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A Markov-based cost-effectiveness model was developed to project long-term effectiveness and costs among patients who undergo nephrectomy for renal cell carcinoma and receive either adjuvant pembrolizumab, adjuvant sunitinib, or routine surveillance alone (no adjuvant treatment). Over a lifetime horizon, pembrolizumab was estimated to prolong quality-adjusted life expectancy and be cost-effective relative to both comparator treatment strategies. Introduction: Pembrolizumab was recently approved as an adjuvant treatment of renal cell carcinoma (RCC), based on prolonged disease-free survival compared to placebo in the phase III KEYNOTE-564 trial. The objective of this study was to evaluate the cost-effectiveness of pembrolizumab as monotherapy in the adjuvant treatment of RCC post-nephrectomy, from a US health sector perspective. Patients and Methods: A Markov model with 4 health states (disease-free, locoregional recurrence, distant metastases, and death) was developed to compare the cost and effectiveness of pembrolizumab versus routine surveillance or sunitinib. Transition probabilities were estimated using patient-level KEYNOTE-564 data (cutoff: June 14, 2021), a retrospective study, and published literature. Costs of adjuvant and subsequent treatments, adverse events, disease management, and terminal care were estimated in 2022 US$. Utilities were based on EQ-5D-5L data collected in KEYNOTE-564. Outcomes included costs, life-years (LYs), and quality-adjusted LYs (QALYs). Robustness was assessed through one-way and probabilistic sensitivity analyses. Results: Total cost per patient was $549,353 for pembrolizumab, $505,094 for routine surveillance, and $602,065 for sunitinib. Over a lifetime, pembrolizumab provided gains of 0.96 QALYs (1.00 LYs) compared to routine surveillance, yielding an incremental cost-effectiveness ratio of $46,327/QALY. Pembrolizumab dominated sunitinib with 0.89 QALYs (0.91 LYs) gained while saving costs. At a $150,000/QALY threshold, pembrolizumab was cost-effective versus both routine surveillance and sunitinib in 84.2% of probabilistic simulations. Conclusion: Pembrolizumab is projected to be cost-effective as an adjuvant RCC treatment versus routine surveillance or sunitinib based on a typical willingness-to-pay threshold. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the efficacy of adjuvant chemotherapy for pathologic stage I non-small cell lung cancer (NSCLC) with high risk for recurrence. Prospectively collected data from 1278 patients with pathologic stage I NSCLC according to eighth edition staging guidelines who were undergoing lobectomy were retrospectively analyzed. Factors associated with high risk for recurrence were determined using the multivariable Cox proportional hazards model for recurrence-free survival (RFS). Survival was compared between patients who received adjuvant chemotherapy and those who did not. In multivariable analysis, age (≥70 years), invasive component size (>2 cm), visceral pleural invasion, lymphatic invasion, and vascular invasion were identified as independent factors for RFS. In patients with high-risk factors for recurrence such as pathologic T1c or T2a or lymphovascular invasion (high-risk group; n = 641), adjuvant chemotherapy resulted in significantly longer RFS and overall survival (n = 222; 5-year RFS, 81.4%; 5-year overall survival, 92.7%) than in patients who did not receive adjuvant chemotherapy (n = 418; 5-year RFS, 73.8%; P =.023; 5-year overall survival, 81.7%; P <.0001). In patients without any high-risk factors for recurrence (low-risk group; n = 637), RFS was not significantly different between those who received adjuvant chemotherapy (n = 83; 5-yeat RFS, 98.1%) and those who did not (n = 554; 5-year RFS, 95.7%; P =.30). Adjuvant chemotherapy may improve survival in patients with pathologic stage I NSCLC who have factors associated with high risk for recurrence, such as pathologic T1c or T2a or lymphovascular invasion. [Display omitted] [ABSTRACT FROM AUTHOR]

Complex segmentectomy creates several intricate intersegmental planes; however, it has not been fully established in lung cancer treatment. We compared the oncologic outcomes of complex segmentectomy and lobectomy through a large cohort, multicenter database using propensity score-matched analysis. We retrospectively analyzed data from 1517 patients with clinical stage I lung cancer with a solid component size 2.0 cm or less, who underwent surgical resection at 3 institutions between 2010 and 2018. Complex segmentectomy (n = 240) and location-adjusted lobectomy (n = 851) as well as surgical results were analyzed for all patients and their propensity score-matched pairs. The prognosis of patients undergoing complex segmentectomy was not significantly different from that of patients undergoing lobectomy (5-year cancer-specific survival [CSS] rate, 96.4% versus 97.2%, P =.69; and 5-year recurrence-free interval [RFI] rate, 95.8% versus 93.4%, P =.19). This trend was also identified in subanalyses for pure solid tumors. However, there were major differences in clinicopathologic features between the 2 groups. After propensity score-matched analysis, proper matching of patients was ascertained. In 219 propensity score-matched pairs, long-term outcomes were similar between patients undergoing complex segmentectomy (5-year CSS, 96.0%; 5-year RFI, 95.5%) and lobectomy (5-year CSS, 97.8%; 5-year RFI, 95.9%). Propensity score-adjusted multivariable analysis for RFI revealed that prognosis associated with complex segmentectomy was comparable to the prognosis obtained with lobectomy (hazard ratio = 0.98; 95% confidence interval, 0.33-2.40; P =.98). Complex segmentectomy provides acceptable oncologic outcomes in clinical stage I lung cancer treatment. [ABSTRACT FROM AUTHOR]

The prognosis of patients with cT1N0 lung adenocarcinoma is better when tumors include mixed ground glass opacity (GGO), compared with pure solid tumors. However, whether the prognosis of patients with mixed GGO tumors is favorable regardless of the solid component size remains unknown. Therefore, we aimed to determine the prognostic role of the solid component size in mixed GGO. We retrospectively analyzed the clinicopathological findings and prognoses of 856 patients with mixed GGO tumors based on solid component size during a median follow-up of 45 months, among 1215 patients with cT1N0 lung adenocarcinoma according to the TNM Classification of Malignant Tumors, Eighth Edition, who underwent R0 resection at 3 institutions between 2010 and 2015. Four-year recurrence-free survival rates were significantly worse for patients with mixed GGO cT1c tumors (solid component size: 2-3 cm; 81.5%; 95% confidence interval [CI], 72.8%-87.7%) than for those with cT1mi+1a tumors (0-1 cm; 96.8%; 95% CI, 94.2%-98.2%) and cT1b (1-2 cm; 95.3%; 95% CI, 92.1%-97.2%) (both P <.001), although that for cT1b tumors was comparably favorable to those of T1mi+1a tumors. Multivariable Cox regression analysis of recurrence-free survival revealed that a solid component size of 2 cm to 3 cm (cT1c) vs less than or equal to 2 cm (cT1mi+1a+1b) was an independent prognostic factor (hazard ratio, 4.16; 95% CI, 2.24-7.72; P <.001). The prognostic impact of a solid component size less than or equal to 2 cm and greater than 2 cm significantly differs after complete resection of GGO-mixed T1N0 lung adenocarcinoma. The prognosis of patients with solid components less than or equal to 2 cm is favorable, whereas the behavior of those solid components greater than 2 cm is more aggressive. [ABSTRACT FROM AUTHOR]

Wheel scribing is a technique widely used in dividing glass substrates. However, the optimization of scribing conditions and tool geometry depends on empirical rules because the dominant factors of crack generation and fracture surface formation are not fully understood. The present study visualizes the crack generation/propagation behavior in the contact area between the scribing wheel and glass substrate employing high-speed imaging. Median cracks appeared under the wheel when the wheel came into contact with the glass, with the cracks being located on a single plane. The fracture surface morphology depended on whether the median cracks were connected with each other. We discuss the formation mechanism of the fracture surface on the basis of the observations of crack generation/propagation behavior. • We observed crack propagation behavior from lateral and back sides of glass sheets. • Three dimensional crack propagation behavior during wheel scribing was revealed. • Fracture surface morphologies were clearly observed by confocal laser microscope. • The formation process of fracture surface depended on crack propagation behavior. [ABSTRACT FROM AUTHOR]

Quantitative computed tomography (CT) histogram analysis of tumors is reported to help distinguish between invasive and less invasive lung cancers. This study aimed to clarify whether CT histogram analysis of tumors can be used to classify patients with clinical stage 0 to IA non-small cell lung cancer according to pathologic lymph node (pN) status. Predictive factors associated with pN metastasis were identified from the derivation dataset including 629 patients with clinical stage 0 to IA non-small cell lung cancer who underwent complete resection with lymph node dissection (surgeries between 2008 and 2013). The validation dataset including 238 patients (surgeries between 2014 and 2015) were subsequently reevaluated. Clinicosurgical factors, including CT histogram analysis of tumors (CT value percentiles 2.5, 25, 50, 75, and 97.5, skewness, and kurtosis) were assessed. Seventy-three patients (12%) in the derivation cohort and 35 patients (15%) in the validation cohort had positive nodes. The pN status significantly affected survival in the entire population: 5-year overall survival of 93.1% vs 71.1% and 5-year disease-free survival of 85.9% vs 43.1% for negative vs positive (both P <.001). On multivariate analysis in the derivation cohort, the 75th percentile CT value (P <.001), age (P =.003), and comorbidities (P =.006) were significantly associated with pN metastasis. The area under the curve and the cutoff level of the 75th percentile CT value relevant to pN metastasis were 0.729 and 1.5 HU, respectively, and the threshold value provided accuracy of 71% for the validation cohort. Histogram analysis of CT imaging metrics of tumors contributes to noninvasive prediction of pN metastasis in patients with clinical stage 0 to IA non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Abstract Objective This study examined the prevalence of chronic comorbidities and the use of co-medications among people living with HIV (PLWH) on antiretrovirals in Japan, compared with age-matched controls without HIV. Methods This was an observational, retrospective, cross-sectional study using a hospital claims database of Japanese hospitals with advanced medical capabilities (i.e., advanced treatment hospitals, general hospitals, acute care hospitals). We extracted data for PLWH aged ≥18 years with a prescription record of antiretrovirals between January 2010 and December 2015, and for age-, sex-, and hospital-matched people without HIV. For each group, chronic comorbidities (diabetes, hypertension, lipid disorders, vascular diseases, chronic kidney failure, cancers, psychiatric disorders, osteoporosis, and hepatitis B/C co-infection), and co-medications were examined by age group. Results We analyzed data for 1445 PLWH and 14,450 people without HIV. The proportion of patients with multiple comorbidities was much greater among PLWH than controls of the same age group. Lipid disorders and diabetes were more prevalent in PLWH than controls (31.6% vs. 10.3% and 26.8% vs. 13.2%, respectively), both of which were more common in PLWH at earlier ages. Cancer was present in 8.1% of PLWH and 8.9% of controls. A greater proportion of PLWH used multiple co-medications other than antiretrovirals at earlier ages than controls. Conclusion PLWH taking antiretrovirals in Japan had a greater burden of comorbidities and co-medications with increasing age than people without HIV. In addition to appropriate management of comorbidities, medication reconciliation according to patients' co-medication profiles is important for successful management of this patient population. [ABSTRACT FROM AUTHOR]

Highlights • 75th percentile CT attenuation value is predictive of lepidic-predominant adenocarcinoma. • Maximum CT attenuation value is associated with lepidic-predominant adenocarcinoma. • SUVmax is also useful in distinguishing lepidic adenocarcinoma from non-lepidic ones. • CT histogram analysis is highly beneficial for understanding lung cancer biology. Abstract Objectives The aim of this study was to analyze the accuracy of computed tomography (CT) and F-18 fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) to distinguish lepidic growth adenocarcinoma (LGA), including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic-predominant adenocarcinoma, all of which have favorable survival outcomes, from the more aggressive and invasive non-LGA subtypes. Materials and Methods We identified 225 patients with c-0/I adenocarcinoma of the lung who underwent PET/CT and 3DCT followed by complete resection. Maximum standardized uptake values (SUVmax) of FDG and several histogram parameters were analyzed. Histological grades were classified according to the predominant subtype (G1: lepidic; G3: micropapillary or solid; and G2: subtypes other than G1/G3). Results The proportion of pathological invasive factors (lymphatic vessel involvement/blood vessel invasion/pleural invasion/lymph node metastasis) of patients with preinvasive adenocarcinoma, G1, G2, and G3 tumors were 0%, 3.6%, 48.0%, and 100%, respectively; p < 0.001). Multivariate analysis with CT-related parameters demonstrated that 75th percentile CT attenuation value (75th%, p < 0.001) and maximum CT attenuation value (maxCT, p = 0.009) were associated with incidence of non-LGA, whereas the value of SUVmax demonstrated a significant correlation (p < 0.001). When all patients were dichotomized according to ground-glass opacities (GGO)/solid-dominancy for CT maximum diameter, a significant correlation with non-LGA was shown in patients with solid-dominant tumor on SUVmax (p < 0.001) and with GGO-dominant tumor on 75th% (p = 0.006) and maxCT (p = 0.007). The combination of one of the two significant histogram parameters and SUVmax revealed higher predictive performance for pathological high malignant features (positive pathological invasive factors, non-LGA, and the highly malignant subtype covering G2 with moderately or poorly-differentiated carcinoma and G3) than the individual use of either factor. Conclusion The 75th%, maxCT, and SUVmax were highly useful in distinguishing LGA from non-LGA in c-0/I adenocarcinoma. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to conduct comparative analyses of the biological malignant potential of clinical stage IA adenocarcinoma using positron emission tomography/computed tomography (PET/CT), high-resolution CT (HRCT), and three-dimensional CT (3DCT). The predictive performance of these parameters was evaluated in terms of clinical outcomes and pathological invasiveness (positive lymphatic permeation, blood-vessel invasion, pleural invasion, and lymph-node metastasis). Materials and methods We enrolled 170 patients with c-IA adenocarcinoma who underwent PET/CT, HRCT, and 3D reconstruction of lung structures using the Synapse Vincent system (Fujifilm Corporation, Tokyo, Japan) followed by complete resection. Maximum standardized uptake values (SUV max ) of F 18 -fluorodeoxyglucose and the size and volume of the solid part of the tumor were quantified and analyzed in relation to surgical outcomes. Results Univariate analysis demonstrated that all the three parameters and whole-tumor volume were associated with unfavorable disease-free survival (DFS), while the volume of the solid part was the independent predictor on multivariate analysis (p < .001). The receiver operating characteristic curves for pathological invasiveness, determined using the variables dichotomized at each cut-off level (SUV max 2.4; solid-part size 1.23 cm; solid-part volume 779 mm 3 ), showed that all were significantly correlated with pathological invasiveness and prognosis, whereas the combination of SUV max and the solid-part volume was the most powerful predictor of survival and pathological invasiveness compared to any other parameters: the 4-year DFS and proportion of pathological invasiveness in patients with SUV max  > 2.4 and solid-part volume > 779 mm 3 versus those with SUV max  ≤ 2.4 or solid-part volume ≤779 mm 3 were 81.2% versus 98.3% (p < .001) and 84.3% versus 15.1% (p < .001), respectively. Conclusion In c-IA adenocarcinoma, the volume of the solid part of the tumor was the independent predictor for unfavorable DFS, and the integration of the volume of the solid part and SUV max was highly beneficial for the prediction of survival and pathological invasiveness. [ABSTRACT FROM AUTHOR]

Background: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints.Methods: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334.Findings: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7-36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50-0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3-4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab.Interpretation: Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy.Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA. [ABSTRACT FROM AUTHOR]

In the phase 3 KEYNOTE-564 study (NCT03142334), adjuvant pembrolizumab prolonged disease-free survival (DFS) in patients with clear cell renal cell carcinoma (ccRCC) at increased risk of recurrence after nephrectomy compared with placebo (DFS at 24 months: 77.3% vs 68.1%; hazard ratio [HR] for recurrence or death, 0.68; 95% CI, 0.53-0.87; P=0.002).;Continued DFS improvement with adjuvant pembrolizumab was observed after 30 months of follow-up. Results of a post hoc exploratory analysis of DFS in patient subgroups based on UCLA Integrated Staging System (UISS) risk groups and disease stage are reported. Patients with histologically confirmed ccRCC (pT2, grade 4 or sarcomatoid, N0, M0; pT3 or pT4, any grade, N0, M0; any pT, any grade, N+, M0; or M1 with no evidence of disease [NED]) were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 17 cycles (∼1 year). DFS was assessed by investigator. UISS risk groups were derived retrospectively from TNM stage, Fuhrman nuclear grade, and Eastern Cooperative Oncology Group performance status (ECOG PS). UISS groups were intermediate risk (pT2, grade 4, N0, M0; pT3, grade 1, N0, M0; or pT3, grades 2-4, N0, M0, ECOG PS of 0), high risk (pT3, grades 2-4, N0, M0, ECOG PS 1; pT4, any grade, N0, M0; or N1, M0), or M1 NED. Other subgroups based on disease stage were also evaluated. Baseline characteristics were generally balanced within subgroups. Median follow-up was 30.1 months (range, 20.8-47.5). Of 994 enrolled patients, most had UISS intermediate risk (n = 732 [73.6%]; pembrolizumab, n = 359; placebo, n = 373); 195 patients (19.6%; pembrolizumab, n = 100; placebo, n = 95) had UISS high risk, and 58 patients (5.8%; pembrolizumab, n = 29; placebo, n = 29) had M1 NED. DFS favored pembrolizumab versus placebo in the UISS intermediate-risk group (HR, 0.65 [95% CI, 0.48-0.88]; 24-month rate: 81.5% vs 72.4%), UISS high-risk group (HR, 0.77 [95%;CI, 0.49-1.20]; 24-month rate: 65.0% vs 55.9%), and M1 NED group (HR, 0.28 [95% CI, 0.12-0.66]; 24-month rate: 78.4% vs 37.9%). DFS favored pembrolizumab versus placebo across all patient subgroups based on disease stage (Table). Consistent with the results of the intention-to-treat (ITT) population, adjuvant pembrolizumab prolonged DFS compared with placebo for all patient subgroups based on UISS risk groups and disease stage. Taken together with results in the ITT population, these results further support the use of adjuvant pembrolizumab as standard of care for patients with RCC at increased risk of recurrence after nephrectomy. ©2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 Genitourinary Cancers Symposium. All rights reserved. [ABSTRACT FROM AUTHOR]

Background: PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma.Methods: KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305.Findings: Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7-36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5-8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4-7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65-0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5-19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3-16·7) in the chemotherapy group (0·86, 0·72-1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1-17·9] with pembrolizumab vs 14·3 months [12·3-16·7] with chemotherapy; HR 0·92, 95% CI 0·77-1·11) and the population with CPS of at least 10 (16·1 months [13·6-19·9] with pembrolizumab vs 15·2 months [11·6-23·3] with chemotherapy; 1·01, 0·77-1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group.Interpretation: The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma.Funding: Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA. [ABSTRACT FROM AUTHOR]

• Risk of recurrence changes by pStage and histological subtype in adenocarcinoma. • Distribution of EGFR mutation also varies among pStage and histological subtypes. • Risk of postoperative relapse should be discussed among cases with recurrent risks. • EGFR mutant cases showed worse RFS in pStageIA1–IB/high risk type and pStgaeIIA–IIIA. • EGFR status can be recurrence risk by considering pStage and histological subtype. Objectives: Recurrence risk of resected lung adenocarcinoma is represented by pathological stage (pStage), histological subtype, and potentially by EGFR mutation. However, the relationship among these factors and their combined impact on prognosis are unclear. Using a multicenter database, we retrospectively investigated the prognostic impact of EGFR mutation status in relation to pStage and histological subtype in resected pN0–1M0 lung adenocarcinoma. Among 1155 pN0–1M0 adenocarcinoma cases, pStage 0 and IA1–IB were confirmed predominantly in EGFR -positive cases. AIS, MIA, and lepidic predominant adenocarcinoma were also more frequently found in EGFR -positive cases and showed no/little recurrence regardless of EGFR mutation status. The 5-year recurrence-free survival (RFS) of papillary, acinar, solid, and micropapillary predominant adenocarcinoma was stratified by pStage (IA1–IB, IIA–IIIA) or histological malignant subtype (intermediate or high malignant subtype), and more finely subdivided by EGFR mutation status. Positive EGFR mutation cases showed worse RFS in both classifications. Low malignant subtype and pStage IA1–IB intermediate malignant subtype showed low frequency of recurrence. Whereas, in pStage IA1–IB high malignant subtype and pStage IIA–IIIA cases, EGFR- positive cases showed poorer 5-year RFS than EGFR -negative (49.6% and 75.6%, respectively, hazard ratio [HR] = 1.84, 95% CI = 1.38–7.42, p < 0.01) and multivariate analysis indicated positive EGFR mutation status was significantly related to poorer PRF (HR = 2.005, 95% CI = 1.029–3.906, p = 0.041). EGFR mutation harbored primarily in early-stage or low-malignant histological subtypes with no/little recurrence. In pN0–1M0 adenocarcinoma with higher risk of recurrence, positive EGFR mutation cases showed worse RFS. EGFR mutation status enables better stratification of recurrence risk when considering pStage and histological malignant subtype. [ABSTRACT FROM AUTHOR]

In this study, we considered the accurate calculation of far-field tsunami waveforms by using the shallow water equations and accounting for the effects of Boussinesq dispersion, seawater density stratification, elastic loading, and gravitational potential change in a finite difference scheme. By comparing numerical simulations that included and excluded each of these effects with the observed waveforms of the 2011 Tohoku tsunami, we found that all of these effects are significant and resolvable in the far field by the current generation of deep ocean-bottom pressure gauges. Our calculations using previously published, high-resolution models of the 2011 Tohoku tsunami source exhibited excellent agreement with the observed waveforms to a degree that has previously been possible only with near-field or regional observations. We suggest that the ability to model far-field tsunamis with high accuracy has important implications for tsunami source and hazard studies. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We examined the appropriate measurement for pathological tumor size by comparing radiological and pathological tumor size of resected lung adenocarcinoma in FSE. Materials and methods: We reviewed records of 59 resected specimens of lung adenocarcinoma for FSE from January to December 2008. Specimens were well-inflated with saline by using an injector before cutting into segments. After selecting the tumor segment of maximal diameter, we compared three ways of measuring pathological tumor size by using paired t-test: (I) macroscopic tumor size (MTS), measured with a metal straight ruler, (II) microscopic frozen section tumor size (FSTS), and (III) microscopic paraffin section tumor size (PSTS). We compared each discrepancy rate (DR) [DR=(CT tumor size−pathological tumor size)/CT tumor size×100] (%) between tumors that were air-containing type and solid-density type on CT scans, and also compared the tumors with lepidic component rates (LCR) ≥50% and LCR <50%, by using Mann–Whitney U-tests. Results: FSE could diagnose malignancy with 100% accuracy. The mean CT tumor size was 18.36mm, and the mean pathological tumor sizes (MTS, FSTS, and PSTS) were 17.81, 14.29, and 14.23mm, respectively. FSTS and PSTS were significantly smaller than CT tumor size (p <0.001). The DR calculated with PSTS was significantly larger in air-containing than in solid-density tumors, and also larger in LCR ≥50% than in LCR <50% tumors. Conclusion: FSE with the inflation method diagnosed malignancy with 100% accuracy. The lung specimen must be sufficiently inflated to prevent tissue shrinking, and we propose MTS as the definition for pathological tumor size in FSE. The greater discordance observed between CT tumor size and microscopic tumor size was assumed to be due to shrinkage of the lepidic component in the tumor. [Copyright &y& Elsevier]

Abstract: We report a rare case of lung adenocarcinoma in which micropapillary components were considered to cause stump recurrence. A woman in her fifties was diagnosed with lung cancer in the right middle lobe with invasion to the upper lobe, which was treated by a right middle lobectomy together with upper lobe partial resection. The cancer was pathologically diagnosed as adenocarcinoma and had a free surgical margin. There was no recurrence during the following 5 years and 8 months, and thus periodical surveillance, including computed tomography, was stopped. However, 2 years and 7 months after this, she was discovered to have an abnormal shadow on chest radiography, and a thorough examination revealed a 3-cm-sized tumor involving the previous surgical margin. Therefore, she underwent right upper lobectomy. We pathologically re-evaluated the first tumor and found that it was an adenocarcinoma with a micropapillary component in the periphery, 6mm away from the surgical margin. In addition, a few tiny clusters of tumor cells were found to be floating within the alveolar spaces near the margin. The first and second tumors showed almost the same histological mixture of components of adenocarcinoma and the same EGFR mutation. From these results, we concluded the second tumor was a stump recurrence originating from the first tumor resection. This case illustrates the importance of careful pathological investigation when an autosuture instrument is used for a partial resection in a case of lung adenocarcinoma with micropapillary components. In such cases, it is particularly important to clarify if micropapillary components are floating near a stump. [Copyright &y& Elsevier]