A retrospective analysis of eosinophilia as a predictive marker of response and toxicity to cancer immunotherapy

Aim: To investigate eosinophilia as a potential on-treatment biomarker for patients receiving cancer immunotherapy. Materials & methods: We evaluated the association between eosinophilia and treatment response and toxicity in a retrospective cohort of patients receiving cancer immunotherapy. Results: The study involved 146 patients. Eosinophilia developed in 22%. Patients who developed eosinophilia were more likely to achieve disease control (p = 0.009), with every 0.1 × 109/l rise in eosinophil count, while receiving treatment was associated with a 28% relative increased chance achieving disease control. Although there was a trend toward improved survival, there was no significant association between eosinophilia and improved overall survival (p = 0.136). Patients with eosinophilia were more likely to develop toxicity (p = 0.042). Conclusion: Eosinophilia is a potentially useful biomarker warranting further prospective clinical investigation.

Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis

ObjectivesEvaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial.MethodsPatients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse.Results188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections.ConclusionsThis large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.

Photodynamic Therapy of Psoriasis Using Photosensitizers of Vegetable Origin

Psoriasis is an immune-mediated, chronic and recurrent inflammatory skin disease, prevalent worldwide, and represents an important burden in life quality of patients. The most common clinical variant is termed as psoriasis vulgaris or plaque psoriasis, which with an individualized and carefully monitored therapy can decrease the patients’ morbidity and improving their life quality. The aim is to achieve disease control, minimize the adverse drug effects, and tailor the treatment to individual patient factors. Photodynamic therapy (PDT) is based on local or systemic administration of a non-toxic photosensitizer followed by irradiation with a particular wavelength to generate reactive oxygen species (ROS), mainly highly cytotoxic singlet oxygen (1O2). The generation of these species results in the attack to substrates involved in biological cycles causing necrosis and apoptosis of affected tissues. Photosensitizers are found in natural products and also obtained by partial syntheses from abundant natural starting compounds. They can be isolated at low cost and in large amounts from plants or algae. Therefore, this manuscript reviews the use of molecules from vegetal sources as photosensitizer agents for the PDT of psoriasis. Psoriasis pathogenesis, management and treatment were reviewed. PDT principles, fundamentals and utilization for the treatment of psoriasis were also discussed. Photosensitizers for PDT of psoriasis are also reviewed focusing on those from vegetal sources. Despite the PDT is utilized for the treatment of psoriasis, very little amount of photosensitizers from plant sources are utilized, such as chlorophyll derivatives and hypericin; however, other natural photosensitizers such as curcumin, could also be investigated. They could constitute a very important, safe and cheap alternative for the successful photodynamic treatment of psoriasis.

Biosimilars in Rheumatic Diseases: Regulatory Guidelines, Efficacy and Safety Implications in Saudi Arabia

Background: Treatment with biologic drugs has enabled many patients with inflammatory rheumatic disease to achieve disease control. In some areas of the world, limited access to biologic therapies has created a demand for lower cost options such as biosimilars, which are highly similar, but not identical to originator biologics. The safe use of biosimilars requires a scientifically rigorous review process for their approval, and guidelines that aid rheumatologists in their use. Discussion: In Saudi Arabia, there are no national or regional guidelines to assist rheumatologists in the proper use of biosimilars in clinical practice, and this may potentially affect the quality of patient care. In this review, we discuss the importance of developing a guidance and the need for healthcare professionals and patients to receive education about biosimilars. We discuss the unique requirements for biosimilar approval, and the differences between biosimilars, originator biologics, and generics. We review important considerations related to biosimilar use, such as switching from originator biologics to biosimilars, switching between different biosimilars, interchangeability, automatic substitution, naming, and pharmacovigilance. We also provide recommendations based on the authors’ expert opinions as rheumatologists to help ensure the appropriate use of biosimilars in Saudi Arabia. Conclusion: The approval and use of biosimilars must be supported by scientifically sound evidence. Guidelines for the use of biosimilars are needed in Saudi Arabia to aid rheumatologists in making clinical decisions. Additionally, educational resources should be provided to healthcare professionals and patients.

Appraisal of the role of radical prostatectomy for rhabdomyosarcoma in children: oncological and urological outcome

The latest multimodal protocols for treatment of bladder/prostate rhabdomyosarcoma (RMS) have shifted the goal of treatment from patient survival to bladder preservation. Consistently, partial resections, such as radical prostatectomy (RP), are favoured when surgery is deemed necessary. We sought to determine the oncological risks – that is, failure to achieve disease control – and the possible benefits in terms of urinary continence associated with RP in RMS patients based on a review of our experience and the data reported in the literature. We identified 18 children undergoing RP for RMS (3 at our institution, 15 in the literature). In five cases, a pubectomy/symphisiotomy was performed to improve surgical exposure. Two cases experienced local relapse, suggesting that this approach can be viable to achieve local control. No clear-cut indications could be extrapolated from the literature, however, to determine how to select the patients most suitable for this approach. We offered this treatment to patients with evidence of disease localized only within the prostate on radiological and endoscopic re-assessment after chemo-/radio-therapy. Eight of the 18 cases (44%) eventually required lower urinary tract reconstruction, suggesting that often this approach does not allow for the preservation of urinary continence with volitional voiding. Finally, data about additional interesting outcomes such as erectile function and fertility in RMS patients undergoing RP are extremely sparse.

Dosis de levotiroxina varía según la etiología del hipotiroidismo y el peso corporal

Objetivo: Determinar las dosis de levotiroxina necesarias para alcanzar control bioquímico del hipotiroidismo según su etiología, peso corporal, TSH inicial y tiempo desde su diagnóstico.Población y métodos: Estudio de cohorte retrospectivo en pacientes hipotiroideos mayores de 14 años con control bioquímico de la enfermedad.Resultados: Se incluyeron 518 pacientes, 90% mujeres. El hipotiroidismo primario fue la forma más común (66,3%), seguido por el hipotiroidismo postiroidectomía total (13,1%), poshemitiroidectomía (6,1%), central (5,9%), posyodo radioactivo (5,7%) y postiroiditis subaguda (2,5%). Los requerimientos respectivos de levotiroxina (µg/kg/día) en ese mismo orden fueron: 1,07± 0,48, 1,65± 0,46, 1,11± 0,52, 1,33± 0,6, 1,51± 0,58 y 1,11± 0,72 (p<0,001). La dosis necesaria en pacientes con hipotiroidismo primario se incrementó con el paso del tiempo desde el diagnóstico: menos de 2 años: 0,77 ± 0,38, entre 2 y 5: 0,90 ± 0,40, mayor de 5: 1,07 ± 0,48 (p<0,001).En pacientes con TSH inicial menor de 10 mUI/L y con menos de dos años de evolución se normalizó la TSH con dosis de 0,65 µg ± 0,33, mientras aquellos con TSH inicial mayor de 20 necesitaron 1,34 µg ± 0,68. (p<0,001). Se observó una diferencia significativa en las dosis requeridas para lograr control de la enfermedad de acuerdo con el índice de masa corporal, siendo menores por kilo de peso a mayor grado de sobrepeso/ obesidad (p = 0,0067).Conclusión: La dosis requerida de levotiroxina para alcanzar el control bioquímico depende de la etiología de la enfermedad, de los valores de TSH al momento del diagnóstico, del peso y el tiempo de evolución del hipotiroidismo. La dosis necesaria para el control de formas leves/tempranas es menor que la recomendada en ausencia de función residual. Abstract Objective: To determine the dose of levothyroxine needed to achieve biochemical control of hypothyroidism based on etiology, body weight, baseline TSH and time since diagnosis. Population and methods: Retrospective cohort study with hypothyroid patients 14 years of age and older with biochemical control of the disease. Results: 518 patients were recruited, 90% of them women. Primary hypothyroidism was the most common form (66.3%), followed by hypothyroidism post-total thyroidectomy (13.1%), post hemi-thyroidectomy (6.1%), central (5.9%), post-radioactive iodine treatment (5.7%), and post thyroiditis (2.5%). The respective levothyroxine requirements (µg/kg/d) in the same order were: 1.07 ± 0.48, 1.65 ± 0.46, 1.11 ± 0.52, 1.33 ± 0.6, 1.51 ± 0.58 and 1.11 ± 0.72 (p <0.001). The required dose in patients with primary hypothyroidism increased as a function of time since initial diagnosis: Less than 2 years: 0.77 ± 0.38, 2 to 5 years: 0.90 ± 0.40, more than 5 years: 1.07 ± 0.48 (p <0.001). In patients with baseline TSH levels lower than 10 mIU/L and less than 2 years of evolution, TSH was normalized with doses of 0.65 µg ± 0.33, whereas those with baseline TSH levels higher than 20 needed 1.34 µg ± 0.68 (p <0.001). A significant difference was observed in the dose required to achieve disease control. This difference was related to body mass index, as follows: The greater the degree of overweight/obesity, the lower the doses needed per kg of body weight (p = 0.0067). Conclusion: The dose of levothyroxine required to achieve biochemical control depends on the etiology of the disease, TSH levels at the time of diagnosis, weight, and time since onset of hypothyroidism. The dose required to control mild and early forms is lower than the dose recommended in the absence of residual function.

Initial gemcitabine/nab-paclitaxel (GA) followed by sequential (S) mFOLFIRINOX or alternating (A) mFOLFIRI in metastatic pancreatic cancer (mPC): The SEENA-1 study.

359 Background: GA, FOLFIRINOX and FOLFIRI are standard chemotherapy (CTX) regimens for mPC.The optimal introduction of these regimens following GA is not known. This phase II study evaluated 2 different approaches to this question. Methods: Eligibility criteria included 1) untreated mPC, 2) ECOG PS 0/1, 3) organ function adequate for Rx. Patients (pts) were treated according to one of 2 methods following GA given per standard dose/schedule: FOLFIRINOX (bolus 5-FU omitted) for up to 12 cycles at 24 weeks or at time of disease progression (S); or GA alternating with FOLFIRI q8 weeks up to 48 weeks total Rx (A). Results: 54 evaluable pts (28S, 26A) were enrolled . Pt characteristics included median age 65, M/F 48/52% , liver involvement 89%. 17/53 pts (31%) did not achieve disease control at 8 weeks (8 toxicity/complications , 6 disease progression, 3 declined further protocol therapy). Of the remaining 37 pts, 24/13 were treated with S/A regimens, respectively. Grade ≥ 3 treatment toxicities reported while on study with frequency ≥ 10% included anemia 21%, neutropenia 43%, thrombocytopenia 15%, and fatigue 22%. Grade ≥ 3 neuropathy occurred in 8% of pts. For all 54 pts using RECIST 1.0, CR/PR/SD/DC was 2 (4%)/20 (37%)/19 (35%)/41(76%). Ca19.9 response ≥ 90% was seen in 20/37 (54%). For all pts, median OS was 12.3 months ( 95% CI 8.6-14.5 mo); 12 and 24 mo OS was 51% and 11%, respectively. For the 37 pts with DC on GA at 8 weeks (calculated from start Rx) median OS was 13.5 mo (95% CI 10.7-15.4 mo); 12 and 24 mo OS was 55% and 16% , respectively. No statistically significant differences were seen between S and A with respect to toxicity, response or survival. Conclusions: 1) As opposed to introduction of 5FU-based CTX at the time of disease progression/prohibitive toxicity, introduction prior to that time may be at least comparable regarding both toxicity and OS. 2) This approach may further enhance OS in pts who achieve DC on GA at 8 weeks. 3) Neither S nor A method of 5FU-based CTX introduction following GA was clearly superior in this study. 4) How best to combine 5FU-based combination CTX following GA in mPC merits further study. Supported by the Seena Magowitz Foundation.

Failure to achieve disease control in acromegaly: cause analysis by a registry-based survey

ContextDisease control is a prime target in acromegaly treatment. This should be achievable in the vast majority of patients by available treatment options. For unknown reasons, however, a significant number of patients do not achieve disease control.ObjectiveTo investigate reasons for failure to achieve disease control in long-standing acromegaly.Design and methodsSurvey based on the German Acromegaly Registry database (1755 patients in 57 centres). Questionnaires were sent to 47 centres treating 178 patients with elevated disease markers (IGF1 and GH) at the last documented database visit out of 1528 patients with a diagnosis dated back ≥2 years. Thirty-three centres returned anonymised information for 120 patients (recall rate 67.4%).ResultsMedian age of the 120 patients (58 females) was 57 years (range 17–84). Ninety-four patients had at least one operation, 29 had received radiotherapy and 71 had been previously treated medically. Comorbidities were reported in 67 patients. In 61 patients, disease activity had been controlled since the last documented database visit, while 59 patients still had biochemically active disease. Reasons were patients' denial to escalate therapy (23.3%), non-compliance (20.6%), fluctuating insulin-like growth factor 1 (IGF-1) and growth hormone (GH) levels with normal values at previous visits (23.3%) and modifications in pharmacotherapy (15.1%). Therapy resistance (9.6%), drug side effects (4.1%) and economic considerations (4.1%) were rare reasons.ConclusionsMain reasons for long-standing active acromegaly were patients' lack of motivation to agree to therapeutic recommendations and non-compliance with medical therapy. Development of patient education programmes could improve long-term control and thus prognosis of acromegalic patients.