Neoadjuvant camrelizumab plus apatinib for locally advanced microsatellite instability-high or mismatch repair-deficient colorectal cancer (NEOCAP): a single-arm, open-label, phase 2 study.

BACKGROUND: PD-1 blockade is highly efficacious for mismatch repair-deficient colorectal cancer in both metastatic and neoadjuvant settings. We aimed to explore the activity and safety of neoadjuvant therapy with PD-1 blockade plus an angiogenesis inhibitor and the feasibility of organ preservation in patients with locally advanced mismatch repair-deficient colorectal cancer. METHODS: We initiated a single-arm, open-label, phase 2 trial (NEOCAP) at Sun Yat-sen University Cancer Center and the Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China. Patients aged 18-75 years with untreated mismatch repair-deficient or microsatellite instability-high or POLE/POLD1-mutated locally advanced colorectal cancer (cT3 or N+ for rectal cancer, and T3 with invasion ≥5mm or T4, with or without N+ for colon cancer) and an Eastern Cooperative Oncology Group performance score of 0-1 were enrolled and given 200 mg camrelizumab intravenously on day 1 and 250 mg apatinib orally from day 1-14, every 3 weeks for 3 months followed by surgery or 6 months if patients did not have surgery. Patients who had a clinical complete response did not undergo surgery and proceeded with a watch-and-wait approach. The primary endpoint was the proportion of patients with a pathological or clinical complete response. Eligible enrolled patients who received at least one cycle of neoadjuvant treatment and had at least one tumour response assessment following the baseline assessment were included in the activity analysis, and patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04715633) and is ongoing. FINDINGS: Between Sept 29, 2020, and Dec 15, 2022, 53 patients were enrolled; one patient was excluded from the activity analysis because they were found to be mismatch repair-proficient and microsatellite-stable. 23 (44%) patients were female and 29 (56%) were male. The median follow-up was 16·4 (IQR 10·5-23·5) months. 28 (54%; 95% CI 35-68) patients had a clinical complete response and 24 of these patients were managed with a watch-and-wait approach, including 20 patients with colon cancer and multiple primary colorectal cancer. 23 (44%) of 52 patients underwent surgery for the primary tumour, and 14 (61%; 95% CI 39-80) had a pathological complete response. 38 (73%; 95% CI 59-84) of 52 patients had a complete response. Grade 3-5 adverse events occurred in 20 (38%) of 53 patients; the most common were increased aminotransferase (six [11%]), bowel obstruction (four [8%]), and hypertension (four [8%]). Drug-related serious adverse events occurred in six (11%) of 53 patients. One patient died from treatment-related immune-related hepatitis. INTERPRETATION: Neoadjuvant camrelizumab plus apatinib show promising antitumour activity in patients with locally advanced mismatch repair-deficient or microsatellite instability-high colorectal cancer. Immune-related adverse events should be monitored with the utmost vigilance. Organ preservation seems promising not only in patients with rectal cancer, but also in those with colon cancer who have a clinical complete response. Longer follow-up is needed to assess the oncological outcomes of the watch-and-wait approach. FUNDING: The National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Long-Term Outcomes of dMMR/MSI-H Rectal Cancer Treated With Anti-PD-1-Based Immunotherapy as Curative-Intent Treatment.

BACKGROUND: Neoadjuvant anti-PD-1 therapy has shown encouraging efficacy in patients with deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) locally advanced rectal cancer (LARC), which suggests its potential as a curative-intent therapy and a promising treatment option for organ preservation. We aimed to investigate the long-term outcomes of patients with dMMR/MSI-H LARC who experienced clinical complete response (cCR) after anti-PD-1 therapy. METHODS: We retrospectively analyzed patients with dMMR/MSI-H LARC who achieved cCR and received nonoperative management following neoadjuvant anti-PD-1-based treatment from 4 Chinese medical centers. Patients were followed up for at least 1 year after they achieved cCR, their clinical data were collected, and survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: A total of 24 patients who achieved cCR and received nonoperative management from March 2018 to May 2022 were included, with a median age of 51.0 years (range, 19.0-77.0 years). The median treatment course to reach cCR was 6.0 (range, 1.0-12.0). Fifteen patients (62.5%) continued their treatments after experiencing cCR, and the median treatment course was 17.0 (range, 3.0-36.0). No local regrowth or distant metastasis was observed in a median follow-up time of 29.1 months (range, 12.6-48.5 months) after cCR. The 3-year disease-free and overall survivals were both 100%. CONCLUSIONS: Patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR following anti-PD-1-based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate these findings.

Neoadjuvant Immunotherapy Leads to Major Response and Low Recurrence in Localized Mismatch Repair-Deficient Colorectal Cancer.

BACKGROUND: Our study aimed to evaluate the efficacy and feasibility of neoadjuvant anti-PD-1 treatment for localized mismatch repair-deficient (dMMR) colorectal cancer (CRC). PATIENTS AND METHODS: The study cohort included patients with localized dMMR CRC who received PD-1 inhibitors as neoadjuvant therapy from 3 medical centers in Southern China. Main eligibility criteria included age between 18 and 75 years, ECOG performance status of 0 or 1, and receipt of ≥2 doses of PD-1 inhibitors. RESULTS: A total of 73 patients were included. Most of the tumors were locally advanced, including 19 (26.0%) T4a and 29 (39.7%) T4b. Most patients (79.5%) received PD-1 inhibitor monotherapy. Objective response per radiologic assessment was achieved in 62 (84.9%) patients, including 17 (23.3%) with complete response (CR) and 45 (61.6%) with partial response, with a median time to response of 9.6 weeks. Patients with T4a/4b disease had a similar response rate as those with T2-3 disease (84.0% vs 85.4%; P=.999). As of writing, a total of 50 patients have undergone surgery. Pathologic CR was achieved in most (57.1%) patients and remained high (59.5%) even among the 38 patients with T4a/4b disease. The 17 patients with CR did not undergo surgery and adopted a watch-and-wait strategy. After a median follow-up of 17.2 months (range, 3.4-45.1 months), the overall median recurrence-free and overall survivals were not reached. Among patients undergoing surgery or achieving CR, the 2-year tumor-specific disease-free and overall survival rates were both 100%. During neoadjuvant treatment, grade 3-4 adverse events occurred in 8 patients; 4 required acute intervention. Severe postoperative complications were recorded in 4 patients, 3 of whom required a second surgery. CONCLUSIONS: Neoadjuvant therapy with PD-1 blockade is highly effective for localized dMMR CRC, with an acceptable safety profile and low recurrence rate. This treatment holds promise for becoming the new standard of care for localized dMMR CRCs.

Neoadjuvant Immune Checkpoint Inhibition Improves Organ Preservation in T4bM0 Colorectal Cancer With Mismatch Repair Deficiency: A Retrospective Observational Study.

BACKGROUND: Colorectal cancer with mismatch repair deficiency is usually less aggressive and associated with a lower risk of distant metastasis. Immune checkpoint inhibition, rather than traditional chemoradiotherapy, has shown great advantages in treating such patients. OBJECTIVE: This study aimed to verify the hypothesis that locally very advanced (T4b) colorectal cancer without distant metastases might present with higher probability of mismatch repair deficiency and be more sensitive to neoadjuvant immune checkpoint inhibition. DESIGN: This study was designed as a single-center retrospective observational study. SETTINGS: The study was conducted in a tertiary referral center in China. PATIENTS: The study included patients who were clinically diagnosed with T4bM0 colorectal cancer from 2008 to 2019. MAIN OUTCOME MEASURES: Clinicopathological characteristics, mismatch repair status, and survival outcomes of patients with mismatch repair deficiency were analyzed. RESULTS: A total of 268 patients were included. The incidence of patients with mismatch repair deficiency in the T4bM0 population was 27.6% (75/268), with 84.0% (63/75) in the colon and 16.0% (12/75) in the rectum. For tumors located in the proximal colon, 45.0% (50/111) exhibited mismatch repair deficiency, whereas the incidence of mismatch repair deficiency in sigmoid colon cancer and rectal cancer was only 15.9% (25/157). Neoadjuvant immune checkpoint inhibition significantly reduced the open surgery rate ( p = 0.000) and multivisceral resection rate ( p = 0.025). The pathological complete remission rate in the neoadjuvant immune checkpoint inhibition group was significantly higher than that in neoadjuvant chemoradiotherapy/chemotherapy group (70.0% vs 0%; p = 0.004). No tumor downstaging was observed after neoadjuvant chemotherapy. Neoadjuvant immune checkpoint inhibition provided significantly better disease-free survival ( p = 0.0078) and relatively longer overall survival ( p = 0.15) than other groups. LIMITATIONS: This study is limited by the possible selection bias and small sample size. CONCLUSIONS: Our data depicted the high incidence of mismatch repair deficiency in T4bM0 mismatch repair deficiency and the effectiveness of the neoadjuvant immune checkpoint inhibition group in organ preservation. Precision oncology requires identification of the protein status of mismatch repair at initial diagnosis to make a rational treatment decision for these patients. See Video Abstract at http://links.lww.com/DCR/B952 . LA INHIBICIN DEL PUNTO DE CONTROL INMUNITARIO NEOADYUVANTE MEJORA LA PRESERVACIN DE RGANOS EN EL CNCER COLORRECTAL TBM CON DEFICIENCIA DE REPARACIN DE ERRORES DE COINCIDENCIA UN ESTUDIO OBSERVACIONAL RETROSPECTIVO: ANTECEDENTES:Los pacientes con cáncer colorrectal con deficiencia en la reparación de desajustes suelen (dMMR) ser menos agresivos y se asocian con un menor riesgo de metástasis a distancia. La inhibición del punto de control inmunitario, en lugar de la quimiorradioterapia tradicional, ha mostrado grandes ventajas en el tratamiento de estos pacientes.OBJETIVO:Este estudio tuvo como objetivo verificar nuestra hipótesis de que el CCR localmente muy avanzado (T4b) sin metástasis a distancia podría presentarse con una mayor probabilidad de dMMR y ser más sensible a la inhibición del punto de control inmunitario neoadyuvante.DISEÑO:Este estudio fue diseñado como un estudio observacional retrospectivo de un solo centro.CONFIGURACIÓN:El estudio se realizó en un centro de referencia terciario en China.PACIENTES:Se incluyeron pacientes con diagnóstico clínico de CCR T4bM0 desde 2008 hasta 2019.PRINCIPALES MEDIDAS DE RESULTADO:Se analizaron las características clinicopatológicas, el estado de MMR y los resultados de supervivencia de los pacientes con dMMR.RESULTADOS:Se incluyeron un total de 268 pacientes. La incidencia de dMMR en la población T4bM0 fue del 27,6% (75/268), con un 84,0% (63/75) en colon y un 16,0% (12/75) en recto. Para los tumores ubicados en el colon proximal, el 45,0% (50/111) exhibió dMMR, mientras que la incidencia de dMMR en el cáncer de colon sigmoideo y el cáncer de recto fue solo del 15,9% (25/157). La inhibición del punto de control inmunitario neoadyuvante redujo significativamente la cirugía abierta y la tasa de resección multivisceral ( p = 0,000 y p = 0,025, respectivamente). La tasa de PCR en el grupo de inhibición del punto de control inmunitario neoadyuvante fue significativamente mayor que en el grupo de quimiorradioterapia/quimioterapia neoadyuvante (70,0% frente a 0%, p = 0,004). No se observó reducción del estadio del tumor después de la quimioterapia neoadyuvante. La inhibición del punto de control inmunitario neoadyuvante proporcionó una supervivencia sin enfermedad significativamente mejor ( p = 0,0078) y una supervivencia general relativamente más larga ( p = 0,15) que otros grupos.LIMITACIONES:Este estudio está limitado por el posible sesgo de selección y el pequeño tamaño de la muestra.CONCLUSIONES:Nuestros datos representan la alta incidencia de dMMR en T4bM0 CRC y la eficacia del grupo de inhibición del punto de control inmunitario neoadyuvante en la preservación de órganos. La oncología de precisión requiere la identificación del estado de la proteína MMR en el diagnóstico inicial para tomar una decisión de tratamiento racional para estos pacientes especiales. Consulte el Video Resumen en http://links.lww.com/DCR/B952 . (Traducción-Dr. Yesenia Rojas-Khalil ).

Universal germline testing among patients with colorectal cancer: clinical actionability and optimised panel.

PURPOSE: Universal germline testing in patients with colorectal cancer (CRC) with a multigene panel can detect various hereditary cancer syndromes. This study was performed to understand how to choose a testing panel and whether the result would affect clinical management. METHODS: We prospectively enrolled 486 eligible patients with CRC, including all patients with CRC diagnosed under age 70 years and patients with CRC diagnosed over 70 years with hereditary risk features between November 2017 and January 2018. All participants received germline testing for various hereditary cancer syndromes. RESULTS: The prevalence of germline pathogenic variants (PVs) in cancer susceptibility genes was 7.8% (38/486), including 25 PVs in genes with high-risk CRC susceptibility (the minimal testing set) and 13 PVs in genes with moderate-risk CRC susceptibility or increased cancer risk other than CRC (the additional testing set). All the clinically relevant PVs were found in patients diagnosed under age 70 years. Among them, 11 patients would not have been diagnosed if testing reserved to present guidelines. Most (36/38) of the patients with PVs benefited from enhanced surveillance and tailored treatment. PVs in genes from the minimal testing set were found in all age groups, while patients carried PVs in genes from the additional testing set were older than 40 years. CONCLUSION: Universal germline testing for cancer susceptibility genes should be recommended among all patients with CRC diagnosed under age 70 years. A broad panel including genes from the additional testing set might be considered for patients with CRC older than 40 years to clarify inheritance risks. TRIAL REGISTRATION NUMBER: NCT03365986.

UPLC-MS/MS method for the determination of voriconazole plasma concentration from pediatric patients with hematologic tumors: An application toward personalized therapy.

Untreated invasive fungal infection is one of the important risk factors affecting the prognosis of pediatric patients with hematologic tumors. Voriconazole (VOR) is the first-line antifungal drug for the treatment of Aspergillus infections. In order to reduce the risk of adverse drug reactions while producing an ideal antifungal effect, therapeutic drug monitoring was performed to maintain the VOR plasma concentration in a range of 1,000-5,500 ng/ml. In the present study, a reliable, accurate, sensitive and quick ultra-high performance liquid chromatograph-tandem mass spectrometry (UPLC-MS/MS) method was developed for the determination of the VOR level. Protein precipitation was performed using acetonitrile, and then the chromatographic separation was carried out by UPLC using a C18 column with the gradient mobile phases comprising 0.1% methanoic acid in acetonitrile (A) and 0.1% methanoic acid in water (B). In the selective reaction monitor mode, the mass spectrometric detection was carried out using an TSQ Endura triple quadruple mass spectrometer. The performance of this UPLC-MS/MS method was validated as per the National Medical Products Administration for Bioanalytical Method Validation. Additionally, the plasma concentrations of VOR in pediatric patients with hematologic tumors were detected using this method, and the analyzed results were used for personalized therapy.

Barrier performance and biodegradability of antibacterial poly(butylene adipate-co-terephthalate) nanocomposites reinforced with a new MWCNT-ZnO nanomaterial.

A new nanomaterial or nano-filler in the form of multiwalled carbon nanotube-zinc oxide (MWCNT-ZnO) was synthesized for the purpose of modifying poly(butylene adipate-co-terephthalate) (PBAT) and its derivative (modified PBAT or MPBAT) through a melt-blending method (MPBAT was obtained by introducing maleic anhydride groups into PBAT). The effect of the new nano-filler on the properties of resultant nanocomposites was determined from the characterization of mechanical properties, morphology, crystallinity, thermal stability, barrier properties, hydrophilicity, conductivity, antibacterial property, and biodegradability. The results showed that MPBAT nanocomposites had stronger mechanical properties, better barrier properties, and higher electrical conductivity than PBAT nanocomposites. Scanning electron microscopy illustrated that MWCNT-ZnO had better compatibility with MPBAT than with PBAT. At 0.2% MWCNT-ZnO, the MPBAT/MWCNT-ZnO nanocomposite film exhibited the greatest mechanical properties (17.74% increase in tensile strength, 22.17% in yield strength, and 14.29% in elongation at break). When the MWCNT-ZnO content was 0.4%, the nanocomposite film demonstrated the best water vapor barrier ability (an increase of 30.4%). The MPBAT/MWCNT-ZnO film with 0.6% MWCNT-ZnO turned out to have the best oxygen barrier performance (an increase of 130% relative to pure PBAT). It was shown from the results of antibacterial evaluation that the new nanomaterial could impart PBAT and MPBAT with antibacterial activity. The biodegradability tests indicated that an MWCNT-ZnO content of 0.2% could slightly reduce the biodegradability, and when the content was higher than 0.2%, the weight loss rate would increase.

[A comprehensive analysis of potential prognostic biomarkers for MYCN-amplified neuroblastoma].

OBJECTIVE: To study the differentially expressed mRNAs between MYCN-amplified neuroblastoma (NB) and non-amplified NB, to screen out the genes which can be used to predict the prognosis of MYCN-amplified NB, and to analyze their value in predicting prognosis. METHODS: NB transcriptome data and the clinical data of children were obtained from the TARGET database. According to the presence or absence of MYCN amplification, the children were divided into two groups: MYCN amplification (n=33) and non-MYCN amplification (n=121). The expression of mRNAs was compared between the two groups to obtain differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analysis was performed to investigate the main functions of DEGs. The Cox proportional-hazards regression model analysis was used to investigate the genes influencing the prognosis of MYCN-amplified NB. The children were divided into a high-risk group (n=77) and a low-risk group (n=77) based on the median of risk score. A survival analysis was used to compare survival rate between the two groups. The receiver operating characteristic (ROC) curve was used to investigate the value of risk score in predicting the prognosis of children with MYCN-amplified NB. RESULTS: A total of 582 DEGs were screened out, and they were involved in important biological functions such as ribosome composition, expression of cell adhesion molecules, and activity of membrane receptor protein. The multivariate Cox regression model analysis showed that FLVCR2, SCN7A, PRSS12, NTRK1, and XAGE1A genes had a marked influence on the prognosis of the children with NB in the MYCN amplification group (P<0.05). The survival analysis showed that the high-risk group had a significantly lower overall survival rate than the low-risk group (P<0.05). The ROC curve analysis showed that risk score had a certain value in predicting the prognosis of the children with NB in the MYCN amplification group (P<0.05), with an area under the ROC curve of 0.729, an optimal cut-off value of 1.316, a sensitivity of 53.2%, and a specificity of 84.4%. CONCLUSIONS: The mRNA expression of FLVCR2, SCN7A, PRSS12, NTRK1, and XAGE1A genes can be used as biomarkers to predict the prognosis of MYCN-amplified NB, which can help to refine clinical risk stratification.

Liver protection strategies in liver transplantation.

BACKGROUND: Liver transplantation is the therapy of choice for patients with end-stage liver diseases. However, the gap between the low availability of organs and high demand is continuously increasing. Innovative strategies for organ protection are necessary to expand donor pool and to achieve better outcomes for liver transplantation. The present review analyzed and compared various strategies of liver protection. DATA SOURCES: Databases such as PubMed, Embase and Ovid were searched for the literature related to donor liver protection strategies using following key words: "ischemia reperfusion injury", "graft preservation", "liver transplantation", "machine perfusion" and "conditioning". Of the 146 studies identified, only those with cutting edge strategies were analyzed. RESULTS: A variety of therapeutic approaches were proposed to alleviate graft ischemia/reperfusion injury, which included static cold storage, machine perfusion (hypothermic, normothermic and subnormothermic), manual conditioning (pre, post and remote), and pharmacological conditioning. Evidences from animal experiments and clinical trials suggested that all these strategies could potentially protect liver graft; however, their clinical applications are limited partially due to their own disadvantages. CONCLUSIONS: There are a plenty of methods suggested to decrease the degree of donor liver transplantation-related injury. However, none of these approaches is perfect in clinical practice. More translational researches (molecular and clinical studies) are needed to improve the techniques in liver graft protection.

Composition-Aware Image Steganography Through Adversarial Self-Generated Supervision.

Steganography is an important and prevailing information hiding tool to perform secret message transmission in an open environment. Existing steganography methods can mainly fall into two categories: predefined rule-based and data-driven methods. The former is susceptible to the statistical attack, while the latter adopts the deep convolution neural networks to promote security. However, deep learning-based methods suffer from perceptible artificial artifacts or deep steganalysis. In this article, we introduce a novel composition-aware image steganography (CAIS) to guarantee both visual security and resistance to deep steganalysis through the self-generated supervision. The key innovation is an adversarial composition estimation module, which has integrated the rule-based composition method and generative adversarial network to help synthesize steganographic images with more naturalness. We first perform a rule-based image blending method to obtain infinite synthetically data-label pairs. Then, we utilize an adversarial composition estimation branch to recognize the message feature pattern from the composite image based on these self-generated data-label pairs. Through the adversarial training, we force the steganography function to synthesize steganographic images, which can fool the composition estimation network. Thus, the proposed CAIS can achieve better information hiding and higher security to resist deep steganalysis. Furthermore, an effective global-and-part checking is designed to alleviate visual artifacts caused by hiding secret information. We conduct a comprehensive analysis of CAIS from various aspects (e.g., security and robustness) to verify the superior performance of the proposed method. Comprehensive experimental results on three large-scale widely used datasets have demonstrated the superior performance of our CAIS compared with several state-of-the-art approaches.

S14G-humanin confers cardioprotective effects against chronic adrenergic and pressure overload-induced heart failure in mice.

S14G-humanin (HNG), an analog of the mitochondria-derived peptide humanin, has demonstrated protective effects against various cardiovascular diseases. However, the specific pharmacological effects of HNG in heart failure (HF) have not been previously reported. Therefore, in this study, we aimed to investigate the potential protective effect of HNG in HF using a mouse model. HF was induced in mice through intraperitoneal injection of isoproterenol or transverse aortic constriction, followed by separate administration of HNG to assess its therapeutic impact. Our results revealed that HNG treatment significantly delayed the onset of cardiac dysfunction and structural remodeling in the HF mouse model. Furthermore, HNG administration was associated with reduced infiltration of inflammatory cells, improved myocardial fibrosis, and attenuation of cardiomyocyte apoptosis in the treated cardiac tissues. Additionally, we identified the involvement of the transforming growth factor-beta signaling pathway in the beneficial effects of HNG in isoproterenol-induced HF mice. Collectively, these findings underscore the therapeutic potential of HNG in preventing the progression of HF, as demonstrated in two distinct HF mouse models.

Efficacy of PD-1 inhibitors for colorectal cancer and polyps in Lynch syndrome patients.

BACKGROUND: Programmed death-1 (PD-1) inhibitor is effective for colorectal cancer (CRC) with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). We aimed to explore its effects on CRCs and colonic polyps in Lynch syndrome (LS) patients. METHODS: LS patients with CRC who had evaluable tumours and received at least 2 cycles of PD-1 inhibitors were retrospectively included. PD-1 inhibitors were given as a monotherapy or in combination with other therapies, including anticytotoxic T-lymphocyte-associated antigen-4 treatment, radiotherapy, chemotherapy, and targeted therapy. Correlations of treatment responses with clinicopathological characteristics and genomic profiles were analysed. RESULTS: A total of 75 LS patients were included, with a median age of 39 years. The median duration of follow-up was 27 months (range, 3-71). The objective response rate (ORR) was 70.7%, including 28.0% (n = 21) complete responses and 42.7% (n = 32) partial responses. Four of five cases of LS CRCs displaying proficient MMR (pMMR) or microsatellite stable (MSS) were not responsive. Mucinous/signet-ring cell differentiation was associated with a lower ORR (P = 0.013). The 3-year overall survival and progression-free survival were 91.2% and 82.2%, respectively. A polyp was detected in 26 patients during surveillance. Seven adenomas disappeared after treatment, and they were all larger than 7 mm. CONCLUSION: PD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs, but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC. Large LS adenomas may also be eliminated by anti-PD-1 treatment. DATA AVAILABILITY STATEMENT: Due to the privacy of patients, the related data cannot be available for public access but can be obtained from Pei-Rong Ding (dingpr@sysucc.org.cn) upon reasonable request. The key raw data have been uploaded to the Research Data Deposit public platform (www.researchdata.org.cn).

[Effects of two implant systems on peri-implant soft tissue].

PURPOSE: To investigate the effect of different implant systems on peri-implant soft tissue. METHODS: Forty patients requiring single implant therapy in posterior teeth at Dental and Ophthalmic Clinic of Putuo District from December 2020 to February 2021 were selected. Ten patients were implanted with bone level implants and 30 patients with soft tissue level implants. Periodontal exploration was performed at the buccal side, lingual side, mesial and distal axial angle of the implants, and the gingival crevicular fluid of these locations were taken to detect the enzyme level. The probing depth, aspartate aminotransferase (AST) and alkaline phosphatase (ALP) level of the two groups were compared at the day, 3 months, 6 months and 12 months after crown restoration. Statistical analysis was completed by SPSS 17.0 software package. RESULTS: The probing depth and ALP level of soft tissue level implants were significantly lower than those of bone level implants at the day, 3 months, 6 months and 12 months after crown restoration(P＜0.05). At the day when crown restoration was accomplished, AST of soft tissue implant was significantly lower than that of bone level implant(P＜0.05). AST in gingival crevicular fluid of bone level implants decreased rapidly in the following three time periods, and close to that of the soft tissue level implants(P＞0.05) at last. CONCLUSIONS: Both bone level implants and soft tissue level implants have good clinical effects, but peri-implant soft tissues of the soft tissue level implants show better stability.

Multi-Modality MR Image Synthesis via Confidence-Guided Aggregation and Cross-Modality Refinement.

Magnetic resonance imaging (MRI) can provide multi-modality MR images by setting task-specific scan parameters, and has been widely used in various disease diagnosis and planned treatments. However, in practical clinical applications, it is often difficult to obtain multi-modality MR images simultaneously due to patient discomfort, and scanning costs, etc. Therefore, how to effectively utilize the existing modality images to synthesize missing modality image has become a hot research topic. In this paper, we propose a novel confidence-guided aggregation and cross-modality refinement network (CACR-Net) for multi-modality MR image synthesis, which effectively utilizes complementary and correlative information of multiple modalities to synthesize high-quality target-modality images. Specifically, to effectively utilize the complementary modality-specific characteristics, a confidence-guided aggregation module is proposed to adaptively aggregate the multiple target-modality images generated from multiple source-modality images by using the corresponding confidence maps. Based on the aggregated target-modality image, a cross-modality refinement module is presented to further refine the target-modality image by mining correlative information among the multiple source-modality images and aggregated target-modality image. By training the proposed CACR-Net in an end-to-end manner, high-quality and sharp target-modality MR images are effectively synthesized. Experimental results on the widely used benchmark demonstrate that the proposed method outperforms state-of-the-art methods.

[Comparative study on the accuracy of implant-borne single restoration by two production processes with Ti-base].

PURPOSE: To study on the accuracy of implant-borne single restoration by two production processes with Ti-base to provide experimental data for proper processes of single implant-borne restoration. METHODS: Thirty patients were selected with single posterior teeth missing from the Department of Oral Implantology of Shanghai Putuo District Eye Disease and Dental Disease Prevention and Treatment Institute. The patients were taken 2 traditional impressions clinically for two plaster model equipped with implant analogue. These models were then divided into 2 groups according to different production processes. The experimental group was scanned with the scan body installed in the model implant analogue, while the control group was scanned directly on the Ti-base abutment installed in the model implant analogue. The implant-borne single restorations of the two groups were cut along the buccal-lingual side and the distance between the measuring point to the Ti-Base abutment was observed by electron microscopy. In addition, the breaking limit of zirconia crown was observed, universal test machine was used to load direct force to the crown. SPSS 22.0 software package was used for data analysis. RESULTS: The gap between the implant-borne single restoration to the Ti-base abutment of the experimental group was significantly smaller than that of the control group. The difference between the two groups was statistically significant (P<0.05). However, by testing the breaking limit of zirconia crown, there was no significant difference(P>0.05). CONCLUSIONS: Using scan body to transfer the implant position and Ti-base abutment data information to the digital dental design software is more accurate and reliable than directly scanning the Ti-base on the model analogue. Using scan body is recommended for processing and manufacture of implant-borne singe restoration.

[Clinical effectiveness evaluation of gingival recession by using perioscope as an adjunct to non-surgical periodontal therapy].

PURPOSE: To investigate the effects of ultrasonic scaling and root planning(SRP) assisted by perioscope on gingival recession of maxillary lateral incisor. METHODS: Thirty-six outpatients with moderate to advanced chronic periodontitis from the Department of Periodontology at Dental and Ophthalmic Clinic of Putuo District from June 2020 to December 2020 were collected as research objects. Periodontal treatment was carried out according to a single-blind split-mouth self-control design randomly with(experimental group, namely perioscope group) or without(control group, namely SRP group) periodontal endoscope．The labial periodontal probing depth (PD), labial attachment loss (AL) and gingival recession(GR) in the maxillary lateral incisors were recorded at baseline, 3 and 6 months, and compared among groups by SPSS 22.0 software package. RESULTS: There was no significant difference between perioscope group and SRP group at baseline. ΔGR (the recession extent of gum within two observation time) in perioscope group was significantly smaller than that in SRP group at 3 months（P<0.05）. There was no significant difference in other periodontal indicators at 3 and 6 months between the 2 groups after treatment, but it can be found that the degree of PD reduction and AL improvement in perioscope group was more than those in SRP group, this trend was most obvious at 3 months. PD and AL were significantly different between baseline and 3 months or 6 months in the two groups. There were significant differences in ΔGR at 3 months and 6 months between the two groups. CONCLUSIONS: Compared with routine SRP, the extent of root surface debridement with perioscope-assisted SRP is thorough and less invasive, and the reduction of gingival recession of labial surface of maxillary lateral incisor at 3 months is significantly less; thus, the aesthetic effect is prominent.

Anti-PD-1-based immunotherapy as curative-intent treatment in dMMR/MSI-H rectal cancer: A multicentre cohort study.

BACKGROUND: In a portion of patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) rectal cancer, clinical complete response (cCR) could be achieved after anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. However, no data are available concerning the safety of omitting surgery and adopting immunotherapy as a curative-intent treatment for these patients. METHODS: We retrospectively collected a series of patients with dMMR/MSI-H rectal adenocarcinoma who had cCR after receiving anti-PD-1 immunotherapy and adopted immunotherapy as curative-intent treatment from six institutions. Survival outcomes were analysed using the Kaplan-Meier method. RESULTS: Nineteen patients were included with a median age of 48 (range 19-63). One patient was diagnosed with stage I disease, four with stage II disease and fourteen with stage III disease. Sixteen patients received anti-PD-1 immunotherapy as the first line of therapy, and eleven patients were treated with single-agent anti-PD-1 antibodies. The median time from the start of treatment to cCR was 3.8 (range 0.7-6.5) months. During a median follow-up of 17.1 (range 3.1-33.5) months since achieving cCR, no local or distant relapse was observed. Two-year local recurrence-free survival, distant metastasis-free survival, disease free-survival and overall survival for the whole cohort were 100%, 100%, 100% and 100%, respectively. CONCLUSIONS: For patients with dMMR/MSI-H locally advanced rectal cancer who achieved cCR during anti-PD-1 immunotherapy, adopting immunotherapy as curative-intent treatment might be an alternative option. Longer follow-up and larger cohorts are warranted to verify this innovative treatment approach.

PD-1 blockade in neoadjuvant setting of DNA mismatch repair-deficient/microsatellite instability-high colorectal cancer.

Background: Although PD-1 blockade has significantly improved the survival of metastatic colorectal cancer with DNA Mismatch Repair-Deficient/Microsatellite Instability-High (MSI-H), the data on neoadjuvant setting is limited. Methods: In this retrospective study, we enrolled eight patients with advanced MSI-H colorectal cancer from three hospitals. Four patients are locally advanced and four are metastatic. All the patients received at least two doses of PD-1 antibody with or without chemotherapy as neoadjuvant therapy. The aim of the present study was to evaluate the short-term efficacy and toxicities of this strategy. Results: All the enrolled eight patients had a major response in imaging and/or pathological evaluation. Five of the seven resected patients were evaluated as pathological complete response. One patient without surgery has a clinical complete response (cCR) tumor response. Conclusions: Neoadjuvant PD-1 blockade induced tumor regression with a major clinical and pathological response in advanced dMMR/MSI-H colorectal cancer. Further studies are required to evaluate the long-term effect of this strategy.

Surgery of hepatocellular carcinoma complicated with cancer thrombi in bile duct: efficacy for criteria for different therapy modalities.

PURPOSE: This study retrospectively compared different therapy modalities in patients with hepatocellular carcinoma (HCC) complicated by bile duct thrombi (BDT). METHODS: A total of 184 patients with BDT were selected from a pool of 12,114 patients with HCC, and their cases were reviewed in this study. RESULTS: The occurrence rate of BDT was 1.84% (223/12,114) in our study. The radical resection rate in types I, II, III, and IV was 70% (7/10), 38.46% (10/26), 20.4% (29/142), 33.3% (2/6), respectively. The mean survival time in patients who underwent radical hepatic resection and BDT removal (group A), palliative hepatectomy and BDT removal (group B), palliative hepatectomy and BDT removal plus unilateral liver artery ligation or postoperative transcatheter arterial chemoembolization (TACE; group C), TACE (group D), drainage to relieve the jaundice by ERCP or PTCD (group E), and conservative treatment (group F) was 37, 6, 16, 11, 3.0, 3.0 months, respectively. The survival rate of patients in group A was significantly greater than in other group (P < 0.0001); the rate in groups C and D was significantly higher than that in groups B, E, and F (P < 0.001). In group A, 1-year recurrence rate was 20.8% (10/48). One patient with severe jaundice suffered chronic liver failure after right lobe resection and died 2 months after operation. In groups B, C, D, E, and F, in ten cases, cholangitis occurred, in eight cases, hemobilia occurred, and 72 of 136 patients suffered liver failure and died within 6 months. Five patients underwent orthotopic liver transplantation; at the time of writing, three patients are still alive, and the longest survivor has now survived for 37 months since undergoing transplantation. CONCLUSIONS: Radical hepatic resection and removal of BDT, combined with TACE, are the best approach for treating HCC patients with BDT. Biliary drainage to relieve the jaundice is critical.

Describing Video With Attention-Based Bidirectional LSTM.

Video captioning has been attracting broad research attention in the multimedia community. However, most existing approaches heavily rely on static visual information or partially capture the local temporal knowledge (e.g., within 16 frames), thus hardly describing motions accurately from a global view. In this paper, we propose a novel video captioning framework, which integrates bidirectional long-short term memory (BiLSTM) and a soft attention mechanism to generate better global representations for videos as well as enhance the recognition of lasting motions in videos. To generate video captions, we exploit another long-short term memory as a decoder to fully explore global contextual information. The benefits of our proposed method are two fold: 1) the BiLSTM structure comprehensively preserves global temporal and visual information and 2) the soft attention mechanism enables a language decoder to recognize and focus on principle targets from the complex content. We verify the effectiveness of our proposed video captioning framework on two widely used benchmarks, that is, microsoft video description corpus and MSR-video to text, and the experimental results demonstrate the superiority of the proposed approach compared to several state-of-the-art methods.