Circulating tumor tissue-modified viral (TTMV) human papillomavirus (HPV) DNA is a dynamic, clinically relevant biomarker for HPV-positive oropharyngeal squamous cell carcinoma. Reasons for its wide ...pretreatment interpatient variability are not well understood.
To characterize clinicopathologic factors associated with TTMV HPV DNA.
This cross-sectional study included patients evaluated for HPV-positive oropharyngeal squamous cell carcinoma at Dana-Farber Cancer Institute in Boston, Massachusetts, between December 2019 and January 2022 and who were undergoing curative-intent treatment.
Clinicopathologic characteristics including demographic variables, tumor and nodal staging, HPV genotype, and imaging findings.
Pretreatment circulating TTMV HPV DNA from 5 genotypes (16, 18, 31, 33, and 35) assessed using a commercially available digital droplet polymerase chain reaction-based assay, considered as either detectable/undetectable or a continuous score (fragments/mL).
Among 110 included patients, 96 were men (87%) and 104 were White (95%), with a mean (SD) age of 62.2 (9.4) years. Circulating TTMV HPV DNA was detected in 98 patients (89%), with a median (IQR) score of 315 (47-2686) fragments/mL (range, 0-60 061 fragments/mL). Most detectable TTMV HPV DNA was genotype 16 (n = 86 88%), while 12 patients (12%) harbored other genotypes. Circulating TTMV HPV DNA detection was most strongly associated with clinical N stage. Although few patients had clinical stage N0 disease, only 4 of these 11 patients (36%) had detectable DNA compared with 94 of 99 patients (95%) with clinical stage N1 to N3 disease (proportion difference, 59%; 95% CI, 30%-87%). Among patients with undetectable TTMV HPV DNA, more than half (7 of 12 58%) had clinical stage N0 disease. The TTMV HPV DNA prevalence and score increased with progressively higher clinical nodal stage, diameter of largest lymph node, and higher nodal maximum standardized uptake value on positron emission tomography/computed tomography. In multivariable analysis, clinical nodal stage and nodal maximum standardized uptake value were each strongly associated with TTMV HPV DNA score. Among 27 surgically treated patients, more patients with than without lymphovascular invasion had detectable TTMV HPV DNA (12 of 12 100% vs 9 of 15 60%).
In this cross-sectional study, circulating TTMV HPV DNA was statistically significantly associated with nodal disease at HPV-positive OPSCC diagnosis. The few patients with undetectable levels had predominantly clinical stage N0 disease, suggesting assay sensitivity for diagnostic purposes may be lower among patients without cervical lymphadenopathy. Mechanisms underlying this association, and the use of this biomarker for surveillance of patients with undetectable baseline values, warrant further investigation.
RAS mutations occur across the spectrum of thyroid neoplasms, and more tools are needed for better prognostication. The objective of this study was to evaluate how additional genetic events affecting ...key genes modify prognosis in patients with RAS-mutant thyroid cancers, and specifically differentiated thyroid cancers (DTC).
We performed a clinical-genomic analysis of consecutive patients with DTC, poorly differentiated (PDTC), or anaplastic thyroid cancer (ATC) between January 2014 and December 2021, in whom a custom-targeted next generation sequencing assay was performed. Patients harboring RAS mutations were included, and we compared their clinical features and outcomes based upon the presence of additional oncogenic alterations.
Seventy-eight patients were identified, with 22% (17/78) harboring a driver RAS mutation plus an additional oncogenic alteration. All six (100%) ATCs had an additional mutation. Compared to DTCs harboring a solitary RAS mutation, DTC patients with RAS and additional mutation(s) were more likely to be classified as American Thyroid Association high-risk of recurrence (77% vs. 12%; P<0.001), have larger primary tumors (4.7 vs. 2.5 cm; P=0.002) and advanced stage (III or IV) at presentation (67% vs. 3%; P<0.001). Importantly, over an average 65-month follow-up, DTC-specific-mortality was more than 10-fold higher (20% vs. 1.8%, P=0.011) when additional mutations were identified.
Identification of key additional mutations in patients with RAS-mutant thyroid cancers confers a more aggressive phenotype, increases mortality risk in DTC, and can explain the diversity of RAS-mutated thyroid neoplasia. These data support genomic profiling of DTCs to inform prognosis and clinical decision making.
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Background: Pembrolizumab (P) administered every 3 weeks ± chemotherapy is a standard treatment option for advanced NSCLC. However, there have been no post-approval studies to ...determine the optimal frequency of administration or if longer intervals between administrations are effective. Methods: We conducted a retrospective review of patients with advanced NSCLC treated with P for at least 4 cycles at a single academic center (02/2016-12/2018). Patients received P-based regimens administered at a standard frequency (3 weeks ± 3 days, group A), ≥ 25% of total treatment cycles outside the standard frequency (group B), and < 25% of total treatment cycles outside the standard frequency (group C). We extracted demographic, tumor characteristic, treatment detail and outcomes data. Results: Of 84 P-treated patients, 43 (51%) were identified as receiving at least 4 cycles (groups A: 17, B: 10, C: 16). There were no significant differences in sex, stage at diagnosis, smoking status, tumor histology, driver oncogene mutations, PD-L1 expression, tumor mutation burden, line of therapy, performance status, or immune-related adverse events (irAEs). Patients in group A were more likely to receive P+chemotherapy (groups A: 41.2%, B: 10%, C: 6.3%; p = 0.03). The reasons for non-standard cycles were: patient-physician preference (65.4% patients), irAEs (15.4%), and non-irAE medical issues (42.3%). Time to treatment discontinuation was significantly longer in groups B & C receiving P-based therapy at longer non-standard intervals and with no statistically significant differences in overall survival. Conclusions: Our data, though limited by sample size and single institution design, shows that a significant proportion of patients receive P at extended intervals in routine clinical practice and with comparable outcomes as would be expected for those with advanced NSCLC receiving P at label-specified 3-week intervals. Given the durability of benefit seen in such patients, this requires confirmation in larger datasets and prospective trials so as to maximize patient experience and clinical outcomes while minimizing financial toxicity.
Primary aldosteronism (PA) has been broadly dichotomized into unilateral and bilateral forms. Adrenal vein sampling (AVS) lateralization indices (LI) ≥2 to 4 are the standard-of-care to recommend ...unilateral adrenalectomy for presumed unilateral PA. We aimed to assess the rates and characteristics of residual PA after AVS-guided adrenalectomy.
We conducted an international, retrospective, cohort study of patients with PA from 7 referral centers who underwent unilateral adrenalectomy based on LI≥4 on baseline and/or cosyntropin-stimulated AVS. Aldosterone synthase (CYP11B2) immunohistochemistry and next generation sequencing were performed on available formalin-fixed paraffin-embedded adrenal tissue.
The cohort included 283 patients who underwent AVS-guided adrenalectomy, followed for a median of 326 days postoperatively. Lack of PA cure was observed in 16% of consecutive patients, and in 22 patients with lateralized PA on both baseline and cosyntropin-stimulated AVS. Among patients with residual PA postoperatively, 73% had multiple CYP11B2 positive areas within the resected adrenal tissue (versus 23% in those cured), wherein
mutations were most prevalent (63% versus 33% in those cured). In adjusted regression models, independent predictors of postoperative residual PA included Black versus White race (odds ratio, 5.10 95% CI, 1.45-17.86), AVS lateralization only at baseline (odds ratio, 8.93 95% CI 3.00-26.32 versus both at baseline and after cosyntropin stimulation), and CT-AVS disagreement (odds ratio, 2.75 95% CI, 1.20-6.31).
Multifocal, asymmetrical bilateral PA is relatively common, and it cannot be excluded by robust AVS lateralization. Long-term postoperative monitoring should be routinely pursued, to identify residual PA and afford timely initiation of targeted medical therapy.
Past research has evidently proved that public key cryptosystems are usually slower than symmetric key cryptosystems due to the reason that they use one additional cryptographic key and different ...methods for encryption and decryption. RSA is one of the most common asymmetric key cryptography algorithms. Recent research has focused on speeding up RSA using various techniques. With the introduction of distributed computing, parallelization of algorithms enables them to run on multiple cores concurrently at a time. RSA consists of two resource intensive operations namely Modular Exponentiation of up to 1024-bit exponents and repeated calculation of Greatest common divisor. Thus, RSA lays the perfect base for application of Montgomery Reduction algorithm to optimize the Repeated Modular multiplication in exponentiation. In this paper we proposed a parallel scheme for RSA using a new parallel data structure known as Concurrent Indexed List of character blocks. The aim of our research was to improve the speed of RSA encryption and decryption using parallelism and also make it compatible with leading industry cryptography standards. We have simulated four different approaches namely both parallel and sequential with and without Montgomery. We have also integrated our parallel paradigm with renowned C++ Crypto library and achieved a speed-up of upto four times than sequential approach. Unlike any other previous approaches, our implementation got easily integrated with any external library and thus can be adopted by any other algorithmic scheme.
Most vaccines depend on coadministration of Ags and adjuvants that activate APCs. Nanoparticles (NPs) have emerged as an attractive vehicle for synchronized delivery of Ags and adjuvants to APCs and ...can be targeted to specific cell types, such as dendritic cells (DCs), which are potent APCs. Which subset of human DCs should be targeted for optimal activation of T cell immunity, however, remains unknown. In this article, we describe a poly-lactic-coglycolic acid-based NP platform, wherein avidin-decorated NPs can be targeted to multiple human DC subsets via biotinylated Abs. Both BDCA3(+) and monocyte-derived DC-SIGN(+) NP-loaded DCs were equally effective at generating Ag-specific human T cells in culture, including against complex peptide mixtures from viral and tumor Ags across multiple MHC molecules. Ab-mediated targeting of NPs to distinct DC subsets led to enhanced T cell immunity. However, combination targeting to both DC-SIGN and BDCA3(+) DCs led to significantly greater activation of T cells compared with targeting either DC subset alone. Enhanced T cell activation following combination targeting depended on DC-mediated cytokine release and was IL-15 dependent. These data demonstrate that simultaneous targeting of multiple DC subsets may improve NP vaccines by engaging DC crosstalk and provides a novel approach to improving vaccines against pathogens and tumors.
AbstractObjectiveTo develop and externally validate a prediction model for severe cisplatin associated acute kidney injury (CP-AKI).DesignMulticenter cohort study.SettingSix geographically diverse ...major academic cancer centers across the US.ParticipantsAdults (≥18 years) receiving their first dose of intravenous cisplatin, 2006-22.Main outcome measuresThe primary outcome was CP-AKI, defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of intravenous cisplatin. Independent predictors of CP-AKI were identified using a multivariable logistic regression model, which was developed in a derivation cohort and tested in an external validation cohort. For the primary model, continuous variables were examined using restricted cubic splines. A simple risk model was also generated by converting the odds ratios from the primary model into risk points. Finally, a multivariable Cox model was used to examine the association between severity of CP-AKI and 90 day survival.ResultsA total of 24 717 adults were included, with 11 766 in the derivation cohort (median age 59 (interquartile range (IQR) 50-67)) and 12 951 in the validation cohort (median age 60 (IQR 50-67)). The incidence of CP-AKI was 5.2% (608/11 766) in the derivation cohort and 3.3% (421/12 951) in the validation cohort. Each of the following factors were independently associated with CP-AKI in the derivation cohort: age, hypertension, diabetes mellitus, serum creatinine level, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose. A simple risk score consisting of nine covariates was shown to predict a higher risk of CP-AKI in a monotonic fashion in both the derivation cohort and the validation cohort. Compared with patients in the lowest risk category, those in the highest risk category showed a 24.00-fold (95% confidence interval (CI) 13.49-fold to 42.78-fold) higher odds of CP-AKI in the derivation cohort and a 17.87-fold (10.56-fold to 29.60-fold) higher odds in the validation cohort. The primary model had a C statistic of 0.75 and showed better discrimination for CP-AKI than previously published models, the C statistics for which ranged from 0.60 to 0.68 (DeLong P<0.001 for each comparison). Greater severity of CP-AKI was monotonically associated with shorter 90 day survival (adjusted hazard ratio 4.63 (95% CI 3.56 to 6.02) for stage 3 CP-AKI versus no CP-AKI).ConclusionThis study found that a simple risk score based on readily available variables from patients receiving intravenous cisplatin could predict the risk of severe CP-AKI, the occurrence of which is strongly associated with death.
Immune thrombocytopenia (ITP) is an autoimmune disorder of childhood characterized by immune-mediated destruction of platelets. The mechanisms underlying the pathogenesis of ITP and the therapeutic ...efficacy of intravenous immunoglobulins (IVIG) in this disorder remain unclear. We show that monocytes from patients with ITP have a distinct gene expression profile, with increased expression of type I interferon response (IR) genes. Plasma from ITP patients had increased levels of several cytokines indicative of immune activation, including an increase in interferon-α. ITP patients also had an increase in plasmacytoid dendritic cells (pDCs) compared to healthy donors. Therapy-induced remission of ITP was associated with abrogation of the IR gene signature in monocytes without reduction in the levels of circulating interferon-α itself. IVIG altered the ratio of activating/inhibitory Fcγ receptors (FcγRs) in vivo primarily by reducing FcγRIII (CD16). The engagement of activating FcγRs was required for IVIG-mediated abrogation of monocyte response to exogenous interferon-α in culture. Moreover, plasma from ITP patients led to activation of monocytes and myeloid DCs in culture with an increase in T cell stimulatory capacity; this activation depended on the engagement of activating FcγRs and interferon-α receptor (IFNAR) and was inhibited by antibody-mediated blockade of these pathways. These data point to a central role of type I interferon in the pathogenesis of ITP and suggest targeting pDCs and blockade of IR as potential therapeutic approaches in this disorder. They also provide evidence for the capacity of IVIG to extinguish IR in vivo, which may contribute to its effects in autoimmunity.
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