Objective:This study aims to develop a deep multiscale image learning system (DMILS) to differentiate malignant from benign thyroid follicular neoplasms on multiscale whole-slide images (WSIs) of intraoperative frozen pathological images. Methods:A total of 1,213 patients were divided into training and validation sets, an internal test set, a pooled external test set, and a pooled prospective test set at three centers. DMILS was constructed using a deep learning-based weakly supervised method based on multiscale WSIs at 10×, 20×, and 40× magnifications. The performance of the DMILS was compared with that of a single magnification and validated in two pathologist-unidentified subsets. Results:The DMILS yielded good performance, with areas under the receiver operating characteristic curves (AUCs) of 0.848, 0.857, 0.810, and 0.787 in the training and validation sets, internal test set, pooled external test set, and pooled prospective test set, respectively. The AUC of the DMILS was higher than that of a single magnification, with 0.788 of 10×, 0.824 of 20×, and 0.775 of 40× in the internal test set. Moreover, DMILS yielded satisfactory performance on the two pathologist-unidentified subsets. Furthermore, the most indicative region predicted by DMILS is the follicular epithelium. Conclusions:DMILS has good performance in differentiating thyroid follicular neoplasms on multiscale WSIs of intraoperative frozen pathological images.

The present case report investigated the clinicopathological features and potential mechanisms underlying the transformation to peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), following treatment for classical Hodgkin lymphoma (CHL) in a 73-year-old man. The patient was admitted to hospital in 2012 and underwent a left cervical lymph node biopsy, which confirmed CHL of the nodular sclerosing type, with evident bone marrow involvement. The patient received four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine chemotherapy, after which they achieved complete remission. However, after 3 years, the patient presented with enlarged left inguinal lymph nodes and a biopsy revealed PTCL-NOS. Molecular studies indicated a T-cell receptor-γ gene rearrangement. A literature review, together with the current case, identified 11 patients with CHL that transformed into PTCL-NOS. Among these, nine patients (81.82%) were middle-aged or elderly (>45 years old), and eight (72.73%) experienced transformation within 3 years post-treatment of CHL. Among these eight patients, seven (87.50%) predominantly exhibited the nodular sclerosis subtype, with a median recurrence time of 26 months. Five (45.45%) patients died of the disease. The rare transformation of CHL to PTCL-NOS, primarily among men, underscores its clinical significance. Notably, nodular sclerosing-type CHL appears to be particularly prone to transformation into PTCL-NOS. The poor prognosis in such cases may be attributed to the complex tumor microenvironment of CHL.

Background: In patients (pts) with previously treated aHCC, pembro demonstrated comparable efficacy and safety vs placebo (pbo) in the phase 3 KEYNOTE-240 (NCT02702401) and KEYNOTE-394 (NCT03062358) studies in global and Asian populations, respectively. The hazard ratio ([HR]; 95% confidence interval [CI]) for OS was 0.781 (0.611-0.998) in KEYNOTE-240 and 0.79 (0.63-0.99) in KEYNOTE-394; HR (95% CI) for PFS was 0.78 (0.61-0.99) and 0.74 (0.60-0.92), respectively. ORR differences with pembro vs pbo were similar in KEYNOTE-240 (13.8% [95% CI, 7.7-19.5]) and KEYNOTE-394 (11.4% [95% CI, 6.7-16.0]). We performed a prespecified meta-analysis of KEYNOTE-240 and KEYNOTE-394 to obtain a more precise estimate of the pembro treatment effect. Methods: In KEYNOTE-240 and KEYNOTE-394, pts with confirmed aHCC and progression or intolerance to sorafenib or oxaliplatin-based chemotherapy (KEYNOTE-394 only) were randomized 2:1 to pembro (200 mg IV Q3W) or pbo for ≤35 cycles, both with best supportive care. Inclusion/exclusion criteria were similar. Meta-analysis of pt data pooled from the ITT population of the pembro and pbo arms of each study was completed. OS, PFS (blinded independent central review [BICR] per RECIST 1.1), and ORR (BICR per RECIST 1.1) were assessed. Results: In total, 578 pts who received pembro and 288 who received pbo were included. The HR for OS and PFS and the difference in ORR for pembro vs pbo in all pts was 0.79 (95% CI, 0.67-0.93), 0.76 (0.64-0.89), and 12.5 (8.8-16.2), respectively (Table). Results were consistent across subgroups, including viral etiology, BCLC stage, and age. Conclusions: This meta-analysis of two studies with similar design, inclusion/exclusion criteria, and endpoints, showed improvement in OS, PFS, and ORR with pembro vs pbo across studies. These data also show consistent outcomes between the studies, providing further evidence for the benefit of second-line pembro for aHCC globally. All Patients Patients With Sorafenib-Treated aHCC Pembrolizumab(n = 578) Placebo(n = 288) Pembrolizumab(n = 550) Placebo (n = 274) OS, median (95% CI), mo 14.2 (12.8-16.2) 12.5 (10.2-13.6) 14.2 (12.8-16.0) 12.5 (10.4-13.6) HR (95% CI)a,b 0.79 (0.67-0.93) 0.78 (0.66-0.92) PFS, median (95% CI), mo 2.8 (2.7-2.9) 2.7 (1.6-2.8) 2.8 (2.7-2.9) 2.7 (1.6-2.8) HR (95% CI)a,b 0.76 (0.64-0.89) 0.76 (0.64-0.90) ORR, % (95% CI) 15.4 (12.6-18.6) 2.8 (1.2-5.4) 15.6 (12.7-18.9) 2.9 (1.3-5.7) Estimated treatment difference, (95% CI)b,c 12.5 (8.8-16.2) 12.6 (8.8-16.4) aHCC, advanced hepatocellular carcinoma; CI, confidence interval; HR, hazard ratio.aStratified Cox proportional hazard model with treatment as a single covariate and Efron’s method of tie handling was used to estimate the OS and PFS HR and its 95% CI.bStratification was performed per protocol and within each protocol, by strata used in the analysis of the respective protocol.cMiettinen & Nurminen method was used to estimate the difference in ORR and its 95% CI. Citation Format: Richard S. Finn, Kangsheng Gu, Xi Chen, Philippe Merle, Kyung-Hun Lee, Mohamed Bouattour, Peiguo Cao, Wei Wang, Ann-Lii Cheng, Liangjun Zhu, Ho Yeong Lim, Masatoshi Kudo, Yueyin Pan, Ting-Tsung Chang, Julien Edeline, Wei Li, Ping Yang, Chen Li, Jianfeng Li, Abby B. Siegel, Shukui Qin. Pembrolizumab (pembro) for previously treated advanced hepatocellular carcinoma (aHCC): Meta-analysis of the phase 3 KEYNOTE-240 and KEYNOTE-394 studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT222.

6 Background: KEYNOTE-177 (NCT02563002) evaluated the antitumor activity of pembrolizumab (pembro) vs chemotherapy ± bevacizumab or cetuximab (chemo) as first-line therapy for patients with microsatellite-instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). We present results of the final PFS analysis and analysis of PFS2. Methods: Patients with locally-determined MSI-H/dMMR mCRC and ECOG PS 0 or 1 were randomized 1:1 to first-line pembro 200 mg Q3W for up to 2 years or investigator’s choice of mFOLFOX6 or FOLFIRI Q2W ± bevacizumab or cetuximab (chosen before randomization). Treatment continued until progression, unacceptable toxicity, patient/investigator decision to withdraw, or completion of 35 cycles (pembro only). Patients receiving chemo could crossover to pembro for up to 35 cycles after confirmed PD. Primary end points were PFS (RECIST v1.1, central review) and OS. Secondary end points included ORR (RECIST v1.1, central review) and safety. Exploratory endpoints included duration of response (DOR), PFS2 (time from randomization to progression on next line of therapy or any cause death), and health-related quality of life (HRQoL). Data cutoff was Feb 19, 2020. Results: At data cutoff a total of 307 patients were randomized (153 to pembro, 154 to chemo). Median (range) study follow-up was 32.4 mo (24.0-48.3). Pembro was superior to chemo for PFS (median 16.5 mo vs 8.2 mo; HR 0.60; 95% CI, 0.45-0.80; P= 0.0002). The 12- and 24-mo PFS rates were 55.3% and 48.3% with pembro vs 37.3% and 18.6% with chemo. Confirmed ORR was 43.8% vs 33.1%; median (range) DOR was not reached (2.3+ to 41.4+) with pembro vs 10.6 mo (2.8 to 37.5+) with chemo. PFS2 was longer with pembro vs chemo (median not reached vs 23.5 mo [HR 0.63; 95% CI, 0.45-0.88]). OS analysis is ongoing. Grade ≥3 treatment related adverse event (TRAE) rates were 22% vs 66% for pembro vs chemo. There were no grade 5 TRAEs in the pembro arm and 1 grade 5 intestinal perforation in the chemo arm. HRQoL scores were improved with pembro vs chemo. Conclusions: Pembro provided a statistically significant improvement in PFS vs chemo as first-line therapy for patients with MSI-H/dMMR mCRC, with fewer TRAEs observed. Furthermore, pembro provided a clinically meaningful improvement in PFS2 for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02563002.

BACKGROUND:In the KEYNOTE-177 study, pembrolizumab monotherapy provided statistically significant and clinically meaningful improvements in progression-free survival versus chemotherapy as first-line treatment in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. To further support the efficacy and safety findings of the KEYNOTE-177 study, results of the health-related quality of life (HRQOL) analyses are reported here. METHODS:KEYNOTE-177 is an open-label, randomised, phase 3 trial being done at 192 cancer centres in 23 countries, in patients aged 18 years and older with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had not received previous systemic therapy for metastatic disease. Eligible patients were randomly assigned (1:1) centrally by use of interactive voice response or integrated web response technology to receive pembrolizumab 200 mg intravenously every 3 weeks or investigator's choice chemotherapy (mFOLFOX6 [leucovorin, fluorouracil, and oxaliplatin] or FOLFIRI [leucovorin, fluorouracil, and irinotecan] intravenously every 2 weeks with or without intravenous bevacizumab or cetuximab). Patients and investigators were not masked to treatment assignment. The primary endpoints were progression-free survival (previously reported) and overall survival (data to be reported at the time of the final analysis). HRQOL outcomes were evaluated as prespecified exploratory endpoints. The analysis population comprised all randomly assigned patients who received at least one dose of study treatment and completed at least one HRQOL assessment. HRQOL outcomes were mean change from baseline to prespecified week 18 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29) scale and item scores, and in the EuroQoL 5 Dimensions 3 Levels (EQ-5D-3L) visual analogue scale and health utility scores; the proportion of patients with improved, stable, or deteriorated scores from baseline to prespecified week 18 in EORTC QLQ-C30 scales and items; and time to deterioration in EORTC QLQ-C30 global health status/quality of life (GHS/QOL), physical functioning, social functioning, and fatigue scores and EORTC QLQ-CR29 urinary incontinence scores. The threshold for a small and clinically meaningful mean difference in EORTC QLQ-C30 score was 5-8 points. This study is registered with ClinicalTrials.gov, NCT02563002 and is ongoing; recruitment is closed. FINDINGS:Between Feb 11, 2016, and Feb 19, 2018, 307 patients were enrolled and randomly assigned to receive pembrolizumab (n=153) or chemotherapy (n=154). The HRQOL analysis population comprised 294 patients (152 receiving pembrolizumab and 142 receiving chemotherapy). As of Feb 19, 2020, median time from randomisation to data cutoff was 32·4 months (IQR 27·7-37·8). Least squares mean (LSM) change from baseline to prespecified week 18 showed a clinically meaningful improvement in EORTC QLQ-C30 GHS/QOL scores with pembrolizumab versus chemotherapy (between-group LSM difference 8·96 [95% CI 4·24-13·69]; two-sided nominal p=0·0002). Median time to deterioration was longer with pembrolizumab versus chemotherapy for GHS/QOL (hazard ratio 0·61 [95% CI 0·38-0·98]; one-sided nominal p=0·019), physical functioning (0·50 [95% CI 0·32-0·81]; one-sided nominal p=0·0016), social functioning (0·53 [95% CI 0·32-0·87]; one-sided nominal p=0·0050), and fatigue scores (0·48 [95% CI 0·33-0·69]; one-sided nominal p<0·0001). INTERPRETATION:Pembrolizumab monotherapy led to clinically meaningful improvements in HRQOL compared with chemotherapy in patients with previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These data, along with the previously reported clinical benefits, support pembrolizumab as a first-line treatment option for this population. FUNDING:Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.

The phase 3 KEYNOTE-177 (NCT02563002) study assessed first-line (1L) pembrolizumab (P) vs chemotherapy (C) in patients (pts) with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Results from pts enrolled in Asia are shown. Pts with dMMR/MSI-H mCRC and ECOG PS of 0-1 were randomized 1:1 to 1L P 200 mg Q3W or investigator choice of C (mFOLFOX6/FOLFIRI Q2W +/- bevacizumab/cetuximab). Primary endpoints were PFS per RECIST 1.1 by central review and OS. Secondary endpoints were ORR and safety. Of 307 pts (P, 153; C, 154) in the total population (pop), 48 (P, 22; C, 26) were in the Asia subgroup (sg). At data cutoff (Feb 19, 2020), median follow-up in the Asia sg was 28.7 mo in P vs 23.3 mo in C. Median PFS was 16.5 mo in P vs 8.2 mo in C in total pop (HR 0.60; 95% CI 0.45-0.80) and not reached (NR) vs 10.4 mo in Asia sg (HR 0.65; 95% CI 0.30-1.41). PFS rate at 12 mo was 55.3% in P vs 37.3% in C in total pop and 62.0% vs 45.9% in Asia sg. ORR was 43.8% (17 CR; 50 PR) in P vs 33.1% (6 CR; 45 PR) in C in total pop and 45.5% (2 CR; 8 PR) vs 46.2% (3 CR; 9 PR) in Asia sg. Median DOR (range) was NR (2.3+ to 41.4+) in P vs 10.6 mo (2.8 to 37.5+) in C in total pop and NR (4.4+ to 33.1+) vs 28.8 mo (3.4+ to 35.5+) in Asia sg; 82.6% of pts in P vs 35.3% in C in total pop and 87.5% vs 51.1% in Asia sg had response duration >=24 mo. Treatment-related AEs (TRAEs) occurred in 122 pts (79.7%) in P vs 141 pts (98.6%) in C in total pop and in 14 pts (63.6%) vs 25 pts (100.0%) in Asia sg; grade 3-5 TRAEs occurred in 33 pts (21.6%) vs 94 pts (65.7%) in total pop and in 2 pts (9.1%) vs 20 pts (80.0%) in Asia sg. 1L P provided clinically meaningful improvement in PFS, longer DOR, and improved safety vs C in total pop of KEYNOTE-177. Results from Asia sg were generally consistent with those of total pop of pts with dMMR/MSI-H mCRC.

Paraneoplastic pemphigus (PNP) is an autoimmune bullous dermatosis associated with tumors, first described by Anhalt et al. in 1990. Reports of paraneoplastic pemphigus complicated by follicular lymphoma (FL) are rare in the medical literature. Here, we retrospectively analyze a case of PNP accompanied by FL. The patient was a 54-year-old woman who suffered from PNP associated with FL at the beginning. She had received a pathological diagnosis and was treated with R-CHOP and other drugs. Her mucosal lesions and cutaneous lesions improved, and the FL was in remission. Eleven months later, she died of BO after receiving the diagnosis of PNP. We also review most of the studies and reports about PNP accompanied by FL. We list the clinicopathologic features, therapeutic schedule, and prognosis in order to improve hematologists' understanding and treatment of the diseases.

Pembro monotherapy significantly improved PFS vs standard of care (SOC) chemotherapy as first-line treatment in pts with MSI-H or dMMR mCRC in the phase III KEYNOTE-177 (NCT02563002) study. HRQoL results are reported. Pts with confirmed MSI-H/dMMR mCRC with no prior systemic therapy for mCRC were randomized 1:1 to pembro 200 mg Q3W for up to 2 y or investigator's SOC choice of mFOLFOX6 or FOLFIRI Q2W ± bevacizumab or cetuximab. EORTC QLQ-C30, EORTC QLQ-CR29, and EQ-5D-3L were administered at baseline and at various time points up to 1 y or end of treatment, whichever came first, and at 30 days after treatment discontinuation. Data from pts receiving ≥1 dose of study treatment and completing ≥1 HRQoL assessment were analyzed. Least-squares mean (LSM) score change from baseline to prespecified wk 18, 95% CI, and nominal 2-sided P values were calculated. Time to deterioration (TTD; ≥10-point decline from baseline) was assessed by Kaplan-Meier method and Cox regression model. HRs, 95% CIs, and nominal 1-sided P values are provided. Data for 294 pts (152, pembro; 142 SOC) were available for HRQoL analyses. Compliance at baseline was >90% in pembro and SOC arms for all 3 questionnaires and remained high at wk 18 (>85% and >75%, respectively). LSM change from baseline to wk 18 showed clinically meaningful improvement in QLQ-C30 global health status (GHS)/QoL (LSM difference: 8.96; 95% CI, 4.24-13.69; P=0.0002) and EQ-5D VAS (LSM difference: 7.38; 95% CI, 2.82-11.93; P=0.0016) for pts receiving pembro vs SOC. Prolonged TTD for pts receiving pembro vs SOC was observed for GHS/QoL (HR, 0.61; 95% CI, 0.38-0.98; P=0.0195), physical functioning (HR, 0.50; 95% CI, 0.32-0.81; P=0.0016), social functioning (HR, 0.53; 95% CI, 0.32-0.87; P=0.0050), and fatigue (HR, 0.48; 95% CI, 0.33-0.69; P≤0.0001). Pembro monotherapy demonstrated clinically meaningful improvements in HRQoL vs SOC chemotherapy in pts with previously untreated MSI-H/dMMR mCRC.

Malignant peripheral nerve sheath tumor (MPNST) is a rare malignant soft tissue tumor that accounts for approximately 5% of all soft tissue sarcomas. This tumor originates from the peripheral nerves and occurs mainly in the limbs, head and neck, and spine. As a more aggressive tumor, it has higher recurrence and metastasis rates, and patient prognosis is poor. MPNST has a variety of histologic subtypes such as classic MPNST and epithelioid malignant peripheral nerve sheath tumors (EMPNSTs). Due to the diversity of histologic types, these tumors have a high histologic similarity to other benign and malignant soft tissue tumors. Due to the lack of specific diagnostic criteria, pathologic diagnosis is extremely difficult, since these tumors should be differentiated from other sarcomas according to the site of tumor occurrence and morphologic characteristics, which can be determined using immunohistochemical staining. The specific pathogenesis of MPNST is not well understood. Studies have shown that approximately 50% of MPNSTs are closely related to neurofibromatosis I (NF1), while other causes of these tumors include radiotherapy. Herein, we report the first case of a mixed tumor composed of classic MPNST and EMPNST elements in the inguinal region.

KEYNOTE-177 (NCT02563002) was a randomized, open-label phase III study of first-line (1L) pembrolizumab (P) vs chemotherapy (C) in patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). P significantly improved progression-free survival (PFS) vs C in KEYNOTE-177; the Asia subgroup (sg) analysis is presented. Pts with previously untreated dMMR/MSI-H stage IV mCRC and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned 1:1 to P 200 mg every 3 weeks or investigator's choice of C (mFOLFOX6/FOLFIRI every 2 weeks ± bevacizumab/cetuximab). Primary endpoints were PFS per Response Evaluation Criteria in Solid Tumors version 1.1 by central review and overall survival. Hazard ratio and 95% confidence interval of PFS were based on Cox regression model with Efron's method of tie handling with treatment as a covariate. PFS and duration of response (DOR) were assessed per Kaplan-Meier analysis. Secondary endpoints were overall response rate (ORR) and safety. Confirmed responses are shown. Of 307 pts enrolled in the study, 153 were randomly assigned to P and 154 to C. Of the 307 pts, 48 were enrolled from Asia (P, n=22; C, n=26). At data cutoff (19 Feb 2020), median follow-up in the Asia sg was 28.7 mo in the P arm vs 23.3 mo in the C arm. Efficacy and safety in the total population (pop) and Asia sg are presented in the table. 1L P compared with C showed clinically meaningful improvement in PFS, led to more durable responses and improved safety profile in the total pop of pts with dMMR/MSI-H mCRC. The Asia sg results were generally consistent with those of the total pop of KEYNOTE-177Table: 112PP (total pop)C (total pop)P (Asia sg)C (Asia sg)ITT pop, n1531542226Median PFS, mo16.58.2NR10.4HR (95% CI)0.60 (0.45-0.80)--0.65 (0.30-1.41)--12-mo PFS rate, %55.337.362.045.9ORR, n (%)67 (43.8)51 (33.1)10 (45.5)12 (46.2)CR, n (%)17 (11.1)6 (3.9)2 (9.1)3 (11.5)PR, n (%)50 (32.7)45 (29.2)8 (36.4)9 (34.6)Median DOR, (range), moNR (2.3+-41.4+)10.6 (2.8-37.5+)NR (4.4+-33.1+)28.8 (3.4+-35.5+)Response duration ≥24 mo, %82.635.387.551.1APAT pop, n1531432225Any grade TRAE, n (%)122 (79.7)141 (98.6)14 (63.6)25 (100.0)Grade 3-5 TRAE, n (%)33 (21.6)94 (65.7)2 (9.1)20 (80.0)APAT, all patients as treated; NR, not reached; TRAE, treatment-related adverse event. Open table in a new tab .

Sclerosing pneumocytoma (SP) is a rare and benign tumor predominantly occurring in Asian women, easily misdiagnosed by imaging and pathologic frozen diagnosis during surgery because of its diverse histomorphology (4 structures, 2 types of cells). It may form multiple tumors. When SP is combined with carcinoid, adenoma, or other tumors (although rare), diagnosis is more complicated. SP mixed with carcinoid tumor is rare. At present, only 4 cases have been reported in English literature. Here, we report a case of sclerosing pneumocytoma combined not only with carcinoid, but also with clear cell adenoma of the lung. The patient was a 52-year-old female and CT found a nodule in the middle lobe of the right lung. SP was not excluded by intraoperative frozen section diagnosis. The above 3 components formed a 1.4 cm nodule. The related literature is reviewed to strengthen the understanding of SP, and aid clinicopathological diagnosis.

Tauopathy has been linked to the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson disease (PD). Our previous research indicates that interactions between dopamine and oxidative damage in the striatum are involved in the late-stages of neurodegenerative diseases, and distinct density change patterns in translocator protein (TSPO) may associate with microglia dystrophy in neurodegeneration. We investigated whether microglia dystrophy is associated with oxidative damage thus effecting the pathological spread of tau and finally tau proteostasis disturbances. This study investigated TSPO and Tau densities in the caudate and putamen of 65 postmortem human brains using autoradiography in PD, PDD, DLB, AD, and controls. Sample concentrations of myeloperoxidase (MPO), poly (ADP-Ribose) (PAR), and triggering receptors expressed on myeloid cell 2 (TREM2) were determined via ELISA. All samples were genotyped for TSPO, TREM2, and bridging integrator 1 (BIN1) using SNP Assays. TREM2 gene variants were absent. The associations between TSPO and BIN1 gene polymorphisms and TSPO, MPO, TREM2, and PAR level variations were found - potentially elucidating the interrelationship of relevant biological events. Significantly lower PAR levels were found in all LBD caudate samples (PD, PDD, and DLB). TSPO and Tau densities in LBD brains were remarkably lower, these levels increased in AD cases. These data provide evidence that microglia dystrophy in LBD cases, in contrast to AD, are mainly a result of oxidative damage induced by misfolded tau proteins causing reduced tau propagation and proteostasis disturbances. Results indicate BIN1 gene G allele SNPs as a potential risk factor for tauopathy.

BACKGROUNDProgrammed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown.METHODSIn this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival.RESULTSAt the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group.CONCLUSIONSPembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.).

The rapid development of castration-resistant prostate cancer (CRPC) is a poor prognostic sign for loco-regionally advanced prostate cancer. Non-metastatic CRPC (nmCRPC) with bulky regional lymph node metastases is extremely rare and difficult to treat clinically without reported case. We present a case of a 72-year-old man with locally advanced prostate cancer with bulky lymph node metastases (53 mm × 77 mm × 67 mm), developing nmCRPC after 9-month ADT treatment. Immunohistochemistry (IHC) tests found partially positive MUC1 and negative BRCA1 expression in the initial biopsy specimens. Next-generation sequence analysis on the blood specimen after CRPC predicted a good tolerance to docetaxel. According to the multidisciplinary team recommendations, he was administrated docetaxel 75 mg/m2 on day 1 every 21 days for 6 cycles, and subsequently radiotherapy, with the delivery of a total dose of 67.5, 60-65 and 47.5 Gy in 25 fractions to the prostate, the enlarged lymph nodes and the whole pelvis respectively. Over a follow-up of 50 months, his disease has achieved good local control and he is alive without evidence of distant metastases or late adverse events. This case highlights individualized and multimodal therapy of intensification of systemic therapy and timely application of radiotherapy in such rare condition.