Grade 3 and 4 events occurred in fewer patients allocated single-agent everolimus (25 [50%]) compared with those assigned lenvatinib alone (41 [79%]) or lenvatinib plus everolimus (36 [71%]). The most common grade 3 or 4 treatment-emergent adverse event in patients allocated lenvatinib plus everolimus was diarrhoea (ten [20%]), in those assigned single-agent lenvatinib it was proteinuria (ten [19%]), and in those assigned single-agent everolimus it was anaemia (six [12%]). Two deaths were deemed related to study drug, one cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial infarction with single-agent lenvatinib. Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma. Eisai Inc.

Effects of immunosuppressants on immune response to vaccine in inflammatory bowel disease.

Objective:To evaluate the response rate to vaccination in different treatment groups (nonimmunosuppressants and immunosuppressants).Data Sources:We completed an online systematic search using PubMed to identify all articles published in English between January 1990 and December 2013 assessing the effect of the response rate to vaccination in different treatment groups (with and without immunomodulators). The following terms were used: “inflammatory bowel disease (IBD)” OR “Crohn's disease” OR “ulcerative colitis” AND (“vaccination” OR “vaccine”) AND (“corticosteroids” OR “mercaptopurine” OR “azathioprine” OR “methotrexate [MTX]”) AND “immunomodulators.”Study Selection:The inclusion criteria of articles were that the studies: (1) Randomized controlled trials which included patients with a diagnosis of IBD (established by standard clinical, radiographic, endoscopic, and histologic criteria); (2) exposed patients received immunomodulators for maintenance (weight-appropriate doses of 6-mercaptopurine/azathioprine or within 3 months of stopping, 15 mg or more MTX per week or within 3 months of stopping; (3) exposed patients received nonimmunomodulators (no therapy, antibiotics only, mesalazine only, biological agent only such as infliximab, adalimumab, certolizumab or natalizumab or within 3 months of stopping one of these agents). The exclusion criteria of articles were that the studies: (1) History of hepatitis B virus (HBV), influenza or streptococcus pneumoniae infection; (2) patients who had previously been vaccinated against HBV, influenza or streptococcus pneumoniae; (3) any medical condition known to cause immunosuppression (e.g. chronic renal failure and human immunodeficiency virus infection); (4) individuals with positive hepatitis markers or liver cirrhosis; (5) patients with a known allergy to eggs or other components of the vaccines and (6) pregnancy.Results:Patients treated with immunomodulators were associated with lower response rates to vaccination.Conclusions:Immunomodulators may impair the immune response to vaccination in patients with IBD. Vaccination should be made at the time of diagnosis or before starting immunosuppressed therapy.