Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study.

BACKGROUND: Clonal haemopoiesis of indeterminate potential (CHIP) is an age-associated genetic event linked to increased risk of primary haematological malignancies and increased all-cause mortality, but the prevalence of CHIP in patients who develop therapy-related myeloid neoplasms is unknown. We did this study to investigate whether chemotherapy-treated patients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms. METHODS: We did a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not develop these neoplasms (controls). We identified cases from our internal biorepository of 123 357 patients who consented to participate in the Total Cancer Care biobanking protocol at Moffitt Cancer Center (Tampa, FL, USA) between Jan 1, 2006, and June 1, 2016. We included all individuals who were diagnosed with a primary malignancy, were treated with chemotherapy, subsequently developed a therapy-related myeloid neoplasm, and were 70 years or older at either diagnosis. For inclusion in this study, individuals must have had a peripheral blood or mononuclear cell sample collected before the diagnosis of therapy-related myeloid neoplasm. Controls were individuals who were diagnosed with a primary malignancy at age 70 years or older and were treated with chemotherapy but did not develop therapy-related myeloid neoplasms. Controls were matched to cases in at least a 4:1 ratio on the basis of sex, primary tumour type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow-up. We used sequential targeted and whole-exome sequencing and described clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available. The primary endpoint of this study was the development of therapy-related myeloid neoplasm and the primary exposure was CHIP. FINDINGS: We identified 13 cases and 56 case-matched controls. The prevalence of CHIP in all patients (23 [33%] of 69 patients) was higher than has previously been reported in elderly individuals without cancer (about 10%). Cases had a significantly higher prevalence of CHIP than did matched controls (eight [62%] of 13 cases vs 15 [27%] of 56 controls, p=0·024; odds ratio 5·75, 95% CI 1·52-25·09, p=0·013). The most commonly mutated genes in cases with CHIP were TET2 (three [38%] of eight patients) and TP53(three [38%] of eight patients), whereas controls most often had TET2 mutations (six [40%] of 15 patients). In most (four [67%] of six patients) cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available, the mean allele frequency of CHIP mutations had expanded by the time of the therapy-related myeloid neoplasm diagnosis. However, a subset of paired samples (two [33%] of six patients) had CHIP mutations that decreased in allele frequency, giving way to expansion of a distinct mutant clone. INTERPRETATION: Patients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms. The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk. FUNDING: Moffitt Cancer Center.

Evaluation of invasive breast cancer samples using a 12-chemokine gene expression score: correlation with clinical outcomes.

BACKGROUND: A unique 12-chemokine gene expression score (CS) accurately predicted the presence of tumor-localized, ectopic lymph node-like structures (TL-ELNs) and improved overall survival (OS) in primary colorectal cancer and metastatic melanoma. We analyzed the correlation between CS, clinicopathological variables, molecular data, and 366 survival in Moffitt Cancer Center's Total Cancer Care (TCC) patients with non-metastatic breast cancer. METHODS: Affymetrix gene expression profiles were used to interrogate the CS by the principal component method. Breast tumors were classified as high or low score based on median split, and correlations between clinicopathologic variables, PAM50 molecular subtype, and ELN formation were analyzed using the TCC dataset. Differences in overall survival (OS) and recurrence-free survival (RFS) in the larger KM Plot breast cancer public datasets were compared using Kaplan-Meier curves. RESULTS: We divided the Total Cancer Care (TCC) breast cancer patients into two groups of high or low CS. Mean CS was 0.24 (range, 2.2-2.1). Patients with higher CS were more likely to be white (172 vs. 159; p = 0.03), had poorly differentiated tumors (112 vs. 59; p <0.0001), ER/PR negative (41 vs. 26) and HER2 positive (36 vs. 19; p = 0.001), and contain TL-ELNs. Higher CS scores were also seen in the basal and HER2+ molecular subtypes. In the KM Plot breast cancer datasets higher CS patients demonstrated superior OS (HR = 0.73, p = 0.008) and RFS (HR 0.76, p = <0.0001), especially in basal and HER2+ patients. CONCLUSIONS: High CS breast tumors tend to be higher grade, basal or HER2+, and present more frequently in Caucasians. However, this group of patients also shows the presence of TL-ELNs within the tumor microenvironment and has better survival outcomes. The CS is a novel tool that can identify breast cancer patients with tumors of a unique intratumoral immune composition and better prognosis. Whether or not the CS is a predictive response marker in breast cancer patients undergoing immunotherapy remains to be determined.

Use of axillary lymph node dissection (ALND) in patients with micrometastatic breast cancer.

BACKGROUND: Sentinel lymph node (SLN) biopsy is the current prognostic tool for clinically node-negative breast cancer patients. If the SLN reveals macrometastasis, axillary lymph node dissection (ALND) is recommended. However, the use of ALND in patients with micrometastasis is debated. The objective of this study was to assess the utilization of ALND in the treatment of micrometastatic breast cancer. METHODS: An IRB approved, retrospective study of a pooled dataset of breast cancer patients with micrometastatic disease on SLN biopsy was performed. Patients diagnosed from 1999-2016 were identified via query of a single-institution National Comprehensive Cancer Network (NCCN) breast cancer database as well as a prospective tumor board. RESULTS: A total of 91 patients were diagnosed with micrometastatic nodal disease. The median age at diagnosis was 56 y (range: 31-85); median follow-up time was 47 mo (range: 0-203 mo). 42/91(46.2%) patients had ALND of which 37/42 (88.1%) were a second operation; 3/42(7.1%) patients had additional positive nodes found at ALND. 44/91 (48.4%) patients received radiation. 7/91 (7.7%) patients had a recurrence, 5/7 local, including one axillary (2.1%; patient declined ALND). CONCLUSIONS: Given that the risk of lymphedema after ALND ranges between 20%-53%, the morbidity of ALND may far exceed the likelihood of detecting further nodal involvement in women with micrometastatic disease: 7.1% in this series.

Early Postoperative Complications after Oncoplastic Reduction.

BACKGROUND: Breast-conserving surgery with adjuvant radiation therapy (BCT) has been established as safe oncologically. Oncoplastic breast surgery uses both oncologic and plastic surgery techniques for breast conservation to improve cosmetic outcomes. We evaluated the risk factors associated with complications after oncoplastic breast reduction. METHODS: A single-institution, institutional review board-approved, retrospective review of electronic medical records of female patients with breast cancer who underwent oncoplastic breast reduction from 2008 to 2014. A review of electronic medical records collected relevant medical history, clinical and pathological information, and data on postoperative complications within 6 months stratified into major or minor complications. Categorical variables analyzed with the χ2 exact method; continuous variables were analyzed with the Wilcoxon rank sum test exact method. RESULTS: We identified 59 patients; 4 required re-excision for positive margins, and 1 moved on to completion mastectomy. The overall complication rate was 33.9% (n = 20): 12 major (20.3%) and 8 minor (13.6%). Of the continuous variables (age, body mass index, and tissue removed), increased age was associated with minor complications (P = 0.02). Among the categorical variables (stratified body mass index, prior breast surgery, hypertension, diabetes mellitus, hyperlipidemia, vascular disease, pulmonary disease, and stratified weight of tissue removed), none were associated with overall or major complications. Pulmonary disease was associated with minor complications (P = 0.03). Bilateral versus unilateral oncoplastic breast reduction showed no statistically significant increase in complications. CONCLUSIONS: The overall complication rate after oncoplastic breast reduction was markedly higher than that in nationally published data for breast-conserving surgery. The complication rate resembled more closely the complication rate after bilateral mastectomy with immediate reconstruction. No risk factors were associated with major or overall complications. Age and pulmonary disease were associated with minor complications. Patients should be selected and counseled appropriately when considering oncoplastic breast reduction.

Complications and Recurrence in Implant-Sparing Oncologic Breast Surgery.

BACKGROUND: Patients with a history of prior breast augmentation and newly diagnosed breast cancer represent a rapidly expanding and unique subset of patients. Prior studies have described changes in breast parenchyma and characteristic body habitus of previously augmented patients, as well as increased rates of capsular contracture associated with breast conservation therapy. In our current study, we aimed to study the risk factors contributing to morbidity and whether recurrence rates are higher in patients with prior breast augmentation undergoing lumpectomy or mastectomy for breast cancer and identify differences in complications between these 2 groups. METHODS: Retrospective analysis approved by institutional review board was performed on patients with prior breast augmentation undergoing lumpectomy (N = 52) and mastectomy (N = 64) for breast cancer. RESULTS: Patients with prior breast augmentation undergoing mastectomy had a higher rate of complications compared with those undergoing lumpectomy (20.3% vs 5.9% respectively, P = 0.031), after adjusting for patient-specific factors including body mass index [odds ratio (OR), 0.242; 95% confidence interval (CI), 0.063-0.922; P = 0.0376], tumor stage (OR, 0.257; 95% CI, 0.064-1.036; P = 0.0562), smoking status (OR, 0.244; 95% CI, 0.065-0.918; P = 0.0370), and chemotherapy (OR, 0.242; 95% CI, 0.064-0.914; P = 0.0364). Four patients (7.7%) developed late complications in the lumpectomy group with 2 developing capsular contractures, 1 had fat necrosis and 1 needed complex reconstruction because of flattening of the nipple-areolar complex. There was no difference in recurrence or tumor margins between lumpectomy and mastectomy groups. CONCLUSIONS: Patients with prior breast augmentation undergoing mastectomy have higher complication rates compared with lumpectomy even after adjusting for tumor stage. There appears to be no increased oncologic risk associated with either procedure given our current follow-up. Understanding these operative risks may help in patients' decision-making process with regards to type of oncologic surgery.

Quality of Life after post-prostatectomy intensity modulated radiation therapy to the prostate bed with or without the use of gold fiducial markers for image guidance or higher total radiotherapy doses.

PURPOSE: To evaluate quality of life (QoL) after post-prostatectomy intensity modulated radiation therapy (IMRT) in the "adjuvant" setting starting within 4 months of radical prostatectomy for adverse features; and "salvage" setting for a PSA≥0.2ng/mL. MATERIALS AND METHODS: Retrospective review of 130 patients who underwent IMRT to the prostate bed±gold fiducial marker placement for image guidance to 64.8-72.0Gy (median, 70.2Gy) between 2004 and 2013. Higher doses were defined as 70.2-72.0Gy and lower doses were defined as 64.8-68.4Gy. Androgen deprivation therapy (ADT) was given to 4/48 (8%) adjuvant patients and 9/82 (11%) salvage patients. International Prostate Symptom Score (IPSS), Sexual Health Inventory for Men (SHIM), and Expanded Prostate Cancer Index Composite-26-bowel (EPIC-26-bowel) questionnaires were used to assess urinary, sexual, and bowel QoL, respectively. RESULTS: Median follow-up was 46 months. There were better urinary (p=0.03) and sexual (p=0.002) QoL scores with adjuvant IMRT relative to salvage IMRT. The use of prostate bed fiducial markers did not significantly affect urinary, sexual, or bowel QoL (p=0.39, p=0.49, and p=0.40, respectively). Higher total radiotherapy doses did not significantly affect urinary, sexual, or bowel QoL (p=0.21, p=0.61, and p=0.36, respectively). CONCLUSIONS: There was no significant change in urinary, sexual, and bowel sexual QoL with post-prostatectomy IMRT regardless of whether prostate bed fiducial markers or higher total radiotherapy doses were used. QoL with IMRT in the present study compares favorably with prior reports for three-dimensional conformal radiation therapy.

Synthesis of furo[3,2-c]coumarin derivatives using visible-light-promoted radical alkyne insertion with bromocoumarins.

The synthesis of privileged structures, which are potent drug candidates, is an impetus for drug discovery. The construction of heterocyclic framework furo[3,2-c]coumarins using a visible-light promoted photoredox neutral coupling of 3-bromo-4-hydroxycoumarins with commercially available alkynes has been reported. These reactions can be carried out at room temperature under visible light irradiation with good chemical yields. This work presents 17 furocoumarins, 12 of which are new. Three of the newly synthesized compounds show potent cytotoxicity, and one shows moderate acetylcholinesterase inhibitory activity with IC50 values of 2.16 ± 0.13 µM.

Multi-objective optimization of hydrogen production system based on the combined supercritical cycle and gas turbine plant.

In this paper, considering the hydrogen production cycle coupled with the supercritical CO2 cycle, hydrogen is produced as a clean fuel along with power and heat production. Also, the world's need for clean energy doubles the solutions to achieve clean hydrogen energy. The investigated cycle has a supercritical CO2 cycle with a combustion chamber where enriched fuel is introduced. Combustion products produce work in the gas turbine, and further hydrogen separation is formed with the help of water gas shift reaction and hydrogen separation membrane. In the thermodynamic analysis, combustion chamber known as the most irreversible member of set, where the most exergy is lost. The energy and exergy efficiency for whole set are 64.82%, 52.46% respectively. Produced hydrogen mass flow rate calculated 46.8 kg/h. Also, multi-objective optimization based on genetic algorithm were done and the results were reported. All calculation and optimization method has been done in MATLAB software.

Performance amelioration of single basin solar still integrated with V- type concentrator: Energy, exergy, and economic analysis.

Solar desalination is one of the most sustainable solutions to produce freshwater from brackish water. The present research work aims to experimentally investigate the effect of a V-shape concentrator integrated with solar still (SS). The V-shape concentrator integrated with the conventional solar still (CSS) is used to supply the saline water at elevated temperature to the basin of SS, which augments the freshwater yield compared to CSS. The experimental investigation was performed at different brackish water depths of 0.01, 0.02, and 0.03 m, respectively. The SS system was evaluated based on water yield, energy, exergy, concentrator efficiency, and economic analysis. The freshwater yield of the solar still integrated with V-shape concentrator (SSVC) was found to be 5.47, 5.10, and 4.89 L/m2.day, whereas the yield of the CSS was 3.73, 3.27, and 2.91 L/m2 .day at the water depths of 0.01, 0.02, and 0.03 m, respectively. The daily energy and exergy efficiency of CSS were 38.5, 33.5, and 29.4% and 1.9, 1.5, and 0.97 % in the case of 0.01, 0.02, and 0.03m water depth , respectively. However, the integration of concentrator significantly augmented the energy efficiency to 57.4, 51.7, and 44.9% and exergy efficiency to 3.8, 3.3, and 2.8% for the respective water depths . Life cycle studies demonstrated that the freshwater cost per liter for CSS and SSVC were 0.0102 $ and 0.0117 $ respectively, at a water depth of 0.01 m. It was concluded that the addition of V-shape concentrator and minimum water depth is useful to augment the energy efficiency, exergy efficiency, and yield of the SS in the very economical way.

A case study of SARS-CoV-2 transmission behavior in a severely air-polluted city (Delhi, India) and the potential usage of graphene based materials for filtering air-pollutants and controlling/monitoring the COVID-19 pandemic.

Globally, humanity is facing its most significant challenge in 100 years due to the novel coronavirus, SARS-CoV-2, which is responsible for COVID-19. Under the enormous pressure created by the pandemic, scientists are studying virus transmission mechanisms in order to develop effective mitigation strategies. However, no established methods have been developed to control the spread of this deadly virus. In addition, the ease in lockdown has escalated air pollution which may affect SARS-CoV-2 transmission through attachment to particulates. The present review summarizes the role of graphene nanomaterials, which show antimicrobial behavior and have antiviral efficacy, in reducing the spread of COVID-19. Graphene and its derivatives have excellent antimicrobial efficacy, providing both physical and chemical mechanisms of damage. Coupled with their lightness, optimal properties, and ease of functionalization, they are optimal nanomaterials for coating onto fabrics such as personal protection equipment, face masks and gloves to control the transmission of SARS-CoV-2 effectively. Biosensors using graphene can effectively detect the virus with high accuracy and sensitivity, providing rapid quantification. It is envisioned that the present work will boost the development of graphene-based highly sensitive, accurate and cost-effective diagnostic tools for efficiently monitoring and controlling the spread of COVID-19 and other air-borne viruses.

The Efficacy and Safety of Rivaroxaban and Dalteparin in the Treatment of Cancer Associated Venous Thrombosis.

Venous thromboembolism (VTE) is a complication of malignancy that is associated with significant mortality. The CLOT trial showed superiority of dalteparin in comparison to warfarin in preventing VTE recurrence. Rivaroxaban has been approved for treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE). In the absence of large randomized trials in the oncology population, the efficacy and safety of rivaroxaban for the treatment of VTE in cancer patients needs to be assessed. A single-center retrospective chart review was conducted to assess the efficacy and safety of rivaroxaban compared with dalteparin in cancer-associated thrombosis. Out of 671 patients identified, 286 patients (107 in the rivaroxaban group and 179 in the dalteparin group) were eligible for analysis. The rivaroxaban group had a rate of VTE recurrence at 6 months of 4.9 versus 11.1% with dalteparin (p = 0.252). The incidence of recurrent DVT at 6 months was lower in patients treated with rivaroxaban (0%) compared with dalteparin (8.2%) at 6 months (p = 0.025). Incidence of recurrent PE in the rivaroxaban group (5%) versus dalteparin group (3.1%) at 6 months was not statistically significant (p = 0.675). No significant difference was identified between the rivaroxaban group and dalteparin group in the rate of major bleeding (2.8 vs. 1.1%, respectively). Rivaroxaban was comparable to dalteparin in prevention of VTE recurrence while having no significant differences with major or minor bleeding.

A modified Edmonton Symptom Assessment Scale for symptom clusters in radiation oncology patients.

Patient-reported outcomes regarding symptom burden may provide valuable information in addition to physician assessment. Systematic collection of patient-reported outcomes may be an important metric to identify unmet needs and improve quality of patient care. To understand common symptoms of patients seen in radiation oncology clinic, we examined the prospectively collected modified Edmonton Symptom Assessment Scale (ESAS-r) data to explore symptom clusters. Our clinic established use of a modified Edmonton Symptom Assessment Scale in August 2015. All outpatients presenting for radiation oncology services completed the form at each clinic visit. Symptom clusters are defined by two or more symptoms that are interrelated and occur simultaneously with a high degree of predictability. A sample of 916 de-identified surveys was assessed statistically using principal component analysis (PCA) with varimax rotation to determine independent clustering between the symptoms queried. We found four major clusters of symptoms: Tiredness (tired, drowsiness; PC1), Loss of Appetite (nausea, lack of appetite; PC2), Low Well-Being (overall & spiritual well-being; PC3), and Depression (depression, anxiety; PC4). These accounted for 46%, 9.2%, 7.6%, and 7% of total variance, respectively. Internal consistency using Cronbach's alpha was 0.87, 0.7, 0.82, and 0.87, respectively. The most frequent write-in item was itchiness, present in 24% of the 148 patients responding. Assessment of patients seen in a large radiation oncology clinic revealed several symptom clusters. {Tiredness and drowsiness} represents a major symptom cluster. Itchiness may be underrecognized.

Comparison of the Mutational Profiles of Primary Myelofibrosis, Polycythemia Vera, and Essential Thrombocytosis.

OBJECTIVES: To compare the mutational profiles of patients with primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET). METHODS: Next-generation sequencing results of 75 cases of PMF, 33 cases of PV, and 27 cases of ET were compared. RESULTS: Mutation rates of ASXL1 and SRSF2 were significantly higher in PMF than in PV or ET. ASXL1 mutations appeared to be more frequently associated with risk of transformation to acute myeloid leukemia than JAK2 or TET2 mutations. The most common mutation-cytogenetic combinations in myeloproliferative neoplasm (MPN) were mutations of JAK2 or ASXL1 with del(20q) and were more common in patients with PMF and PV than in patients with ET. Differences were also found between patients with PMF and PV. CONCLUSIONS: PMF, PV, and ET show different mutational profiles, which may be helpful in resolving the differential diagnosis between MPNs. Due to the relatively small number of cases and variable testing over time, larger controlled studies are necessary to confirm the findings.

Evaluation of ThyroSeq v2 performance in thyroid nodules with indeterminate cytology.

ThyroSeq v2 claims high positive (PPV) and negative (NPV) predictive values in a wide range of pretest risks of malignancy in indeterminate thyroid nodules (ITNs) (categories B-III and B-IV of the Bethesda system). We evaluated ThyroSeq v2 performance in a cohort of patients with ITNs seen at our Academic Cancer Center from September 2014 to April 2016, in light of the new diagnostic criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Our study included 182 patients (76% female) with 190 ITNs consecutively tested with ThyroSeq v2. Patient treatment followed our institutional thyroid nodule clinical pathway. Histologies of nodules with follicular variant papillary thyroid carcinoma or NIFTP diagnoses were reviewed, with reviewers blinded to molecular results. ThyroSeq v2 performance was calculated in nodules with histological confirmation. We identified a mutation in 24% (n = 45) of the nodules. Mutations in RAS were the most prevalent (n = 21), but the positive predictive value of this mutation was much lower (31%) than that in prior reports. In 102 resected ITNs, ThyroSeq v2 performance was as follows: sensitivity 70% (46-88), specificity 77% (66-85), PPV 42% (25-61) and NPV 91% (82-97). The performance in B-IV nodules was significantly better than that in B-III nodules (area under the curve 0.84 vs 0.57, respectively; P = 0.03), where it was uninformative. Further studies evaluating ThyroSeq v2 performance are needed, particularly in B-III.

Adjuvant pelvic radiation is associated with improved survival and decreased disease recurrence in pelvic node-positive penile cancer after lymph node dissection: A multi-institutional study.

PURPOSE: Few studies have examined the role of radiation therapy in advanced penile squamous cell carcinoma. We sought to evaluate the association of adjuvant pelvic radiation with survival and recurrence for patients with penile cancer and positive pelvic lymph nodes (PLNs) after lymph node dissection. MATERIALS AND METHODS: Data were collected retrospectively across 4 international centers of patients with penile squamous cell carcinoma undergoing lymph node dissections from 1980 to 2013. Further, 92 patients with available adjuvant pelvic radiation status and positive PLNs were analyzed. Disease-specific survival (DSS) and recurrence were analyzed using the Kaplan-Meier method and multivariable Cox proportional hazards model. RESULTS: 43% (n = 40) of patients received adjuvant pelvic radiation after a positive PLN dissection. Median follow-up was 9.3 months (interquartile range: 5.2-19.8). Patients receiving adjuvant pelvic radiation had a median DSS of 14.4 months vs. 8 months in the nonradiation group, respectively (P = 0.023). Patients without adjuvant pelvic radiation were associated with worse overall survival (hazard ratio [HR] = 1.7; 95% CI: 1.01-2.92; P = 0.04) and DSS (HR = 1.9; 95% CI: 1.09-3.36; P = 0.02) on multivariable analysis. Median time to recurrence was 7.7 months vs. 5.3 months in the radiation and nonradiation arm, respectively (P = 0.042). Patients without adjuvant pelvic radiation was also independently associated with higher overall recurrence on multivariable analysis (HR = 1.8; 95% CI: 1.06-3.12; P = 0.03). CONCLUSIONS: Adjuvant pelvic radiation is associated with improved survival and decreased recurrence in this population of patients with penile cancer with positive PLNs.

Point success rate for patient therapeutic response prediction by continuous biomarker scores.

Various predictive diagnostic tests are highly demanded to guide optimal treatments for individual patients, as individual patients with the same disease such as cancer frequently exhibit dramatically different therapeutic responses to multiple available treatment options. A large number of clinical trials have thus been performed to test the predictive ability and utility of various therapeutic biomarker tests. However, in these trial designs the conventional optimization criteria such as positive predictive value or negative predictive value cannot reflect each patient's true chance of success associated with continuous predictive biomarker scores. We have developed a novel statistical concept, point success rate (PSR), to overcome deficiencies in these conventional methods for optimizing biomarker-based clinical trials. We demonstrate statistical superiority as well as clinical improvement by a PSR-based treatment selection both with simulated and breast cancer patient data.

New American Thyroid Association Sonographic Patterns for Thyroid Nodules Perform Well in Medullary Thyroid Carcinoma: Institutional Experience, Systematic Review, and Meta-Analysis.

BACKGROUND: The 2015 American Thyroid Association (ATA) thyroid nodule guidelines recommend selecting nodules for biopsy based on a sonographic pattern classification. These patterns were developed based on features of differentiated thyroid cancer. This study aimed to evaluate the performance and the inter-observer agreement of this classification system in medullary thyroid carcinoma (MTC). METHODS: The medical records of all patients with MTC evaluated at the authors' institution between 1998 and 2014 were retrospectively reviewed. Only patients with presurgical thyroid ultrasound available for review were included in the study. Five independent reviewers assessed the stored ultrasound images for composition, echogenicity, margins, presence of calcifications, and extrathyroidal extension for each nodule. The presence of suspicious lymph nodes was also evaluated when presurgical lateral neck ultrasound was available for review. Each nodule was classified according to the ATA sonographic patterns. Inter-observer agreement was calculated for each sonographic feature and for the sonographic patterns. To validate the findings, a systematic review of the literature and meta-analysis on the sonographic features of MTC was conducted. RESULTS: In this institutional cohort, the inter-observer agreement for individual sonographic features was moderate to good (κ = 0.45-0.71), and for the ATA classification it was good (κ = 0.72). Ninety-seven percent (29/30) of the MTCs were classified in the intermediate or high suspicion patterns. A total of 249 MTCs were included in the meta-analysis. Based on pooled frequencies for solid composition and hypoechogenicity, >95% of MTCs would be classified at least in the intermediate suspicion pattern, warranting the lowest-size threshold for biopsy (≥1 cm). CONCLUSIONS: The sonographic patterns proposed by the ATA perform well in MTC, and inter-observer agreement is good to very good.

Balancing continuous covariates based on Kernel densities.

The balance of important baseline covariates is essential for convincing treatment comparisons. Stratified permuted block design and minimization are the two most commonly used balancing strategies, both of which require the covariates to be discrete. Continuous covariates are typically discretized in order to be included in the randomization scheme. But breakdown of continuous covariates into subcategories often changes the nature of the covariates and makes distributional balance unattainable. In this article, we propose to balance continuous covariates based on Kernel density estimations, which keeps the continuity of the covariates. Simulation studies show that the proposed Kernel-Minimization can achieve distributional balance of both continuous and categorical covariates, while also keeping the group size well balanced. It is also shown that the Kernel-Minimization is less predictable than stratified permuted block design and minimization. Finally, we apply the proposed method to redesign the NINDS trial, which has been a source of controversy due to imbalance of continuous baseline covariates. Simulation shows that imbalances such as those observed in the NINDS trial can be generally avoided through the implementation of the new method.

Quality of Life after post-prostatectomy intensity modulated radiation therapy to the prostate bed with or without the use of gold fiducial markers for image guidance or higher total radiotherapy doses

ABSTRACT Purpose To evaluate quality of life (QoL) after post-prostatectomy intensity modulated radiation therapy (IMRT) in the "adjuvant" setting starting within 4 months of radical prostatectomy for adverse features; and "salvage" setting for a PSA≥0.2ng/mL. Materials and Methods Retrospective review of 130 patients who underwent IMRT to the prostate bed±gold fiducial marker placement for image guidance to 64.8-72.0Gy (median, 70.2Gy) between 2004 and 2013. Higher doses were defined as 70.2-72.0Gy and lower doses were defined as 64.8-68.4Gy. Androgen deprivation therapy (ADT) was given to 4/48 (8%) adjuvant patients and 9/82 (11%) salvage patients. International Prostate Symptom Score (IPSS), Sexual Health Inventory for Men (SHIM), and Expanded Prostate Cancer Index Composite-26-bowel (EPIC-26-bowel) questionnaires were used to assess urinary, sexual, and bowel QoL, respectively. Results Median follow-up was 46 months. There were better urinary (p=0.03) and sexual (p=0.002) QoL scores with adjuvant IMRT relative to salvage IMRT. The use of prostate bed fiducial markers did not significantly affect urinary, sexual, or bowel QoL (p=0.39, p=0.49, and p=0.40, respectively). Higher total radiotherapy doses did not significantly affect urinary, sexual, or bowel QoL (p=0.21, p=0.61, and p=0.36, respectively). Conclusions There was no significant change in urinary, sexual, and bowel sexual QoL with post-prostatectomy IMRT regardless of whether prostate bed fiducial markers or higher total radiotherapy doses were used. QoL with IMRT in the present study compares favorably with prior reports for three-dimensional conformal radiation therapy.