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Engineered T cells expressing tumor-specific T-cell receptors (TCRs) are emerging as a mode of personalized cancer immunotherapy that requires identification of TCRs against the products of known driver mutations and novel mutations in a timely fashion. We present a nonviral and non-next-generation sequencing platform for rapid, and efficient neoantigen-specific TCR identification and evaluation that does not require the use of recombinant cloning techniques. The platform includes an innovative method of TCRα detection using Sanger sequencing, TCR pairings and the use of TCRα/β gene fragments for putative TCR evaluation. Using patients' samples, we validated and compared our new methods head-to-head with conventional approaches used for TCR discovery. Development of a unique demultiplexing method for identification of TCRα, adaptation of synthetic TCRs for gene transfer, and a reliable reporter system significantly shortens TCR discovery time over conventional methods and increases throughput to facilitate testing prospective personalized TCRs for adoptive cell therapy.

Surface texture can be perceived not only from tactile, but also from auditory and visual sensory cues. In our previous psychophysical study, we demonstrated that humans can recognize surface stickiness using only one kind of sensory modality without any difficulty. However, the brain regions that would be activated by non-corresponding sensory cues, for example, auditory and visual cues, remain unknown. In this human functional MRI study, we explored brain regions associated with surface stickiness perception in each of three different sensory modalities, and sought for common neural activities across modalities. In the tactile condition, participants actually touched a sticky surface with their right index finger. In the auditory and visual conditions, audio and video clips of tactile explorations of a sticky surface were presented and participants were asked to recall the perceived stickiness as vividly as possible. Our results, based on a general linear model analysis, showed that somatosensory cortices including postcentral gyrus, anterior insula, and anterior intraparietal sulcus were significantly activated across all modalities. Moreover, we observed significant activation of primary sensory regions of each modality. A follow-up conjunction analysis identified that postcentral gyrus, anterior intraparietal sulcus, precentral gyrus, and supplementary motor area were activated in common. These findings could deepen our understanding of the surface stickiness perception in the human brain.

Background and Objectives: The paradoxical rise in overall and cancer-specific mortality despite increased detection and treatment of renal cell carcinoma (RCC) is termed "treatment disconnect." We reassess this phenomenon by evaluating impact of missing data and rising incidence on mortality trends., Research Design, Subjects, and Measures: Using Surveillance, Epidemiology, and End Results data, we identified patients with RCC diagnosis from 1973 to 2011. We estimated mortality rates by tumor size after accounting for lags from diagnosis to death using multiple imputations for missing data from 1983. Mortality rates were estimated irrespective of tumor size after adjustment for prior cumulative incidence using ridge regression., Results: A total of 78,891 patients met inclusion criteria. Of 70,212 patients diagnosed since 1983, 10.4% had missing data. Significant attenuation in cancer-specific mortality was noted from 1983 to 2011 when comparing observed with imputed rates: Δobs0.05 versus Δimp0.10 (P=0.001, <2 cm tumors); Δobs0.29 versus Δimp0.18 (P=0.005, 2-4 cm tumors); Δobs0.46 versus Δimp-0.20 (P<0.001, 4-7 cm tumors); Δobs0.93 versus Δimp-0.15 (P<0.001, >7 cm tumors). Holding incidence of RCC constant to 2011 rates, temporal increase in overall mortality for all patients was attenuated (P<0.001) when comparing observed estimates (3.9-6.8) with 2011 adjusted estimates (5.9-7.1), suggesting that rapidly rising incidence may influence reported overall mortality trends. These findings were supported by assessment of mortality to incidence ratio trends., Conclusions: Missing data and rising incidence may contribute substantially to the "treatment disconnect" phenomenon when examining mortality rates in RCC using tumor registry data. Caution is advised when basing clinical and policy decisions on these data.

In this functional MRI study, we investigated how the human brain activity represents tactile location information evoked by pressure stimulation on fingers. Using the searchlight multivoxel pattern analysis, we looked for local activity patterns that could be decoded into one of four stimulated finger locations. The supramarginal gyrus (SMG) and the thalamus were found to contain distinct multivoxel patterns corresponding to individual stimulated locations. In contrast, the univariate general linear model analysis contrasting stimulation against resting phases for each finger identified activations mainly in the primary somatosensory cortex (S1), but not in SMG or in thalamus. Our results indicate that S1 might be involved in the detection of the presence of pressure stimuli, whereas the SMG and the thalamus might play a role in identifying which finger is stimulated. This finding may provide additional evidence for hierarchical information processing in the human somatosensory areas.

Although more about the somatotopic mapping of fingers continues to be uncovered, there is lack of mapping attempts regarding the integration of within-finger and across-finger somatotopic coordinates in Broadmann area (BA) 3. This study aimed to address the issue by finding an inter-/intradigit somatotopic map with high-frequency (250 Hz) vibrotactile stimulation. Functional magnetic resonance imaging (fMRI) data were acquired while stimulation was applied to 3 phalanxes (distal [p1], intermediate [p2], and proximal [p3] phalanx) of 4 fingers (index, middle, ring, and little finger) for a total of 12 finger-phalanx combinations for a human. Inter-, intra-, and inter-/intradigit distances were calculated from peak activation coordinates in BA 3 for each combination. With regard to interdigit dimensions, the somatotopic coordinates proceeded in the lateral-to-medial direction for the index, middle, ring, and little fingers consecutively. This trend is comparable to that generated from low-frequency stimulation modalities (flutter stimulation). The somatotopic distances between fingers were greatest when p1 was compared across fingers. From an intradigit perspective, stimulation on p1, p2, and p3 yielded BA 3 peak coordinates aligned along the anterior-to-posterior and inferior-to-superior directions for all fingers. An inter-/intradigit map exhibited a radially propagating trend of distances calculated with respect to index p1 as a reference point; this provided an integrated view of inter- and intradigit somatotopies, which are traditionally discussed separately. We expect such an inter-/intradigit somatotopic map approach to contribute in generating a comprehensive somatotopic model of fingers.

In this study, a constant pressure stimulus was applied on the 3 joints (first [p1], second [p2], and third [p3] joints) of 4 fingers (index, middle, ring, and little fingers), and the activation areas within Brodmann area 2 (BA 2) were compared for these different fingers and joints by using functional magnetic resonance imaging. Eight healthy male college students (25.4 ± 1.32 years) participated in the study. Each session was composed of 3 blocks, and each block was composed of a Control phase (30 seconds) and a Pressure phase (30 seconds). No pressure stimulus was applied in the Control phase, during which the subjects would simply lay comfortably with their eyes closed. In the Pressure phase, a pressure stimulus was applied onto one of the joints of the selected finger. For each finger and joint, BA 2 areas activated by the pressure stimulus were extracted by the region of interest method. There was a significant difference in the activation areas for the different fingers (P = .042) as well as for the different joints (P = .050). The activation area decreased in the order of the little, index, and middle fingers, as well as in the order of p1, p3, and p2.

Objectives: To evaluate the contributions of patient and treatment factors to overall expenditures and regional variation for initial treatment of localized prostate cancer (CaP) in the Medicare program., Research Design: Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified 47,517 beneficiaries with localized CaP during 2005-2009 and matched noncancer controls. We employed hierarchical generalized linear models to estimate risk-standardized cancer-related expenditures for each hospital referral region. To identify key contributors to the variation, we sequentially added patient characteristics, treatment intensity (the percentage of patients receiving curative treatments), ancillary procedures (biopsy, hormone therapy, and imaging), and specific treatment modalities into the model. We categorized the expenditures according to the type of services to identify their relative impact on the expenditure variations., Results: The mean expenditure on CaP-related care per CaP beneficiary was $15,900, including $1800 on surgery, $11,200 on radiotherapy, and $1900 on ancillary procedures. The expenditure difference between quintiles 5 and 1 was $6200. Patient characteristics explained 8.4% of this difference. Treatment intensity and treatment modalities accounted for an additional 21.2% and 31.2% of the variation, respectively. Between the highest and lowest expenditure quintiles, the difference in radiotherapy expenditure was $5000, whereas that in surgery or ancillary procedures was <$200., Conclusions: There is substantial geographic variation in CaP expenditures, and the specific modality of radiotherapy is the most important contributor to this variation. Efforts to address the CaP care costs, such as bundled payment development, require targeting both treatment intensity and use of costly modalities.

Background: With the growing concerns about overtreatment in prostate cancer, the extent to which radiation oncologists and urologists perceive active surveillance (AS) as effective and recommend it to patients are unknown., Objective: To assess opinions of radiation oncologists and urologists about their perceptions of AS and treatment recommendations for low-risk prostate cancer., Research Design: National survey of specialists., Participants: Radiation oncologists and urologists practicing in the United States., Measures: A total of 1366 respondents were asked whether AS was effective and whether it was underused nationally, whether their patients were interested in AS, and treatment recommendations for low-risk prostate cancer. Pearson's χ test and multivariate logistic regression were used to test for differences in physician perceptions on AS and treatment recommendations., Results: Overall, 717 (52.5%) of physicians completed the survey with minimal differences between specialties (P=0.92). Although most physicians reported that AS is effective (71.9%) and underused in the United States (80.0%), 71.0% stated that their patients were not interested in AS. For low-risk prostate cancer, more physicians recommended radical prostatectomy (44.9%) or brachytherapy (35.4%); fewer endorsed AS (22.1%). On multivariable analysis, urologists were more likely to recommend surgery [odds ratio (OR): 4.19; P<0.001] and AS (OR: 2.55; P<0.001), but less likely to recommend brachytherapy (OR: 0.13; P<0.001) and external beam radiation therapy (OR: 0.11; P<0.001) compared with radiation oncologists., Conclusions and Relevance: Most prostate cancer specialists in the United States believe AS effective and underused for low-risk prostate cancer, yet continue to recommend the primary treatments their specialties deliver.

Background: Despite little available evidence to determine whether recently introduced selective α-1 blockers and 5-α reductase inhibitors (5-ARIs) are superior to the existing agents in treating benign prostatic hyperplasia (BPH), they are being increasingly prescribed., Objective: To describe the prescribing patterns of new and existing agents among patients with incident BPH after the introduction of several new agents and determine whether these varied by physician specialty., Research Design: We analyzed a retrospective cohort from an administrative claims database from January 2004 through December 2010., Subjects: Patients diagnosed with incident BPH aged 40 years and above and those who received medical management., Measures: Receipt of medical therapy for incident BPH (ie, selective α-1 blockers [prazosin (released 1976), terazosin (1987), doxazosin (1990), tamsulosin (1997), alfuzosin (2003), silodosin (2009)] and 5-ARIs [finasteride (1992) and dutasteride (2002)])., Results: A total of 42,769 men with incident BPH received any selective α-1 blocker or 5-ARI. Tamsulosin and dutasteride were the most widely prescribed agents of their respective drug classes. Predicted probabilities showed that urologists were more likely to prescribe alfuzosin (24.0% vs. 7.8%; P<0.001) and silodosin (2.3% vs. 0.4%; P<0.001) when compared with primary care providers (PCPs) at 6 months after diagnosis. Urologists were more likely to prescribe 5-ARIs but less likely to prescribe older α-1 blockers (terazosin, prazosin, and doxazosin) than PCPs at 6 months postdiagnosis., Conclusions: Among insured patients diagnosed with BPH, our study suggests that the overall use of new agents is rising. In particular, urologists were more likely to prescribe newer selective α-1 blockers compared with PCPs.

Purpose of Review: With clinical guidelines recommending partial nephrectomy for small renal masses, it is essential to understand the benefits of partial nephrectomy in regards to renal function. Our objective was to review current evidence and highlight emerging issues for partial nephrectomy and renal function., Recent Findings: A recent clinical trial of partial and radical nephrectomy found minimal differences in survival or adverse renal sequelae. However, most observational studies and systematic reviews suggest that partial nephrectomy decreases the risks of adverse renal function, in particular, new-onset severe chronic kidney disease, and improves overall survival. Key features associated with long-term renal function include treatment modality (observation, ablation, surgery), ischemia type and duration, amount of healthy renal preservation, and baseline renal function., Summary: Partial nephrectomy should remain the standard of care for small renal masses, if the renal tumor size and complexity are amenable to such a surgical approach. Efforts to minimize ischemia time are important for long-term renal functional recovery, and hypothermia should be considered if longer warm ischemia times are anticipated (i.e. >25 min). Although the preliminary results of zero ischemia partial nephrectomy are promising, further research is needed to determine if these surgical techniques are safely adaptable in the broader urologic community.

The present study examines how gamma oscillations can be modulated by cognitive reappraisal. Thirty-two participants performed cognitive reappraisal tasks to increase or decrease their emotions while viewing neutral and emotional (positive or negative) pictures. As a control task, the participants also simply viewed the pictures without an attempt to manipulate emotions. Electroencephalograms of the participants were recorded during the cognitive reappraisal tasks to extract the gamma oscillations. Gamma activity was quantified by measuring event-related changes in the gamma band power (30-55 Hz). During the tasks, the greatest gamma activity was found at the parietal regions. Greater parietal gamma activity was induced by the emotional pictures compared with the neutral ones when the participants passively viewed the pictures. No such difference in the parietal gamma activity was found when the participants performed the cognitive reappraisal tasks. In addition, parietal gamma activity during the cognitive reappraisal tasks was greater than that during the control task in response to the neutral pictures, implying the role of parietal gamma activity in the top-down cognitive execution process. In contrast, parietal gamma activity during the cognitive reappraisal task to increase emotions was greater than the levels of activity during the task to decrease emotions and during the control task in response to the emotional pictures, implying the role of parietal gamma activity in the bottom-up sensory emotional process. These results suggest that parietal gamma activity may be implicated in the multiple cognitive reappraisal processes.

To the extent that recognition memory relies on interactions among widely distributed neural assemblies across the brain, phase synchronization between brain rhythms may play an important role in meditating those interactions. As the theta rhythm is known to modulate in power during the recognition memory process, we aimed to determine how the phase synchronization of the theta rhythms across the brain changes with recognition memory. Fourteen human participants performed a visual object recognition task in a virtual reality environment. Electroencephalograms were recorded from the scalp of the participants while they either recognized objects that had been presented previously or identified new objects. From the electroencephalogram recordings, we analyzed the phase-locking value of the theta rhythms, which indicates the degree of phase synchronization. We found that the overall phase-locking value recorded during the recognition of previously viewed objects was greater than that recorded during the identification of new objects. Specifically, the theta rhythms became strongly synchronized between the frontal and the left parietal areas during the recognition of previously viewed objects. These results suggest that the recognition memory process may involve an interaction between the frontal and the left parietal cortical regions mediated by theta phase synchronization.

Thalamocortical networks play an important role in information integration during consciousness. However, little is known about how the information flows between the thalamus and the cortex are affected by a loss of consciousness. To investigate this issue, we analyzed effective connectivity between the cortex and the thalamus in animals during anesthesia-induced transitions. By recording the electroencephalogram from the primary motor and the primary somatosensory cortex and by recording local field potentials from the ventral lateral and the ventrobasal thalamic nuclei, we evaluated changes in the conditional Granger causality between cortical and thalamic electrical activity as mice gradually lost consciousness from the use of anesthesia (ketamine/xylazine). The point of loss of consciousness was indicated by a moment of loss of movement that was measured using a head-mounted motion sensor. The results showed that 65% of the thalamocortical information flows were changed by anesthesia-induced loss of consciousness. Specifically, the effective connectivity between the cortex and the ventral lateral thalamus was altered such that the primary motor and the primary somatosensory cortex Granger-caused the ventral lateral thalamus before loss of consciousness whereas the ventral lateral thalamus Granger-caused the primary motor cortex and the primary somatosensory cortex after loss of consciousness. In contrast, the primary somatosensory cortex consistently Granger-caused the ventrobasal thalamus, regardless of the loss of consciousness. These results suggest how information flows change across the thalamocortical network during transitions in consciousness.

Objectives: The canine model has been used extensively to improve the human pancreatic islet isolation technique. At the functional level, dog islets show high similarity to human islets and thus can be a helpful tool for islet research. We describe and compare 2 manual isolation methods, M1 (initial) and M2 (modified), and analyze the variables associated with the outcomes, including islet yield, purity, and glucose-stimulated insulin secretion (GSIS)., Methods: Male mongrel dogs were used in the study. M2 (n = 7) included higher collagenase concentration, shorter digestion time, faster shaking speed, colder purification temperature, and higher differential density gradient than M1 (n = 7)., Results: Islet yield was similar between methods (3111.0 ± 309.1 and 3155.8 ± 644.5 islets/g, M1 and M2, respectively; P = 0.951). Pancreas weight and purity together were directly associated with the yield (adjusted R(2) = 0.61; P = 0.002). Purity was considerably improved with M2 (96.7% ± 1.2% vs 75.0% ± 6.3%; P = 0.006). M2 improved GSIS (P = 0.021). Independently, digestion time was inversely associated with GSIS., Conclusions: We describe an isolation method (M2) to obtain a highly pure yield of dog islets with adequate β-cell glucose responsiveness. The isolation variables associated with the outcomes in our canine model confirm previous reports in other species, including humans.

Acute lower gastrointestinal hemorrhage associated with the appendix is rare. We report on a 42-year-old male patient who presented with hematochezia from solitary appendiceal bleeding. The patient was admitted to our hospital with rectal bleeding, and abdominal computed tomography identified active contrast leakage in the distal portion of the appendix. During a subsequent urgent colonoscopy, active bleeding in the appendiceal orifice was identified. The patient was successfully treated with a laparoscopic appendectomy and hematochezia did not recur postoperatively. Microscopic examination revealed an eroded appendiceal mucosa, focal inflammatory infiltrates, and a normal submucosal vessel without evidence of vascular malformation.

Objectives: To assess the value of using intramucosal pH (pHi) measurements to evaluate the viability of the gastric tube after thoracic esophagectomy, and to determine whether these measurements may be used for early prediction of anastomotic insufficiency., Design: Prospective, observational study., Setting: University hospital in Japan., Patients: Thirty-nine patients who had undergone thoracic esophagectomy as a treatment for esophageal cancer., Interventions: The blood flow within the gastric tube was measured using a laser Doppler flowmeter during surgery. Periodic measurement of the pHi within the gastric tube (gastric pHi) began during surgery and continued until the second postoperative day. In 30 patients, the pHi within the rectum (rectal pHi) was measured simultaneously with the gastric pHi. The patients were divided into two groups: those patients who experienced anastomotic insufficiency constituted the leakage(+) group (n = 13); those patients who did not experience these complications were designated the leakage(-) group (n = 26)., Measurements and Main Results: The gastric pHi values correlated significantly with simultaneous measurements of the blood flow at the anastomotic site (p < .01). The postoperative gastric pHi values increased gradually in the leakage(-) group but stopped increasing after surgery in the leakage(+) group. The rectal pHi values increased gradually after surgery in both groups. Furthermore, there was a significant difference between the two groups when their gastric pHi values were subtracted from their rectal pHi values from the morning of the first postoperative day until the morning of the second postoperative day (p < .05)., Conclusions: The gastric pHi values well reflected the viability of the gastric tube, especially when combined with the rectal pHi values. By measuring pHi, we can more accurately predict the risk of anastomotic insufficiency earlier after surgery and therefore give those patients who need it additional care to improve the viability of the gastric tube.

A 22-year-old Korean soldier, who had received blows to the neck and epigastrium from an officer 10 h earlier, suddenly died after massive hematemesis. He had been in relatively good health except for episodes of blood-tinged vomiting approximately 5 and 7 months prior to this event. Postmortem examination revealed angiodysplasia involving the gastroesophageal junction, and the stomach was distended with blood. No abnormal findings were present around the whole viscera, and the duodenum was free of blood. The pathologic significance of upper gastrointestinal angiodysplasia as a potential source of bleeding and a chronologic correlation between the trauma and bleeding are discussed.