Summary Background Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the ...treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. Methods We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov , number NCT02314169. Results We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% 95% CI 15–33) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. Interpretation To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. Funding National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.
Background Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with ...CID/HIES is of clinical importance because of the difference in prognosis and management. Objectives We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. Methods Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. Results DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/μL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4+ and CD8+ T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. Conclusions DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.
Abstract
Background
Disease-free survival (DFS) with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival (OS) with a 5-year median follow-up (5-year OS) in ...adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence in patients who received adjuvant FOLFOX. Hence, reevaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed.
Methods
Individual patient data from 9 randomized studies conducted between 1998 and 2009 were included; 3 trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (RWLS2) and Copula bivariate (RCopula2) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation.
Results
Data from a total of 18 396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (T1-3 and N1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high or deficient mismatch repair tumors. Trial-level correlation between 3-year DFS and 5-year OS remained strong (RWLS2 = 0.82, 95% CI = 0.67 to 0.98; RCopula2 = 0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results.
Conclusions
Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.
يهدف هذا البحث إلى مقارنة تأثيرات التحفيز الكهربائي العصبي العضلي مع القولبة التسلسلية المتقطعة إلى القولبة التسلسلية وحدها على جوانب مختلفة من وظيفة الطرف السفلي لدى الأطفال الذين يعانون من الشلل ...الدماغي المزدوج. تمثل القولبة التسلسلية تقنية سريرية تستخدم لزيادة المدى السلبي للحركة، وخفض فرط التوتر، وتحسين المشي لدى الأطفال المصابين بالشلل الدماغي.
شملت هذه التجربة المقارنة العشوائية ثلاثة وثلاثين طفلا مصابا بالشلل الدماغي المزدوج. عند دخولهم في البحث، تم تعيينهم بشكل عشوائي إما إلى المجموعة (أ) أو المجموعة (ب). تلقت المجموعة (أ) قولبة تسلسلية جنبا إلى جنب مع برنامج علاج طبيعي مخصص، بينما تلقت المجموعة (ب) تدخلات مماثلة مثل المجموعة أ جنبا إلى جنب مع التحفيز الكهربائي العصبي العضلي المطبق من خلال النوافذ أثناء القولبة. شملت التقييمات نطاق الحركة، ومقياس التارديو المعدل، ومقياس الدينامومتر المحمول، ومقياس المشية الرصدي. وأجريت التقييمات قبل وبعد ثمانية أسابيع من التدخل.
أظهرت كلا المجموعتين تحسينات كبيرة في نطاق عطف ظهري للحركة، والزاوية المأبضية، والتشنج الديناميكي في عضلات الساق، والتشنج الديناميكي في أوتار الركبة بعد التدخل. ومع ذلك، لوحظت فروق ذات دلالة إحصائية بين المجموعتين بعد التدخل في قوة المثنية الظهرية، وقوة الباسطة في الركبة، ودرجة مقياس المشية الرصدية، لصالح المجموعة (ب).
قد يساعد استخدام التحفيز الكهربائي العصبي العضلي أثناء الشلل الدماغي في التغلب على الانخفاض الكبير في القوة الذي يحدث نتيجة للقولبة التسلسلية. يتيح ذلك تحقيق نتائج أفضل في تقليل النغمة وتحسين نطاق الحركة دون انخفاض كبير في القوة، بالإضافة إلى تحسن أكبر في وظيفة المشي.
This research was aimed at comparing the effects of neuromuscular electrical stimulation (NMES) combined with interrupted serial casting (SC) versus SC alone on various aspects of lower limb function in children with diplegic cerebral palsy. SC is a clinical technique used to increase passive range of motion (ROM), decrease hypertonicity, and improve walking in children with cerebral palsy (CP).
This randomized comparative trial involved 33 children with diplegic CP, who were randomly assigned to group A or group B at recruitment. Group A received SC along with a customized physical therapy program, whereas group B received the same interventions as group A along with NMES applied through cast windows during casting. Evaluations were based on ROM, the Modified Tardieu Scale, handheld dynamometer measurements, and the Observational Gait Scale. Assessments were conducted before and after 8 weeks of intervention.
Both groups exhibited significant improvements in dorsiflexion ROM, popliteal angle, gastrocnemius dynamic spasticity, and hamstring dynamic spasticity after the intervention (P = 0.0001 for all). However, significant differences (P < 0.05) in dorsiflexor strength, knee extensor strength, and observational gait scale score were observed between groups after the intervention, favoring group B.
The use of NMES during SC may help overcome the substantial decrease in strength resulting from casting, thus achieving less reduction of tone, improving ROM without significantly decreasing strength, and attaining greater improvements in gait function.
Cyclin-dependent kinase 9 (CDK9) is a transcription-associated protein involved in controlling the cell cycle and is often deregulated in stress conditions. CDK9 is being studied as a well-known ...druggable target for developing effective therapeutics against a wide range of cancer, cardiac dysfunction and inflammatory diseases. Owing to the significance of CDK9 in the etiology of hematological and solid malignancies, its structure, biological activity, regulation and its pharmacological inhibition are being explored for therapeutic management of cancer. We employed a structure-based virtual high-throughput screening of bioactive compounds from the IMPPAT database to discover potential bioactive inhibitors of CDK9. The preliminary results were obtained from the Lipinski criteria, ADMET parameters and sorting compounds without any PAINS patterns. Subsequently, binding affinity and selectivity analyses were used to find effective CDK9 hits. This screening resulted in the identification of two natural compounds, Glabrene and Guggulsterone with high affinity and specificity for the CDK9 binding site. Both compounds exhibit drug-like characteristics, as projected by ADMET analysis, physicochemical data and PASS evaluation. Both compounds preferentially bind to the ATP-binding pocket of CDK9 and interact with functionally important residues. Further, the dynamics and consistency of CDK9 interaction with Glabrene and Guggulsteron were evaluated through all-atom molecular dynamic (MD) simulations which suggested the stability of both complexes. The results might be deployed to introduce novel CDK9 inhibitors that may treat life-threatening diseases, including cancer.
Communicated by Ramaswamy H. Sarma
Background Clinical application of adoptive T cell therapy has been hindered by an inability to generate adequate numbers of nontolerized, functionally active, tumor-specific T cells, which can ...persist in vivo. In order to address this, we evaluated the impact of interleukin (IL)-12 signaling during tumor-specific CD8+ T cell priming in terms of persistence and antitumor efficacy using an established B16 melanoma tumor adoptive therapy model. Study Design B6 mice were injected subcutaneously with B16 melanoma tumor cells. On day 12 of tumor growth, mice were preconditioned with cyclophosphamide (4mg dose, intraperitoneally), and 1 day later were treated by adoptive transfer of tumor-specific pmel-1 CD8+ T cells primed ex vivo 3 days earlier with both IL-12 and antigen (hGP10025-33 peptide) or antigen only. Tumors were measured biweekly, and infused donor T cells were analyzed for persistence, localization to the tumor, phenotype, and effector function. Results Adoptive transfer of tumor-specific CD8+ T cells primed with IL-12 was significantly more effective in reducing tumor burden in mice preconditioned with cyclophosphamide compared with transfer of T cells primed without IL-12. This enhanced antitumor response was associated with increased frequencies of infused T cells in the periphery and tumor as well as elevated expression of effector molecules including granzyme B and interferon-γ (IFNγ). Conclusions Our findings demonstrate that ex vivo priming of tumor-specific CD8+ T cells with IL-12 dramatically improves their in vivo persistence and therapeutic ability on transfer to tumor-bearing mice. These findings can be directly applied as novel clinical trial strategies.
Primary Burkitt lymphoma of the thyroid gland is exceptionally rare. This highly aggressive, potentially curable malignancy arises from B cells. It presents as a rapidly expanding thyroid mass ...causing compressive symptoms. This article reports a very rare occurrence of Burkitt-like lymphoma in the thyroid, a variant of Burkitt lymphoma.
A 60-year-old white female developed a rapidly expanding thyroid mass associated with airway compression and difficulty in swallowing.
Fine needle aspiration and cytometry studies established the diagnosis of lymphoma. The patient underwent an incisional neck biopsy which confirmed the final diagnosis according to the latest World Health Organization criteria. It was successfully treated with 1 cycle of appropriate therapeutic chemotherapy.
In patients with lymphoma diagnosed on fine needle aspiration, an incisional thyroid and bone marrow biopsies are required to aid in the diagnosis and assure the appropriate chemotherapy protocol.
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