Highly sensitive trace gas detection based on a miniaturized 3D-printed Y-type resonant photoacoustic cell.

We report, what we believe to be, a novel miniaturized 3D-printed Y-type resonant photoacoustic cell (YRPAC) consisting of a frustum of cone-type buffer chamber and a cylindrical resonant chamber. The volume of the designed YRPAC is about 7.0 cm3, which is only about a half of the T-resonant photoacoustic cell (TRPAC). The finite element simulation of the sound field distribution of the TRPAC and YRPAC based on COMSOL shows that the photoacoustic signal is enhanced with the shape of the buffer chamber changing from the traditional cylinder to a frustum of cone. The photoacoustic spectroscopy (PAS) system, utilizing the YRPAC and TRPAC as the photoacoustic reaction units, a 1653.7 nm distributed feedback (DFB) laser as the excitation light source, a cantilever beam acoustic sensor as the acoustic sensing unit, and a high-speed spectrometer as the demodulation unit, has been successfully developed for high-sensitivity trace CH4 sensing. When the CH4 concentration is 1000 ppm, the 2f signal of YRPAC in the first-order resonance mode is 2.3 nm, which is 1.7 times higher than the 2f signal amplitude of TRPAC. The detection sensitivity and minimum detection limit for the PAS system are 2.29 pm/ppm and 52.8 parts per billion (ppb) at 100 s of averaging time. The reported YRPAC has higher sensitivity, smaller size, and faster response time compared to the conventional TRPAC, which can provide a new solution for PAS development.

Measurement of adherence and health-related quality of life during anticoagulation therapy in cancer-associated venous thromboembolism (VTE): a multicenter quantitative study.

PURPOSE: Therapy for cancer-associated venous thromboembolism (VTE) includes long-term anticoagulation, which may have substantial impact on the health-related quality of life (HRQL) of patients. We assessed patient-reported outcomes to characterize the HRQL associated with VTE treatment and to begin to examine those HRQL elements impacting anticoagulation adherence (AA). METHODS: Participants were adult cancer patients with confirmed symptomatic acute lower extremity deep venous thrombosis. Patients were excluded if there was an indication for anticoagulation other than VTE, ECOG performance status >3, or life expectancy < 3 months. Participants were assessed with a self-reported adherence tool. HRQL was measured with a 6-domain questionnaire using a seven-point Likert scale. Evaluations were performed at 30 days and 3 months after enrollment. For the primary objective, an overall adherence rate was calculated at each time point of evaluation. For the HRQL domains, non-parametric testing was used to compare results between subgroups. RESULTS: Seventy-four patients were enrolled. AA and HRQL at 30 days and 3 months were assessed in 50 and 36 participants, respectively. At 30 days the AA rate was 90%, and at 3 months it was 83%. In regard to HRQL, patients suffered frequent and moderate-severe distress in the domains of emotional and physical symptoms, sleep disturbance, and limitations to physical activity. An association between emotional or physical distress and AA was observed. CONCLUSION: Patients with VTE suffer a substantial impairment of their HRQL. Increased emotional distress correlated with better long-term AA. These results can be used to inform additional research aimed at developing novel strategies to improve AA.

High-Sensitivity Multitrace Gas Simultaneous Detection Based on an All-Optical Miniaturized Photoacoustic Sensor.

We propose an all-optical miniaturized multigas simultaneous detection photoacoustic (PA) sensor, which is primarily composed of a copper tube, a silica cantilever, and four single-mode fibers. Three single-mode fibers are used as excitation fibers to transmit lasers of different wavelengths, and the remaining one is used as a probe fiber. The volumes of the PA cell (PAC) and the sensor are 36 µL and 71 cubic millimeters, respectively. A laser photoacoustic spectroscopy (PAS) system, using the all-optical miniaturized PA sensor as a detector, 1532.8, 1576.3, and 1653.7 nm distributed feedback (DFB) lasers as the excitation sources for acetylene (C2H2), hydrogen sulfide (H2S), and methane (CH4) gases, and a high-speed spectrometer as a demodulator, has been developed for multigas simultaneous measurements. The minimum detection limits of 4.8, 162, and 16.6 parts per billion (ppb) have been achieved for C2H2, H2S, and CH4, respectively, with an integration time of 100 s. The reported sensor shows a potential for high-sensitivity multigas simultaneous measurements in cubic millimeter-scale space.

Refined HLA-DPB1 mismatch with molecular algorithms predicts outcomes in hematopoietic stem cell transplantation.

HLA-DPB1 mismatches between donor and recipient are commonly seen in allogeneic hematopoietic stem cell transplantation from an unrelated donor. HLA-DPB1 mismatch, conventionally determined by the similarity of the T-cell epitope (TCE), is associated with an increased risk of acute graft-versus-host disease (GVHD) and a decreased risk of disease relapse. We investigated the clinical impact of HLA-DPB1 molecular mismatch quantified by mismatched eplets (ME) and the Predicted Indirectly Recognizable HLA Epitopes Score (PS) in a cohort of 1,514 patients receiving hematopoietic stem cell transplants from unrelated donors matched at HLA-A, -B, -C, -DRB1/3/4/5, and - DQB1 loci. HLA-DPB1 alloimmunity in the graft-versus-host direction, determined by high graft-versus-host ME/PS, was associated with a reduced risk of relapse (hazard ratio [HR]=0.83, P=0.05 for ME) and increased risk of grade 2-4 acute GVHD (HR=1.44, P<0.001 for ME), whereas high host-versus-graft ME/PS was only associated with an increased risk of grade 2-4 acute GVHD (HR=1.26, P=0.004 for ME). Notably, in the permissive mismatch subgroup classified by TCE grouping, high host-versus-graft ME/PS was associated with an increased risk of relapse (HR=1.36, P=0.026 for ME) and grade 2-4 acute GVHD (HR=1.43, P=0.003 for PS-II). Decision curve analysis showed that graftversus- host ME outperformed other models and provided the best clinical net benefit for the modification of acute GVHD prophylaxis regimens in patients with a high risk of developing clinically significant acute GVHD. In conclusion, molecular assessment of HLA-DPB1 mismatch enables separate prediction of host-versus-graft or graft-versus-host alloresponse quantitatively and allows further refinement of HLA-DPB1 permissiveness as defined by conventional TCE grouping.

PIONEER-Panc: a platform trial for phase II randomized investigations of new and emerging therapies for localized pancreatic cancer.

BACKGROUND: Personalized and effective treatments for pancreatic ductal adenocarcinoma (PDAC) continue to remain elusive. Novel clinical trial designs that enable continual and rapid evaluation of novel therapeutics are needed. Here, we describe a platform clinical trial to address this unmet need. METHODS: This is a phase II study using a Bayesian platform design to evaluate multiple experimental arms against a control arm in patients with PDAC. We first separate patients into three clinical stage groups of localized PDAC (resectable, borderline resectable, and locally advanced disease), and further divide each stage group based on treatment history (treatment naïve or previously treated). The clinical stage and treatment history therefore define 6 different cohorts, and each cohort has one control arm but may have one or more experimental arms running simultaneously. Within each cohort, adaptive randomization rules are applied and patients will be randomized to either an experimental arm or the control arm accordingly. The experimental arm(s) of each cohort are only compared to the applicable cohort specific control arm. Experimental arms may be added independently to one or more cohorts during the study. Multiple correlative studies for tissue, blood, and imaging are also incorporated. DISCUSSION: To date, PDAC has been treated as a single disease, despite knowledge that there is substantial heterogeneity in disease presentation and biology. It is recognized that the current approach of single arm phase II trials and traditional phase III randomized studies are not well-suited for more personalized treatment strategies in PDAC. The PIONEER Panc platform clinical trial is designed to overcome these challenges and help advance our treatment strategies for this deadly disease. TRIAL REGISTRATION: This study is approved by the Institutional Review Board (IRB) of MD Anderson Cancer Center, IRB-approved protocol 2020-0075. The PIONEER trial is registered at the US National Institutes of Health (ClinicalTrials.gov) NCT04481204 .

PD-1 inhibitors for cutaneous squamous cell carcinoma: A meta-analysis.

PD-1 inhibitors are immunotherapeutic agents used in the treatment of advanced cutaneous squamous cell carcinoma (cSCC). This study aimed to determine the pooled objective response and disease control rates of patients with advanced cSCC treated with PD-1 inhibitors. Pubmed, Cochrane Library and EMBASE databases were searched up to 1 January 2021 to include eligible articles. Objective response rate (ORR) and disease control rate (DCR) were pooled and analysed. Subgroup analysis of the odds ratio (OR) for ORR for patients by PD-L1 tumour proportion score (TPS) was performed. Seven articles including a total of 453 patients were identified and included. Pooled estimate of ORR was 44% (95% CI: 39-49%, I2 = 23.7%) and of DCR was 66% (95% CI: 57-74%, I2 = 68.2%). Pooled odds ratio of ORR for patients by PD-L1 TPS was 2.81 (95% CI: 1.22-6.51, I2 = 0.0%). These results were derived from single-arm studies, some of which were retrospective. No head-to-head trials comparing PD-1 inhibitors have been reported. We present aggregate estimates of ORR and DCR for patients with advanced cSCC treated with PD-1 inhibitors, as well as subgroup analysis for ORR for patients by PD-L1 TPS.

Ultra-High-Sensitivity, Miniaturized Fabry-Perot Interferometric Fiber-Optic Microphone for Weak Acoustic Signals Detection.

An ultra-high-sensitivity, miniaturized Fabry-Perot interferometric (FPI) fiber-optic microphone (FOM) has been developed, utilizing a silicon cantilever as an acoustic transducer. The volumes of the cavity and the FOM are determined to be 60 microliters and 102 cubic millimeters, respectively. The FOM has acoustic pressure sensitivities of 1506 nm/Pa at 2500 Hz and 26,773 nm/Pa at 3233 Hz. The minimum detectable pressure (MDP) and signal-to-noise ratio (SNR) of the designed FOM are 0.93 µPa/Hz1/2 and 70.14 dB, respectively, at an acoustic pressure of 0.003 Pa. The designed FOM has the characteristics of ultra-high sensitivity, low MDP, and small size, which makes it suitable for the detection of weak acoustic signals, especially in the field of miniaturized all-optical photoacoustic spectroscopy.

A Bayesian hierarchical monitoring design for phase II cancer clinical trials: Incorporating information on response duration into monitoring rules.

We propose a Bayesian hierarchical monitoring design for single-arm phase II clinical trials of cancer treatments that incorporates the information on the duration of response (DOR) into the monitoring rules. To screen a new treatment by evaluating its preliminary therapeutic effect, futility monitoring rules are commonly used in phase II clinical trials to make "go/no-go" decisions timely and efficiently. These futility monitoring rules are usually focused on a single outcome (eg, response rate), although a single outcome may not adequately determine the efficacy of the experimental treatment. For example, targeted agents with a long response duration but a similar response rate may be worth further evaluation in cancer research. To address this issue, we propose Bayesian hierarchical futility monitoring rules to consider both the response rate and duration. The first level of monitoring evaluates whether the response rate provides evidence that the experimental treatment is worthy of further evaluation. If the evidence from the response rate does not support continuing the trial, the second level monitoring rule, which is based on the DOR, will be triggered. If both stopping rules are satisfied, the trial will be stopped for futility. We conducted simulation studies to evaluate the operating characteristics of the proposed monitoring rules and compared them to those of standard method. We illustrated the proposed design with a single-arm phase II cancer clinical trial to assess the safety and efficacy of combined treatment of nivolumab and azacitidine in patients with relapsed/refractory acute myeloid leukemia. The proposed design avoids an aggressive early termination for futility when the experimental treatment substantially prolongs the DOR but fails to improve the response rate.

Simplified molecular classification of lung adenocarcinomas based on EGFR, KRAS, and TP53 mutations.

BACKGROUND: Gene expression profiling has consistently identified three molecular subtypes of lung adenocarcinoma that have prognostic implications. To facilitate stratification of patients with this disease into similar molecular subtypes, we developed and validated a simple, mutually exclusive classification. METHODS: Mutational status of EGFR, KRAS, and TP53 was used to define seven mutually exclusive molecular subtypes. A development cohort of 283 cytology specimens of lung adenocarcinoma was used to evaluate the associations between the proposed classification and clinicopathologic variables including demographic characteristics, smoking history, fluorescence in situ hybridization and molecular results. For validation and prognostic assessment, 63 of the 283 cytology specimens with available survival data were combined with a separate cohort of 428 surgical pathology specimens of lung adenocarcinoma. RESULTS: The proposed classification yielded significant associations between these molecular subtypes and clinical and prognostic features. We found better overall survival in patients who underwent surgery and had tumors enriched for EGFR mutations. Worse overall survival was associated with older age, stage IV disease, and tumors with co-mutations in KRAS and TP53. Interestingly, neither chemotherapy nor radiation therapy showed benefit to overall survival. CONCLUSIONS: The mutational status of EGFR, KRAS, and TP53 can be used to easily classify lung adenocarcinoma patients into seven subtypes that show a relationship with prognosis, especially in patients who underwent surgery, and these subtypes are similar to classifications based on more complex genomic methods reported previously.

Incidence, patterns of progression, and outcomes of preexisting and newly discovered brain metastases during treatment with anti-PD-1 in patients with metastatic melanoma.

BACKGROUND: Melanoma brain metastases (MBM) occur in up to 50% of patients with metastatic melanoma (MM) and represent a frequent site of systemic treatment failure for targeted therapies. However, to the authors' knowledge, little is known regarding the incidence, patterns of disease progression, and outcomes of MBM in patients treated with anti-PD-1 immunotherapy. METHODS: A total of 320 patients with MM who were treated with anti-PD-1 at The University of Texas MD Anderson Cancer Center in Houston were reviewed. Analyses were performed to identify factors associated with brain metastasis-free survival and overall survival (OS) using Cox regression models. RESULTS: The median age of the patients was 63.3 years. OS from the initiation of anti-PD-1 therapy was not significantly different between patients without MBM prior to anti-PD-1 compared with patients with prior MBM (P = .359). Among patients without prior MBM, 21 patients (8.6%) developed MBM during anti-PD-1 therapy, 12 of whom (4.9%) presented with disease progression in the central nervous system (CNS) only. Developing MBM during or after therapy with anti-PD-1 (hazard ratio, 4.70; 95% CI, 3.18-6.93) was associated with shorter OS. Among patients with MBM prior to anti-PD-1 treatment, 15 (20.0%) progressed in the CNS only and 19 (25.3%) progressed both intracranially and extracranially; at the time of the last data cutoff, 27 patients (36.0%) had not developed disease progression. Radiation necrosis occurred in 11.3% of patients (7 of 62 patients) in the group with a prior MBM who received stereotactic radiosurgery. CONCLUSIONS: Anti-PD-1 therapy may change the natural history of patients with preexisting MBM. However, CNS failure during treatment with anti-PD-1 is predictive of a worse prognosis compared with extracranial progression. The results of the current study support the activity of anti-PD-1 in patients with MBM, although routine CNS imaging during therapy is warranted.

Feasibility of fine-needle aspiration for assessing responses to chemotherapy in metastatic nodes marked with clips in breast cancer: A prospective registry study.

BACKGROUND: Clips are often placed to mark axillary nodes with biopsy-confirmed metastases in patients with breast cancer. The evaluation of clipped nodes after chemotherapy can identify patients who have eradication of nodal disease. The goal of this study was to determine whether preoperative fine-needle aspiration (FNA) of clipped nodes after neoadjuvant chemotherapy (NAC) could predict the presence of residual disease. METHODS: This prospective registry study enrolled 50 patients with a clip placed to mark nodes with biopsy-confirmed metastases who had completed NAC. Participants underwent FNA of the clipped node before seed-localized lymph node excision. FNA pathology was compared with surgical pathology. RESULTS: There were 36 patients (72%) with residual disease on surgical pathology: 3 (8%) had a nondiagnostic aspirate, carcinoma was seen in 14 (39%), and 19 (53%) had a false-negative result. The sensitivity of FNA was 42.4%, its specificity was 100%, and its negative predictive value was 40.6%. In a univariate analysis, the odds of a true-positive result increased significantly with the mean initial size of the clipped node (odds ratio [OR], 4.3; P = .004) and the size of the metastatic focus after NAC (OR, 1.3; P = 0.003), whereas normalization of nodes after chemotherapy (OR, 0.1) and a lack of response on ultrasound (OR, 0.11) were associated with a false-negative result (P = .01). CONCLUSIONS: FNA of marked nodes after chemotherapy has a high false-negative rate. This highlights the need for surgical staging of the axilla after NAC to assess the response.

PD-L1 detection in histology specimens and matched pleural fluid cell blocks of patients with NSCLC.

BACKGROUND AND OBJECTIVE: Analysis of programmed death ligand-1 (PD-L1) in tumour samples is necessary to identify candidates for anti-PD-L1/PD-L1 therapy. Because PD-L1 is evaluated by immunohistochemistry (IHC), an adequate amount of tumour tissue is a prerequisite for PD-L1 testing. To examine whether pleural fluid might be an alternative to biopsy/resection specimens for IHC evaluation of PD-L1 in patients with non-small cell lung carcinoma (NSCLC), we compared PD-L1 by IHC between histological specimens and matched pleural fluid. METHODS: A retrospective cohort study of patients with NSCLC who underwent core biopsy of a lung mass/surgical resection with PD-L1 IHC and had a pleural fluid cell block (CB) available for PD-L1 staining was conducted. PD-L1 was categorized as negative (PD-L1 in <1% of tumour cells), moderately positive (PD-L1 in ≥1% to <50%), strongly positive (PD-L1 ≥ 50) or inadequate for PD-L1 testing (<100 tumour cells in the CB). Weighted Cohen's kappa was calculated to evaluate the agreement between PD-L1 on biopsy/resection specimen and pleural fluid for variables with more than two categories. RESULTS: Of the 115 patients included in this study, 82 (71.3%) had at least 100 tumour cells and were included in the analysis. Of these, 80 (97.6%) had adenocarcinoma. For PD-L1 of histological specimens versus pleural fluid categorized as negative, moderately positive or strongly positive, the weighted kappa statistic was 0.76 (95% CI: 0.64-0.88), and the concordance was 0.78 (95% CI: 0.68-0.86). CONCLUSION: Correlation and concordance are high between PD-L1 in histological specimens and matched pleural fluid. Evaluation of PD-L1 in pleural fluid should be considered in patients unable to undergo histological biopsies.

Bayesian personalized treatment selection strategies that integrate predictive with prognostic determinants.

The evolution of "informatics" technologies has the potential to generate massive databases, but the extent to which personalized medicine may be effectuated depends on the extent to which these rich databases may be utilized to advance understanding of the disease molecular profiles and ultimately integrated for treatment selection, necessitating robust methodology for dimension reduction. Yet, statistical methods proposed to address challenges arising with the high-dimensionality of omics-type data predominately rely on linear models and emphasize associations deriving from prognostic biomarkers. Existing methods are often limited for discovering predictive biomarkers that interact with treatment and fail to elucidate the predictive power of their resultant selection rules. In this article, we present a Bayesian predictive method for personalized treatment selection that is devised to integrate both the treatment predictive and disease prognostic characteristics of a particular patient's disease. The method appropriately characterizes the structural constraints inherent to prognostic and predictive biomarkers, and hence properly utilizes these complementary sources of information for treatment selection. The methodology is illustrated through a case study of lower grade glioma. Theoretical considerations are explored to demonstrate the manner in which treatment selection is impacted by prognostic features. Additionally, simulations based on an actual leukemia study are provided to ascertain the method's performance with respect to selection rules derived from competing methods.

Phase II Trial of High-Dose Gemcitabine/Busulfan/Melphalan with Autologous Stem Cell Transplantation for Primary Refractory or Poor-Risk Relapsed Hodgkin Lymphoma.

We conducted a prospective phase 2 trial of gemcitabine, busulfan and melphalan (Gem/Bu/Mel) with autologous stem cell transplantation (ASCT) in patients with primary refractory or poor-risk relapsed Hodgkin lymphoma (HL) (ie, extranodal relapse or within 1 year of frontline therapy). The trial was powered to detect an improvement in 2-year progression-free survival (PFS) from a historical 50% using a BEAM regimen (carmustine/etoposide/cytarabine/melphalan) to 65%. We compared the study population with all other concurrent patients who were eligible for the trial but instead received the BEAM regimen at our center. No patient received post-ASCT maintenance therapy. The Gem/Bu/Mel trial enrolled 80 patients with a median age of 31 years, 41% with primary refractory HL and 59% with relapsed HL (36% extranodal relapses), and 30% with positron emission tomography (PET)-positive lesions at ASCT. The concurrent BEAM (n = 45) and Gem/Bu/Mel cohorts were well balanced except for higher rates of bulky relapse and PET-positive tumors in the Gem/Bu/Mel cohort. There were no transplantation-related deaths in either cohort. At a median follow-up of 34.5 months (range, 26 to 72 months), Gem/Bu/Mel was associated with better 2-year PFS (65% versus 51%; P = .008) and overall survival (89% versus 73%; P = .0003). In conclusion, our data show that Gem/Bu/Mel is safe, in this nonrandomized comparison yielding improved outcomes compared with a concurrently treated and prognostically matched cohort of patients with primary refractory or poor-risk relapsed HL receiving BEAM.

Adjuvant versus neoadjuvant chemotherapy in triple-negative breast cancer patients with BRCA mutations.

PURPOSE: As triple-negative breast cancers are associated with earlier recurrences and poorer survival, optimal treatment of early-stage breast cancer is essential. Several retrospective studies in triple-negative breast cancer have reported conflicting results in overall survival in patients receiving neoadjuvant or adjuvant systemic therapy. This study aims to analyze outcomes of adjuvant versus neoadjuvant in patients with early-stage triple-negative breast cancer with and without BRCA germline mutations. METHODS: Patients with stage I or II triple-negative breast cancer who had BRCA testing were identified from a prospective cohort study of 4027 patients. Clinical, demographic, genetic test results, chemotherapy, recurrence, and survival data were analyzed. Overall survival and disease-free survival were estimated using the Kaplan-Meier method. RESULTS: 319 patients with stage I and II triple-negative breast cancer who met eligibility criteria were included in the analysis. 187 received adjuvant chemotherapy (58.6%) and 132 received neoadjuvant chemotherapy (41.4%). 135 were BRCA positive (42.3%) and 184 were BRCA negative (57.7%). There was no significant association between overall survival or disease-free survival and treatment with neoadjuvant versus adjuvant in the overall cohort. Furthermore, there were no significant differences between patient subgroups (neoadjuvant BRCA positive, neoadjuvant BRCA negative, adjuvant BRCA positive, and adjuvant BRCA negative) with respect to either overall survival or disease-free survival. CONCLUSIONS: Neoadjuvant versus adjuvant with standard anthracycline- and taxane-containing regimens results in similar disease-free survival and overall survival among patients with stage I and II triple-negative breast cancer regardless of BRCA status. Further studies are needed to evaluate whether similar results are observed with newer agents.

Detection of a MicroRNA molecular signature of ultraviolet radiation in the superficial regions of melanocytic nevi on sun-exposed skin.

How melanocytes transform into melanoma cells remains largely unknown. However, prolonged ultraviolet radiation exposure is linked with melanoma, and the DNA of melanomas arising in chronically sun-exposed skin is characterized by an elevated number of pyrimidine transitions, mainly C>T (predominantly caused by ultraviolet B), and transversions of GC>TA or AT>CG (caused by ultraviolet A over indirect mechanisms). Since ultraviolet penetrates mostly only the superficial dermis, we sought to determine the extent to which superficial and deep melanocytes of nevi in sun-exposed skin differ in their miRNA expression and consider the changes as likely secondary to ultraviolet radiation-induced damage. The differentially expressed miRNAs were analyzed for known potential oncomiRs or linked to potential oncogenes or tumor suppressors. Superficial and deep melanocytes were microdissected from the nevi of 14 patients. The suspensions were processed for hybridization to a ribonucleotide protection system with 2280 total probes, including 2256 miRNA probes targeting 2083 human miRNAs. A comprehensive analysis of all human miRNAs registered in miRBase 11.0 was performed using the HTG Molecular Diagnostic database. Statistical analysis of these data yielded for 14 samples a statistically relevant profile of 39 miRNA species at FDR<0.1 that were differentially expressed between superficial and deep melanocytes. Ingenuity Pathway Analysis based on the expression data of these 39 miRNAs suggested the gene transcripts AR, MDM2, SMAD2/3, and YBX1 as the most probable miRNA targets, which were validated at the protein level. Our findings suggest that superficial ultraviolet radiation-damaged melanocytes can be differentiated from deep melanocytes on the basis of the expression of 39 miRNAs, the most probable gene transcript and protein targets of which are AR, MDM2, SMAD2/3, and YBX1, with YBX1 expression validating the best the molecular signature in immunohistochemical analysis.

Characteristics and clinical significance of cytogenetic abnormalities in polycythemia vera.

Up to 20% of patients with polycythemia vera have karyotypic abnormalities at the time of the initial diagnosis. However, the cytogenetic abnormalities in polycythemia vera have not been well characterized and their prognostic impact is largely unknown. In this study, we aimed to address these issues using a large cohort of polycythemia vera patients with cytogenetic information available. The study included 422 patients, 271 in polycythemic phase, 112 with post-polycythemic myelofibrosis, 11 in accelerated phase, and 28 in blast phase. Abnormal karyotypes were detected in 139 (33%) patients, ranging from 20% in those in the polycythemic phase to 90% among patients in accelerated/blast phase. Different phases harbored different abnormalities: isolated del(20q), +8 and +9 were the most common abnormalities in the polycythemic phase; del(20q) and +1q were the most common abnormalities in post-polycythemic myelofibrosis; and complex karyotypes were the most common karyotypes in accelerated and blast phases. Patients with an abnormal karyotype showed a higher frequency of disease progression, a shorter transformation-free survival and an inferior overall survival compared with patients with a normal karyotype in the same disease phase. Cytogenetics could be effectively stratified into three risk groups, low- (normal karyotype, sole +8, +9 and other single abnormality), intermediate- (sole del20q, +1q and other two abnormalities), and high-risk (complex karyotype) groups. We conclude that cytogenetic changes in polycythemia vera vary in different phases of disease, and carry different prognostic impacts.

Bayesian predictive modeling for genomic based personalized treatment selection.

Efforts to personalize medicine in oncology have been limited by reductive characterizations of the intrinsically complex underlying biological phenomena. Future advances in personalized medicine will rely on molecular signatures that derive from synthesis of multifarious interdependent molecular quantities requiring robust quantitative methods. However, highly parameterized statistical models when applied in these settings often require a prohibitively large database and are sensitive to proper characterizations of the treatment-by-covariate interactions, which in practice are difficult to specify and may be limited by generalized linear models. In this article, we present a Bayesian predictive framework that enables the integration of a high-dimensional set of genomic features with clinical responses and treatment histories of historical patients, providing a probabilistic basis for using the clinical and molecular information to personalize therapy for future patients. Our work represents one of the first attempts to define personalized treatment assignment rules based on large-scale genomic data. We use actual gene expression data acquired from The Cancer Genome Atlas in the settings of leukemia and glioma to explore the statistical properties of our proposed Bayesian approach for personalizing treatment selection. The method is shown to yield considerable improvements in predictive accuracy when compared to penalized regression approaches.

Analysis of transtheoretical model of health behavioral changes in a nutrition intervention study--a continuous time Markov chain model with Bayesian approach.

Continuous time Markov chain (CTMC) models are often used to study the progression of chronic diseases in medical research but rarely applied to studies of the process of behavioral change. In studies of interventions to modify behaviors, a widely used psychosocial model is based on the transtheoretical model that often has more than three states (representing stages of change) and conceptually permits all possible instantaneous transitions. Very little attention is given to the study of the relationships between a CTMC model and associated covariates under the framework of transtheoretical model. We developed a Bayesian approach to evaluate the covariate effects on a CTMC model through a log-linear regression link. A simulation study of this approach showed that model parameters were accurately and precisely estimated. We analyzed an existing data set on stages of change in dietary intake from the Next Step Trial using the proposed method and the generalized multinomial logit model. We found that the generalized multinomial logit model was not suitable for these data because it ignores the unbalanced data structure and temporal correlation between successive measurements. Our analysis not only confirms that the nutrition intervention was effective but also provides information on how the intervention affected the transitions among the stages of change. We found that, compared with the control group, subjects in the intervention group, on average, spent substantively less time in the precontemplation stage and were more/less likely to move from an unhealthy/healthy state to a healthy/unhealthy state.