Pretreatment Liver Injury Predicts Poor Prognosis of DLBCL Patients.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of lymphoma, with different clinical manifestation and prognosis. The International Prognostic Index (IPI), an index designed during the prerituximab era for aggressive lymphoma, showed variable values in the prediction of patient clinical outcomes. The aim of this study was to analyze the prognostic value and causes of pretreatment liver injury in 363 de novo DLBCL patients in our institution. Pretreatment liver impairment, commonly detected in lymphoma patients, showed significant association with poor outcomes and increased serum inflammatory cytokines in DLBCL patients but had no relation to hepatitis B virus replication nor lymphomatous hepatic infiltration. Multivariate analysis revealed that liver dysfunction, advanced Ann Arbor stage, and elevated lactate dehydrogenase (LDH) were independent adverse prognostic factors of both PFS and OS. Accordingly, a new liver-IPI prognostic model was designed by adding liver injury as an important factor in determining IPI score. Based on Kaplan-Meier curves for PFS and OS, the liver-IPI showed better stratification in DLBCL patients than either the IPI or the revised IPI in survival prediction.

Downregulation of DAB2IP results in cell proliferation and invasion and contributes to unfavorable outcomes in bladder cancer.

The DOC-2/DAB2 interactive protein (DAB2IP) is a member of the Ras GTPase-activating protein family. It has been shown to be often downregulated and a poor prognostic factor in several human malignancies. In this study, we analyzed the clinicopathological features and outcomes of DAB2IP expression in 135 patients with urothelial carcinoma of the bladder (UCB) treated by radical cystectomy plus bilateral lymph node dissection, and evaluated the effect of DAB2IP knockdown in vitro using the MTT method, colony formation assay, cell cycle assay, and cell migration and invasive assay. We found low expression of DAB2IP was significantly associated with high pathological stage (P = 0.002), high pathological grade (P = 0.02), tumor size more than 3 cm (P = 0.04), and presence of histological variants (P = 0.01). DAB2IP was an independent prognostic factor of disease recurrence (hazard ratio, 2.67; P = 0.034) and cancer-specific survival (hazard ratio, 2.79; P = 0.038). Knockdown of DAB2IP could promote cell proliferation, migration, and invasion. Downregulation of DAB2IP could activate the ERK and Akt pathways and was correlated with the expression of epithelial-mesenchymal transition markers, such as E-cadherin and vimentin. In conclusion, downregulation of DAB2IP is associated with features of biologically aggressive UCB and results in cell proliferation, migration, and invasion of bladder cancer. DAB2IP may serve as a promising biomarker in patients with UCB treated by radical cystectomy and bilateral lymph node dissection.

Down-regulation of Dicer and Ago2 is associated with cell proliferation and apoptosis in prostate cancer.

Dicer and Argonaute2 (Ago2) are critical components responsible not only for RNA interference but also for microRNA synthesis. The present study investigated the roles of Dicer and Ago2 in prostate cancer (Pca). First, the expression levels of Dicer and Ago2 in Pca tissues were determined by immunohistochemistry (IHC) and compared with pathological features. Next, RNA interference was used to down-regulate the expression levels of Dicer and Ago2 in the Pca cell lines LNCaP, PC-3, and DU145, and effects on proliferation, apoptosis, and cell cycle were detected using the CCK-8 assay and flow cytometry, respectively. We found that Dicer and Ago2 expression levels in Pca tissues were higher than those in adjacent benign tissues and correlated with lower Gleason patterns, with the exception of Dicer expression in localized Pca. In vitro, silencing Dicer or Ago2 inhibited cell proliferation and induced apoptosis in LNCaP, PC-3, and DU145, as well as arrested the cell cycle at the G2/M phase in androgen-dependent LNCaP, or at S phase in the androgen-independent PC-3 and DU145. Altogether these findings suggest that Dicer and Ago2 play important roles in proliferation, apoptosis, and the cell cycle in Pca and might serve as both promising biomarkers for Pca progression and potential therapeutic targets.

A nomogram to predict Gleason sum upgrading of clinically diagnosed localized prostate cancer among Chinese patients.

Although several models have been developed to predict the probability of Gleason sum upgrading between biopsy and radical prostatectomy specimens, most of these models are restricted to prostate-specific antigen screening-detected prostate cancer. This study aimed to build a nomogram for the prediction of Gleason sum upgrading in clinically diagnosed prostate cancer. The study cohort comprised 269 Chinese prostate cancer patients who underwent prostate biopsy with a minimum of 10 cores and were subsequently treated with radical prostatectomy. Of all included patients, 220 (81.8%) were referred with clinical symptoms. The prostate-specific antigen level, primary and secondary biopsy Gleason scores, and clinical T category were used in a multivariate logistic regression model to predict the probability of Gleason sum upgrading. The developed nomogram was validated internally. Gleason sum upgrading was observed in 90 (33.5%) patients. Our nomogram showed a bootstrap-corrected concordance index of 0.789 and good calibration using 4 readily available variables. The nomogram also demonstrated satisfactory statistical performance for predicting significant upgrading. External validation of the nomogram published by Chun et al. in our cohort showed a marked discordance between the observed and predicted probabilities of Gleason sum upgrading. In summary, a new nomogram to predict Gleason sum upgrading in clinically diagnosed prostate cancer was developed, and it demonstrated good statistical performance upon internal validation.

Anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab for first-line treatment in advanced natural killer T cell lymphoma.

Natural killer T cell lymphoma (NKTCL) is highly aggressive, with advanced stage patients poorly responding to intensive chemotherapy. To explore effective and safe treatment for newly diagnosed advanced stage NKTCL, we conducted a phase II study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab (NCT04096690). Twenty-two patients with a median age of 51 years (range, 24-74) were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days, followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days. The complete response and overall response rate after induction treatment were 59% (95%CI, 43-79%) and 68% (95%CI, 47-84%), respectively. With a median follow-up of 30 months, the 2 year progression-free and overall survival rates were 68% (95%CI, 45-83%) and 86% (95%CI, 63-95%), respectively. The most frequently grade 3/4 adverse events were neutropenia (32%, n = 7) and hypofibrinogenemia (18%, n = 4), which were manageable and led to no discontinuation of treatment. Tumor proportion score of PD-L1, peripheral blood high-density lipoprotein cholesterol, and apolipoprotein A-I correlated with good response, while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment. In conclusion, the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed, advanced stage NKTCL. Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance, providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.

KMT2D mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-induced regulatory T cell trafficking via FBXW7-NOTCH-MYC/TGF-ß1 axis.

Histone methyltransferase KMT2D is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL) and has been identified as an important pathogenic factor and prognostic marker. However, the biological relevance of KMT2D mutations on tumor microenvironment remains to be determined. KMT2D mutations were assessed by whole-genome/exome sequencing (WGS/WES) in 334 patients and by targeted sequencing in 427 patients with newly diagnosed DLBCL. Among all 761 DLBCL patients, somatic mutations in KMT2D were observed in 143 (18.79%) patients and significantly associated with advanced Ann Arbor stage and MYC expression ≥ 40%, as well as inferior progression-free survival and overall survival. In B-lymphoma cells, the mutation or knockdown of KMT2D inhibited methylation of lysine 4 on histone H3 (H3K4), downregulated FBXW7 expression, activated NOTCH signaling pathway and downstream MYC/TGF-ß1, resulting in alterations of tumor-induced regulatory T cell trafficking. In B-lymphoma murine models established with subcutaneous injection of SU-DHL-4 cells, xenografted tumors bearing KMT2D mutation presented lower H3K4 methylation, higher regulatory T cell recruitment, thereby provoking rapid tumor growth compared with wild-type KMT2D via FBXW7-NOTCH-MYC/TGF-ß1 axis.

GPCR signaling contributes to immune characteristics of microenvironment and process of EBV-induced lymphomagenesis.

Epstein-Barr virus (EBV) is the oncogenic driver of multiple cancers. However, the underlying mechanism of virus-cancer immunological interaction during disease pathogenesis remains largely elusive. Here we reported the first comprehensive proteogenomic characterization of natural killer/T-cell lymphoma (NKTCL), a representative disease model to study EBV-induced lymphomagenesis, incorporating genomic, transcriptomic, and in-depth proteomic data. Our multi-omics analysis of NKTCL revealed that EBV gene pattern correlated with immune-related oncogenic signaling. Single-cell transcriptome further delineated the tumor microenvironment as immune-inflamed, -deficient, and -desert phenotypes, in association with different setpoints of cancer-immunity cycle. EBV interacted with transcriptional factors to provoke GPCR interactome (GPCRome) reprogramming. Enhanced expression of chemokine receptor-1 (CCR1) on malignant and immunosuppressive cells modulated virus-cancer interaction on microenvironment. Therapeutic targeting CCR1 showed promising efficacy with EBV eradication, T-cell activation, and lymphoma cell killing in NKTCL organoid. Collectively, our study identified a previously unknown GPCR-mediated malignant progression and translated sensors of viral molecules into EBV-specific anti-cancer therapeutics.

External validation of a nomogram using RENAL nephrometry score to predict high grade renal cell carcinoma.

PURPOSE: A novel nomogram using the RENAL ([R]adius maximal diameter in cm, [E]xophytic/endophytic properties, [N]earness of the tumor to the collecting system or sinus in mm, [A]nterior/Posterior, [L]ocation relative to the polar lines and [H]ilar) nephrometry score was developed to predict high grade renal cell carcinoma. It showed good performance in internal evaluation. We externally validated the prediction model. MATERIALS AND METHODS: We identified a cohort of 391 Chinese patients in whom renal cell carcinoma was surgically resected at our institution from 2008 to 2011. Fuhrman grade was reviewed by an experienced genitourinary pathologist and radiological images were independently assessed by 2 senior urologists. Using a 2-tiered system high grade disease was defined as Fuhrman grade III/IV. The statistical performance of the prediction model was evaluated by discrimination, calibration and clinical usefulness. RESULTS: Of the 391 patients 45.5% were considered to have high grade tumors. External validation of the nomogram revealed an AUC of 0.73. The calibration plot showed that the predicted probability of high grade disease had concordance comparable to the observed frequency. On decision curve analysis the prediction model provided a superior net benefit and reduction at a greater than 20% probability threshold. CONCLUSIONS: We confirm the predictive value of the nomogram using the RENAL nephrometry score to identify high grade renal cell carcinoma in an independent cohort. Further research is required to evaluate its performance using a head-to-head comparison with renal biopsy results.

Primary yolk sac tumor of seminal vesicle: a case report and literature review.

BACKGROUND: Yolk sac tumor (endodermal sinus tumor) is a rare malignant germ cell tumor arising in the testis or ovary. Extragonadal yolk sac tumor is even rarer and has only been described in case reports. Due to the rarity of the tumors, the appropriately optimal treatment remains unclear. We report a case of yolk sac tumor in the seminal vesicle. CASE: A 38-year-old Asian male presented with gross hematuria and hemospermia. Transrectal ultrasound scan showed a solid mass in the left seminal vesicle and the scrotal sonography showed no abnormalities. Bilateral seminal vesicles were resected, and histopathological examination showed a typical pattern of yolk sac tumor (YST). The patient responded poorly to comprehensive treatment of radiotherapy, chemotherapy and surgeries, developed systemic multiple metastases, and died of cachexia one and half years after diagnosis.

Narrow-band imaging flexible cystoscopy in the detection of clinically unconfirmed positive urine cytology.

INTRODUCTION: The objective of this study was to investigate the value of narrow-band imaging (NBI) cystoscopy in the detection of patients with positive voided urine cytology (VUC) who have no evidence of disease after standard initial investigations. PATIENTS AND METHODS: Between February 2009 and December 2010, 12 patients with positive or suspicious VUC but no regular endoscopic evidence of cancer were investigated with NBI flexible cystoscopy. All the specimens were biopsied both under NBI and white light imaging (WLI). Random biopsies of bladder and prostatic urethra were performed in cases without suspect lesions. RESULTS: Fourteen NBI cystoscopies were carried out in 12 patients. Non-muscle-invasive bladder cancer was diagnosed in 5 of 12 (42%) patients on the first NBI. One patient had carcinoma in situ diagnosed on repeat NBI 3 months later. The sensitivity and specificity in diagnosing unconfirmed positive VUC was 78 and 91% for NBI vs. 50 and 80% for WLI. CONCLUSIONS: NBI cystoscopy significantly improves detection of unconfirmed positive VUC over WLI. It should be carried out early in the investigation of such patients before random biopsies and ureteroscopy.

A combined clinicopathologic analysis of 658 urothelial carcinoma cases of urinary bladder.

OBJECTIVE: To study the clinicopathological features of patients with urothelial carcinoma of the urinary bladder (UCB), and analyze the association of clinicopathological characteristics with tumor recurrence and progression. METHODS: Altogether 658 UCB cases in Fudan University Shanghai Cancer Center were collected from January 2006 to December 2010. The histopathologic materials and the clinical records were reviewed. Univariate and multivariate analyses were preformed to detect the association. RESULTS: The mean age of the patients was 61.97 +/- 12.97 years (range, 20-90 years). Male to female ratio was about 5:1. A total of 517 cases (78.6%) were superficial at the time of diagnosis (stage Ta/T1). The mean follow-up period was 22.36 +/- 24.92 months. Twenty-five patients lacking follow-up information were excluded in calculating recurrence and progression rates, the recurrence rate was about 37.0% (234/633), and progression rate about 6.2% (39/633). Three variables (grade, tumor growth pattern, and pathological stage) were found to be significant risk factors for tumor progression in univariate and multivariate analyses (P < 0.05). CONCLUSIONS: Most of the newly diagnosed UCB cases may be superficial diseases. Grade, tumor growth pattern, and pathological stage are associated with tumor progression of UCB.

[Blastic plasmacytoid dendritic cell neoplasm: a clinicopathologic study].

OBJECTIVE: To study the clinicopathologic features and differential diagnosis of blastic plasmacytoid dendritic cell neoplasm. METHODS: The clinical, morphology and immunophenotypic features were analyzed in 3 cases of blastic plasmacytoid dendritic cell neoplasm, with review of literature. RESULTS: The pathologic changes of these tumors accorded with that of blastic plasmacytoid dendritic cell neoplasm, and they also had new characteristics, including lineage other than T, B, myeloid and NK cells, and immunophenotypes of CD56(+) CD4(-) CD123(+) TdT(+) CD43(+) CD68(+) , CD56(+) CD4(+) CD123(-) TdT(+) CD43(+) CD68(-) and CD56(+) CD4(+) CD123(-/+) TdT(-) CD43(+) CD68(+) in the 3 cases, respectively. Bone marrow involvement was found 5 years later in case 1, and was then stable after chemotherapy; case 2 and case 3 were died 5 and 2 months after diagnosis, respectively. CONCLUSION: Blastic plasmacytoid dendritic cell neoplasm is a heterogeneous group of lymphoproliferative disorders, with different clinical, morphologic and immunophenotypic features.

Comparison of accuracy among three generations of Partin tables in a Chinese cohort.

INTRODUCTION: To perform a head to head comparison among three generations of Partin tables, namely from 1997, 2001 and the last updated version of 2007, in a Chinese cohort of prostate cancer. MATERIAL AND METHODS: Clinical and pathological data of 198 consecutive Chinese patients were retrospectively analyzed, who underwent radical prostatectomy for clinically localized prostate cancer between January 2005 and May 2010. Three versions of the Partin tables were compared for their accuracy and performance to predict final pathological stage using receiver operating characteristic (ROC) curve. RESULTS: Of the whole cohort 58.6% were presented with organ-confined disease (OCD), 10.1% had lymph node involvement (LNI), and 31.3% had locally advanced disease (LAD), while 21.2% had extraprostatic extension (ECE) and 10.1% showed seminal vesicle involvement (SVI). The area under the ROC curve (AUC) of the Partin Tables 1997, 2001 and 2007 was 0.732, 0.722 and 0.695 for OCD; 0.647, 0.594 and 0.577 for LAD; 0.856, 0.872 and 0.829 for LNI, respectively. CONCLUSION: All three generations of the Partin tables showed a good accuracy to predict OCD, and LNI. However, the predictive accuracy for LAD was more limited. Overall, the newer versions of the Partin tables could not exceed the version of 1997 in their predictive accuracy for the present Chinese cohort. Our results suggest caution when using newly introduced predictive tools that are not supported by population-specific accuracy tests.

Erythrocyte sedimentation rate kinetics as a marker of treatment response and predictor of prognosis in Chinese metastatic renal cell carcinoma patients treated with sorafenib.

OBJECTIVES: Previous prognostic factor models for metastatic renal cell carcinoma (mRCC) have not included erythrocyte sedimentation rate (ESR). We designed the present study to evaluate the prognostic value of ESR for mRCC patients treated with sorafenib. METHODS: Sorafenib was given to 83 patients with clear cell mRCC. Serum ESR was tested before treatment and every 4 weeks after first administration of sorafenib. Oncological evaluation was carried out every 8 weeks. Analyzed factors included age, sex, performance status, method of nephrectomy, number of metastatic organs, anemia, lactate dehydrogenase, corrected calcium, albumin, baseline ESR level and ESR kinetics status. Kaplan-Meier and Cox regression analyses on progression-free survival (PFS) were carried out. RESULTS: Baseline ESR levels ranged from 3 to 154 mm/h, and 43 (41.0%) patients had an ESR level higher than 40 mm/h. Median PFS was 10.0 months (95% CI 7.6-12.4 months). Dividing the cohort into three groups according to ESR kinetics status, median PFS was 27 months in the decreased ESR group, 12 months in the stable ESR group and 6 months in the increased ESR group. Performance status, time from diagnoses to sorafenib treatment, number of metastatic organs and ESR kinetics were independent predictors for PFS in multivariable Cox regression model analysis, with an area under the curve of 0.865 in a binary logistic regression model of 12-month PFS probability. CONCLUSIONS: ESR kinetics can be useful to monitor the treatment response and to predict PFS for mRCC patients treated with sorafenib as second-line therapy.

[Urothelial hyperplastic lesion with endophytic growth pattern: a clinicopathologic study].

OBJECTIVE: To study the clinicopathologic features of urothelial hyperplastic lesion with an endophytic growth pattern and the role of immunohistochemistry and multitargeted fluorescence in situ hybridization (FISH) in the differential diagnosis. METHODS: Forty-one cases of urothelial lesions exhibiting endophytic growth patterns were reviewed and reclassified as inverted papilloma, urothelial carcinoma with an endophytic growth pattern, and florid von Brunn nest. The gains of chromosomes 3, 7, and 17 and loss of 9p21 was detected by FISH, and performed immunohistochemical staining for CK20, p53, and Ki-67. Follow-up data of 12 cases were obtained. RESULTS: (1) Twelve inverted papillomas sized 1.2 cm in average, consisted of anastomosing cords and nests with uniform width distribution involving the lamina propria, the central portion contained streaming cells with squamous metaplasia, and the periphery showed palisading. No or rare atypia and mitosis were found. Focal exophytic papillary component lined by less than 6 layers of normal urothelium were observed in 4 cases. (2) Twenty-four urothelial carcinomas with an endophytic growth pattern sized 2.1 cm in average, demonstrated the similar architecture with inverted papilloma, but exhibited thick columns and variable thickness of the cords, irregular size and shape of large nests with transition into solids. Mild to moderate cytologic atypia was shown, and mitotic figures ranged 1 to 8 per 10 HPFs. Exophytic papillary component was not observed in 3 cases, but the superficial urothelium showed dysplasia, while coexisted exophytic component in other cases was associated with low malignant potential or low grade tumor. (3) Five florid von Brunn nests sized 0.9 cm in average, had normal or hyperplastic urothelium, variable nests with cysts compacted in lamina propria, no cytologic atypia and mitosis. Twenty-one of 24 (79.1%) urothelial carcinomas with an endophytic growth pattern displayed abnormally positive results by multitargeted FISH, whereas all inverted papillomas and florid von Brunn nests were negative. Immunohistochemically, CK20 was weakly positive in 2 cases of urothelial carcinoma with an endophytic growth pattern, and negative in all inverted papillomas and florid von Brunn nests. p53 weakly stained 5% to 50% nuclei of the tumor cells in 16 cases of urothelial carcinomas with an endophytic growth pattern and 1 inverted papilloma. 1%-5% tumor cells expressed Ki-67 in urothelial carcinoma with an endophytic growth pattern, and less than 1% in inverted papilloma and florid von Brunn nests. Follow-up study revealed that 2 cases of urothelial carcinoma with an endophytic growth pattern had developed invasive carcinoma, underwent cystectomy, and metastasized remotely. No recurrence occurred in cases of inverted papilloma. CONCLUSIONS: Benign and malignant urothelial lesions with an endophytic growth pattern present histologic overlapping. Urothelial carcinoma with an endophytic growth pattern displays unique characteristics in morphology and immunohistochemistry. Multitargeted FISH analysis is helpful in the differential diagnosis.

Prognostic and predictive significance of tumor infiltrating lymphocytes for ductal carcinoma in situ.

This study aims to identify the density of TILs in ductal carcinoma in situ (DCIS) in terms of prognostic significance with recurrence and the benefit of whole breast irradiation (WBI). The clinicopathological data of DCIS patients from Jan 2009 to Dec 2016 who received breast-conserving surgery (BCS) were retrospectively reviewed. Cox regression analysis was used to confirm independent prognostic factors of ipsilateral breast tumor recurrence (IBTR). Kaplan-Meier method was utilized to analyze IBTR and values of WBI. Touching-tumor-infiltrating lymphocytes (TILs) were defined by TILs touching or within one lymphocyte cell thickness from the malignant ducts' basement membrane. In total, 129 patients were enrolled in this analysis with 98 patients who received WBI. After a median follow-up of 53.0 months, there were 16 IBTR events with five invasive IBTRs. Univariate and multivariate analyses showed that touching-TILs >5 were an independent prognostic factor for higher IBTR (HR = 6.17, 95%CI 1.95-19.56, p < .01). The whole cohort was classified into two subgroups: dense group (>5 touching-TILs per duct) and sparse group (≤5 touching-TILs per duct). Dense touching-TILs were associated with unfavorable biologic characteristics. The 5-y rate of IBTR between dense and sparse group was 29.0% versus 4.5% (p < .01). For the sparse group, WBI significantly reduced the rate of 5-y-IBTR risk from 13.2% to 1.7% (p = .02), but there was no benefit of WBI in the dense group. Touching-TILs density was heterogeneous in patients with DCIS. Sparse touching-TILs were associated with better prognosis and benefit from WBI. Dense touching-TILs not only were associated with a higher risk of IBTR but also lack of benefit from WBI.

A novel lncRNA TCLlnc1 promotes peripheral T cell lymphoma progression through acting as a modular scaffold of HNRNPD and YBX1 complexes.

Long noncoding RNAs (lncRNAs) play an essential role in tumor progression. Few researches focused on the clinical and biological relevance of lncRNAs in peripheral T cell lymphoma (PTCL). In this research, a novel lncRNA (ENST00000503502) was identified overexpressed in the main subtypes of PTCL, and designated as T cell lymphoma-associated lncRNA1 (TCLlnc1). Serum TCLlnc1 was associated with extranodal involvement, high-risk International Prognostic Index, and poor prognosis of the patients. Both in vitro and in vivo, overexpression of TCLlnc1 promoted T-lymphoma cell proliferation and migration, both of which were counteracted by the knockdown of TCLlnc1 using small interfering RNAs. As the mechanism of action, TCLlnc1 directly interacted with transcription activator heterogeneous nuclear ribonucleoprotein D (HNRNPD) and Y-box binding protein-1 (YBX1) by acting as a modular scaffold. TCLlnc1/HNRNPD/YBX1 complex upregulated transcription of TGFB2 and TGFBR1 genes, activated the tumor growth factor-ß signaling pathway, resulting in lymphoma progression, and might be a potential target in PTCL.

A cohort autopsy study defines COVID-19 systemic pathogenesis.

Severe COVID-19 disease caused by SARS-CoV-2 is frequently accompanied by dysfunction of the lungs and extrapulmonary organs. However, the organotropism of SARS-CoV-2 and the port of virus entry for systemic dissemination remain largely unknown. We profiled 26 COVID-19 autopsy cases from four cohorts in Wuhan, China, and determined the systemic distribution of SARS-CoV-2. SARS-CoV-2 was detected in the lungs and multiple extrapulmonary organs of critically ill COVID-19 patients up to 67 days after symptom onset. Based on organotropism and pathological features of the patients, COVID-19 was divided into viral intrapulmonary and systemic subtypes. In patients with systemic viral distribution, SARS-CoV-2 was detected in monocytes, macrophages, and vascular endothelia at blood-air barrier, blood-testis barrier, and filtration barrier. Critically ill patients with long disease duration showed decreased pulmonary cell proliferation, reduced viral RNA, and marked fibrosis in the lungs. Permanent SARS-CoV-2 presence and tissue injuries in the lungs and extrapulmonary organs suggest direct viral invasion as a mechanism of pathogenicity in critically ill patients. SARS-CoV-2 may hijack monocytes, macrophages, and vascular endothelia at physiological barriers as the ports of entry for systemic dissemination. Our study thus delineates systemic pathological features of SARS-CoV-2 infection, which sheds light on the development of novel COVID-19 treatment.

Characteristics and prognosis of primary thyroid non-Hodgkin's lymphoma in Chinese patients.

BACKGROUND AND OBJECTIVES: There exists no universally accepted treatment for primary thyroid non-Hodgkin's lymphoma (TNHL) due to the rarity of this entity. The aim of this study is to assess the role of surgery and to explore prognostic factors in Chinese TNHL patients. METHODS: Patient presentations, pathologies, surgical interventions, multidisciplinary treatment, prognostic factors and the value of fine needle aspiration were analyzed. RESULTS: Between 1991 and 2007, 40 patients of TNHL were diagnosed. Thirty-eight patients underwent an initial surgical procedure. Further treatments consisted of radiotherapy or chemotherapy alone, and the majority of patients were treated with combined chemo-radiation. After a median follow-up of 95 months, the 5-year overall survival (OS) and relapse-free survival (RFS) was 82% and 74%, respectively. Survival curves showed no significant difference between therapeutic operations when compared with diagnostic operations. A univariate analysis showed both International Prognostic Index (IPI) and staging significantly influenced OS and RFS. In multivariate analysis, IPI was found to be the only prognostic factor. CONCLUSIONS: Combined chemotherapy and radiotherapy may offer better outcome without the need for extensive resection, and surgery should be reserved to providing tissue for diagnosis. The patients with low-intermediate risk (IPI = 2) or stage IIE need be treated more aggressively.

Feasibility and activity of sorafenib and sunitinib in advanced penile cancer: a preliminary report.

INTRODUCTION: We describe our experience with sorafenib and sunitinib in the treatment of chemotherapy-refractory advanced penile squamous cell carcinoma (SCC). PATIENTS AND METHODS: Between May 2008 and June 2009, 6 advanced penile cancer patients were treated with sorafenib or sunitinib in our center. All of them had previously received at least two chemotherapy regimens. Tumor responses were evaluated by radiologic assessment and serum SCC antigen change. Immunohistochemical staining of CD34 and Ki-67 was performed in 3 paired tumor tissues before and after treatment. RESULTS: In the 6 patients, 1 partial response and 4 stable diseases were observed. Three patients showed pain response and had an improvement in quality of life. After molecular-targeted therapies, reduction in microvessel density and Ki-67 labeling index was observed in paired specimens. Serum SCC antigen levels were decreased in 5 patients after 1 week of medication. The patient who achieved partial response had an SCC antigen reduction of nearly 95% after treatment with sunitinib. Serious adverse events were fatal infection and rupture of the femoral vessel, which were unlikely related to the medication. CONCLUSIONS: The feasibility and activity of sorafenib and sunitinib in our series suggest that this approach may be a promising alternative in chemotherapy-refractory advanced penile SCC.