Publications by authors named "Toyonori Tsuzuki"

196 Publications

Improving function of cytotoxic T-lymphocytes by transforming growth factor-β inhibitor in oral squamous cell carcinoma.

Cancer Sci 2021 Jul 26. Epub 2021 Jul 26.

Department of Maxillofacial Surgery School of Dentistry, Aichi Gakuin University, Nagoya, Japan.

Immunotherapy with immune-checkpoint therapy has recently been used to treat oral squamous cell carcinomas (OSCCs). However, improvements in current immunotherapy are expected because response rates are limited. Transforming growth factor-β (TGF-β) creates an immunosuppressive tumor microenvironment (TME) by inducing the production of regulatory T-cells (Tregs) and cancer-associated fibroblasts and inhibiting the function of cytotoxic T-lymphocytes (CTLs) and natural killer cells. TGF-β may be an important target in the development of novel cancer immunotherapies. In this study, we investigated the suppressive effect of TGF-β on CTL function in vitro using OSCC cell lines and their specific CTLs. Moreover, TGFB1 mRNA expression and T-cell infiltration in 25 OSCC tissues were examined by in situ hybridization and multi-fluorescence immunohistochemistry. We found that TGF-β suppressed the function of antigen-specific CTLs in the priming and effector phases in vitro. Additionally, TGF-β inhibitor effectively restored the CTLs function, and TGFB1 mRNA was primarily expressed in the tumor invasive front. Interestingly, we found a significant negative correlation between TGFB1 mRNA expression and the CD8+ T-cells/Tregs ratio and between TGFB1 mRNA expression and the Ki-67 expression in CD8+ T-cells, indicating that TGF-β also suppressed the function of CTLs in situ. Our findings suggest that the regulation of TGF-β function restores the immunosuppressive TME to active status and is important for developing new immunotherapeutic strategies, such as a combination of immune-checkpoint inhibitors and TGF-β inhibitors, for OSCCs.
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http://dx.doi.org/10.1111/cas.15081DOI Listing
July 2021

Prognostic value of programmed death-ligand 1 status in Japanese patients with renal cell carcinoma.

Int J Clin Oncol 2021 Jul 21. Epub 2021 Jul 21.

Department of Surgical Pathology, Aichi Medical University Hospital, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.

Background: Programmed death-ligand 1 (PD-L1) positivity is associated with poor prognosis in renal cell carcinoma (RCC). Because the prognostic impact and effect of confounding factors are less known, we investigated the prognostic significance of PD-L1 expression in Japanese patients with recurrent/metastatic RCC who started systemic therapy in 2010-2015.

Methods: This multicenter, retrospective study recruited patients from 29 Japanese study sites who had prior systemic therapy for RCC (November 2018 to April 2019) and stored formalin-fixed paraffin-embedded primary lesion samples. The primary outcome was overall survival (OS) by PD-L1 expression. Secondary outcomes included OS in subgroups and duration of first- and second-line therapies by PD-L1 expression. OS distributions were estimated using Kaplan-Meier methodology.

Results: PD-L1 expression (on immune cells [IC] ≥ 1%) was observed in 315/770 (40.9%) patients. PD-L1 positivity was more prevalent in patients with poor risk per both Memorial Sloan Kettering Cancer Center [MSKCC] and International Metastatic RCC Database Consortium, and high-risk pathological features (higher clinical stage, nuclear grade and sarcomatoid features). Median OS for PD-L1-positive patients was 30.9 months (95% CI 25.5-35.7) versus 37.5 months (95% CI 34.0-42.6) for PD-L1-negative patients (HR 1.04 [90% CI 0.89-1.22, p = 0.65]; stratified by MSKCC risk and liver metastases). Propensity score weight (PSW)-adjusted OS was similar between PD-L1-positive and -negative patients (median 34.4 versus 31.5 months; estimated PSW-adjusted HR 0.986).

Conclusions: This study suggests PD-L1 status was not an independent prognostic factor in recurrent/metastatic RCC during the study period because PD-L1 positivity was associated with poor prognostic factors, especially MSKCC risk status.
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http://dx.doi.org/10.1007/s10147-021-01993-xDOI Listing
July 2021

Elevated expression of B7 homolog 4 is associated with disease progression in upper urinary tract urothelial carcinoma.

Cancer Immunol Immunother 2021 Jul 18. Epub 2021 Jul 18.

Department of Urology, Dokkyo Medical University, 880 Kitakobayashi Mibu, Mibu, Tochigi, 321-0293, Japan.

Background: B7 homolog 4 (B7-H4) is a negative regulator of immune responses, but its immunoregulatory role in the tumor microenvironment of upper urinary tract urothelial carcinoma (UTUC) remains unclear.

Methods: We measured the immunohistochemical expression of B7-H4, CD8 and T cell intracellular antigen 1 (TIA-1), a marker of activated CD8, in 133 patients with UTUC who underwent nephroureterectomy. We also studied the relationship between B7-H4, CD8 and TIA-1 expression and clinicopathological characteristics.

Results: B7-H4 was mainly expressed on the surface in tumor cells, while CD8 and TIA-1 were often expressed in tumor-infiltrating lymphocytes. Elevated expression of B7-H4 in tumor cells was associated with a poorer histological grade, higher pT stage, regional lymph node metastasis, lymphovascular invasion, poorer response of recurrent metastatic lesions to systemic chemotherapy and shorter overall survival. Expression of CD-8 or TIA-1 alone did not correlate directly with clinicopathological characteristics, but among the patients with higher B7-H4 expression in the primary tumors, those with higher CD8 or TIA-1 expression had a better response to systemic chemotherapy, and longer survival, than these with lower CD8 or TIA-1 expression. Cox multivariate regression analysis revealed that higher expression of B7-H4 was associated with shorter overall survival.

Conclusions: These findings suggest that B7-H4 expression in the tumor microenvironment influences the progression of UTUC through cancer immunity and metabolic activity. Tumor cell-associated B7-H4 might be a potential target for cancer immunotherapies.
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http://dx.doi.org/10.1007/s00262-021-03011-5DOI Listing
July 2021

Re: Editorial Comment on Intraoperative pathology consultation during urological surgery: Impact on final margin status and pitfalls of frozen section diagnosis.

Authors:
Toyonori Tsuzuki

Pathol Int 2021 Jul 7. Epub 2021 Jul 7.

Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute, Japan.

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http://dx.doi.org/10.1111/pin.13141DOI Listing
July 2021

A patient with very early onset FH-deficient renal cell carcinoma diagnosed at age seven.

Fam Cancer 2021 Jun 22. Epub 2021 Jun 22.

Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by heterozygous germline variants in the fumarate hydratase (FH) gene and is associated with increased susceptibility to cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma (RCC). HLRCC-associated RCC usually occurs in the middle age, with the median age being 40-44 years. This report describes a seven-year-old (84-month-old) male who developed a large right kidney tumor with multiple cystic lesions that contained enhanced solid components. There was no evidence of distant metastasis. The male patient underwent right nephrectomy and has been recovering well without metastasis or recurrence. Pathological examination revealed that tumor cells with relatively prominent nucleoli and surrounded by halos, were located in a limited area. Immunohistochemical staining was negative for FH. Whole-exome sequencing identified his germline variant in the FH gene and its loss of heterozygosity in the tumor. At nine years (114 months) of age, the male patient showed no recurrence of the tumor. This was the youngest-onset case of HLRCC-associated RCC to date. This report may affect the starting age for future RCC-surveillance programs for patients with HLRCC.
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http://dx.doi.org/10.1007/s10689-021-00268-8DOI Listing
June 2021

Presence of corpora amylacea among prostate cancer cells: an unrecognised feature of intraductal carcinoma of the prostate.

Pathology 2021 Aug 18;53(5):574-578. Epub 2021 Jun 18.

Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute, Japan. Electronic address:

Corpora amylacea (CA) is usually present in benign prostatic ducts and acini, and its presence is considered suggestive of negative or low-risk prostate cancer. The clinicopathological definition of CA among prostate cancer cells (CAPCCs)-described as CA entirely surrounded by invasive cancer cells-has not been discussed. As intraductal carcinoma of the prostate (IDC-P) is a well-known adverse prognostic factor in prostate cancer, this study aimed to elucidate the relationship between CAPCC and IDC-P. We enrolled 366 patients who underwent robotic-assisted radical prostatectomies between 2012 and 2018 at Aichi Medical University Hospital. All surgical specimens were independently reviewed by two genitourinary pathologists. The median age of the patients was 68.5 years; the median serum prostate-specific antigen was 6.49 ng/mL. IDC-P was observed in 143 (39.1%) patients, while the presence of CAPCC was observed in 47 cases (12.8%). Patients with CAPCC were associated with more advanced clinical and pathological T stages, as well as Gleason scores, than those without CAPCC (p=0.018, p<0.001, p=0.036). Notably, the presence of CAPCC was significantly associated with the presence of IDC-P (39 cases) and a high Gleason score compared with the absence of CAPCC (12 cases) (p<0.001 and p=0.036, respectively). The presence of CAPCC is an adverse pathological feature, often closely related to IDC-P. Therefore, CAPCC may be a surrogate finding to detect IDC-P via haematoxylin and eosin staining.
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http://dx.doi.org/10.1016/j.pathol.2020.09.033DOI Listing
August 2021

A case of resected hepatocellular carcinoma with gallbladder metastasis.

Surg Case Rep 2021 Jun 17;7(1):145. Epub 2021 Jun 17.

Division of Gastroenterological Surgery, Department of Surgery, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.

Background: Advanced hepatocellular carcinoma (HCC) can often spread as intrahepatic metastases. Extrahepatic metastasis (e.g., lung, lymph nodes, and bones) is rare, and gallbladder metastasis from HCC is extremely rare.

Case Presentation: A 66-year-old woman who presented with right hypochondrial pain was referred to our hospital for further examination of a liver tumor. The blood chemistry data showed elevated levels of serum α-fetoprotein (AFP) (3730 ng/mL), protein induced by vitamin K absence or antagonist II (PIVKA-II) (130 mAU/mL), and carcinoembryonic antigen (CEA) (358.6 ng/mL). Hepatitis B surface antigen and hepatitis C virus antibody were negative. Dynamic computed tomography (CT) showed a tumor measuring 12 × 7 cm in the right lobe of the liver. This tumor was contrast-enhanced in the hepatic arterial phase and then became less dense than the liver parenchyma in the portal phase. A well-enhanced tumor was found in the gallbladder. No regional lymph nodes were enlarged. Contrast-enhanced magnetic resonance imaging (MRI) demonstrated that the liver tumor showed a pattern of early enhancement and washout. The gallbladder tumor was also detected as an enhanced mass. Endoscopic retrograde cholangiography (ERC) showed compression of the left hepatic duct due to the liver tumor. The patient was diagnosed with simultaneous HCC and gallbladder cancer. Right hepatic trisectionectomy and caudate lobectomy with extrahepatic bile duct resection were performed. Histopathological examination of the resected liver specimen showed a poorly differentiated HCC cell component with a trabecular and solid growth, and diffuse invasion of the portal vein. The same tumor cells were found in the gallbladder, but no continuity with the liver tumor was identified. Immunohistochemistry of the liver tumor and gallbladder was positive for AFP, Glypican 3, and CK7, and negative for CK19. The final pathological diagnosis was the gallbladder metastasis from HCC. A follow-up diagnostic image 33 months after surgery showed a mass in the upper lobe of the left lung. The patient underwent left upper lobectomy. Postoperative pathology revealed that the lung lesion was a metastasis of HCC. The patient was still alive with lung metastasis and was being treated with a molecular-targeting drug in good health 42 months after the initial surgery.

Conclusions: The standard treatment for advanced HCC with extrahepatic metastases is molecularly targeted drugs, but surgery is also an option if the lesion can be resected en bloc without remnants.
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http://dx.doi.org/10.1186/s40792-021-01222-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211791PMC
June 2021

Impact of histological variants on outcomes in patients with urothelial carcinoma treated with pembrolizumab: a propensity score matching analysis.

BJU Int 2021 Jun 10. Epub 2021 Jun 10.

Department of Urology, University of Toyama, Toyama, Japan.

Objectives: To assess the impact of histological variants on survival and response to treatment with pembrolizumab in patients with chemo-resistant urothelial carcinoma (UC).

Patients And Methods: The medical records of 755 patients with advanced UC who received pembrolizumab were reviewed retrospectively. Patients were classified into pure UC (PUC) and each variant. Best overall response (BOR) and overall survival (OS) were compared between the groups using a propensity score matching (PSM).

Results: Overall, 147 (19.5%) patients harboured any histological variant UC (VUC). After PSM, there were no significant differences in the objective response rate (ORR, 24.5% vs 17.3%, P = 0.098) or disease control rate (DCR, 36.7% vs 30.2%, P = 0.195) when comparing patients with any VUC and PUC. Furthermore, any VUC, as compared with PUC, was associated with a similar risk of death (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.68-1.20; P = 0.482). Squamous VUC, which was the most frequent variant in the cohort, had a comparable ORR, DCR and OS as compared with PUC or non-squamous VUC. The patients with sarcomatoid VUC (n = 19) had significantly better ORR (36.8%, P = 0.031), DCR (52.6%, P = 0.032), and OS (HR 0.37, 95% CI 0.15-0.90; P = 0.023) compared to patients with PUC.

Conclusions: The presence of variant histology did not seem to affect BOR or OS after pembrolizumab administration in patients with chemo-resistant UC. The patients with sarcomatoid VUC achieved favourable responses and survival rates compared to PUC.
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http://dx.doi.org/10.1111/bju.15510DOI Listing
June 2021

The emerging role of artificial intelligence in the reporting of prostate pathology.

Pathology 2021 Aug 6;53(5):565-567. Epub 2021 Jun 6.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.1016/j.pathol.2021.04.002DOI Listing
August 2021

Bronchial carcinoid tumor managed with bronchial artery embolization before endobronchial resection: A case report.

Thorac Cancer 2021 07 6;12(14):2134-2137. Epub 2021 Jun 6.

Department of Respiratory Medicine and Allergology, Aichi Medical University, Nagakute, Japan.

Endobronchial resection using a bronchoscope is often selected as treatment for carcinoid tumors located in the central airways. However, massive bleeding is one of the most serious complications during bronchoscopic surgery. Here, we report the case of a 77-year-old female with a typical carcinoid tumor located in the right truncus intermedius who underwent bronchial artery embolization (BAE) one day before endobronchial intervention using a flexible bronchoscope. The tumor was successfully resected without bleeding. BAE prior to endobronchial resection of carcinoid tumors may be useful for reducing the risk of bleeding.
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http://dx.doi.org/10.1111/1759-7714.14050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287016PMC
July 2021

Comparable survival outcome between acquired cystic disease associated renal cell carcinoma and clear cell carcinoma in patients with end-stage renal disease: a multi-institutional central pathology study.

Pathology 2021 May 1. Epub 2021 May 1.

Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute, Japan.

Acquired cystic disease (ACD) associated renal cell carcinoma (RCC) is designated as a new subtype unique to patients with end-stage renal disease (ESRD) according to the 2016 World Health Organization (WHO) classification. However, the oncological outcomes of the prognostic factors for patients with this subtype are not fully understood. In the present study, we compared the survival of ACD associated RCC patients who underwent nephrectomy with that of patients with other histological subtypes who developed ESRD. Over 378 patients who underwent nephrectomy at three Japanese institutes between 1987 and 2016 were included in this study. A central pathologist reviewed the sections from all patients according to the 2016 WHO classification. The central pathological review showed a clear cell subtype in 165 patients (43.6%), ACD associated RCC in 112 (29.6%), papillary in 61 (16.1%), and others in 40 (10.7%). The proportion of patients with pathological stage 1 was extremely high in both clear cell and ACD associated RCC cohorts (86.6%, 85.7%). The cancer specific survival (CSS) and recurrence free survival rates of patients with ACD associated RCC were comparable with those with clear cell carcinoma and significantly better than those with the papillary subtype. The factors predictive of unfavourable outcomes were long dialysis duration, tumour size, pathological stage, grade 4 tumour, and the presence of lymphovascular invasion or a sarcomatoid component. Patients with a pre-operative dialysis duration of 20 years or longer showed a significantly worse CSS than other patients, probably owing to sarcomatoid differentiation and stage migration during the advanced stages. In conclusion, this study included the largest number of patients with ACD associated RCC, showing a survival similar to that of clear cell histology patients with ESRD, except for the rarity of late recurrence. ACD associated RCC was not as indolent as initially recognised when patients were on long term dialysis.
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http://dx.doi.org/10.1016/j.pathol.2021.01.014DOI Listing
May 2021

The Positivity of Phosphorylated STAT3 Is a Novel Marker for Favorable Prognosis in Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma.

Am J Surg Pathol 2021 06;45(6):832-840

Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine).

On the basis of immunohistochemistry, diffuse large B-cell lymphoma (DLBCL) is categorized as a germinal center B-cell (GCB) or non-GCB subtype. Recent integrated genomic analyses have highlighted the importance of the JAK-STAT3 pathway in the molecular pathogenesis of DLBCL. However, its relevance to clinical outcomes remains controversial. Therefore, we evaluated the extent of the nuclear expression of phosphorylated STAT3 (pSTAT3), a surrogate marker of signal transducer and activator of transcription 3 (STAT3) activation, by immunohistochemistry. We also analyzed the potential relationship between pSTAT3 positivity (defined as ≥40% positive neoplastic cells) and clinicopathologic characteristics in 294 patients with DLBCL. pSTAT3 was detected in 122 patients (42%), with a higher rate in the non-GCB subtype than in the GCB subtype (57% vs. 28%, P<0.001). Factors potentially activating STAT3, MYD88L265P, and Epstein-Barr virus-encoded small RNA were identified in the pSTAT3-positive non-GCB subtype, whereas the pSTAT3-positive GCB subtype often showed STAT3 mutations and lacked EZH2 mutations and the rearrangements of BCL2 and MYC. Multivariate analyses revealed that the pSTAT3-positive GCB subtype showed a favorable prognosis (HR: 0.17; 95% confidence interval, 0.04-0.7; P=0.014). These findings suggest that pSTAT3 positivity may have a unique impact on the clinicopathologic characteristics of DLBCL, making it a promising novel marker for the favorable prognosis of patients with the GCB subtype.
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http://dx.doi.org/10.1097/PAS.0000000000001691DOI Listing
June 2021

Primary Testicular Neuroendocrine Tumor Coexisting With Seminoma Sharing Germ Cell Origin.

Int J Surg Pathol 2021 Apr 13:10668969211008980. Epub 2021 Apr 13.

118084Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.

A 40-year-old, male, Japanese patient presented with the complaint of painless, right testicular swelling. Tumor markers for testicular cancer were normal. He underwent radical orchiectomy with the clinical diagnosis of stage I seminoma. Pathological examination revealed seminoma and coexisting neuroendocrine tumor (NET). Germ cell neoplasia in situ (GCNIS) was present in the vicinity of seminoma, but there was no continuity between NET and seminoma. Tumor cells of both lesions displayed amplification of 12p and isochromosome 12p on fluorescence in situ hybridization, suggesting that both tumors originated from GCNIS. The present report is the first to describe a case of primary testicular NET coexisting with seminoma in an ipsilateral testis.
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http://dx.doi.org/10.1177/10668969211008980DOI Listing
April 2021

Expression and Prognostic Significance of CD47-SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer.

Int J Mol Sci 2021 Mar 7;22(5). Epub 2021 Mar 7.

Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.

Despite the confirmed anti-cancer effects of T-cell immune checkpoint inhibitors, in colorectal cancer (CRC) they are only effective in a small subset of patients with microsatellite-unstable tumors. Thus, therapeutics targeting other types of CRCs or tumors refractory to T-cell checkpoint inhibitors are desired. The binding of aberrantly expressed CD47 on tumor cells to signal regulatory protein-alpha (SIRPA) on macrophages allows tumor cells to evade immune destruction. Based on these observations, drugs targeting the macrophage checkpoint have been developed with the expectation of anti-cancer effects against T-cell immune checkpoint inhibitor-refractory tumors. In the present study, 269 primary CRCs were evaluated immunohistochemically for CD47, SIRPA, CD68, and CD163 expression to assess their predictive utility and the applicability of CD47-SIRPA axis-modulating drugs. Thirty-five percent of the lesions (95/269) displayed CD47 expression on the cytomembrane of CRC cells. CRCs contained various numbers of tumor-associated immune cells (TAIs) with SIRPA, CD68, or CD163 expression. The log-rank test revealed that patients with CD47-positive CRCs had significantly worse survival than CD47-negative patients. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio (R) = 0.23), age < 70 years (HR = 0.48), and high SIRPA-positive TAI counts (HR = 0.55) as potential favorable factors. High tumor CD47 expression (HR = 1.75), lymph node metastasis (HR = 2.26), and peritoneal metastasis (HR = 5.80) were cited as potential independent risk factors. Based on our observations, CD47-SIRPA pathway-modulating therapies may be effective in patients with CRC.
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http://dx.doi.org/10.3390/ijms22052690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975978PMC
March 2021

Cribriform prostate cancer: Morphologic criteria enabling a diagnosis, based on survey of experts.

Ann Diagn Pathol 2021 Jun 22;52:151733. Epub 2021 Mar 22.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Among four sub-patterns of Gleason grade 4 prostate cancer, voluminous evidence supports that the cribriform pattern holds an unfavorable prognostic impact, as compared with poorly-formed, fused, or glomeruloid. The International Society of Urological Pathology (ISUP) recommends specifying whether invasive grade 4 cancer is cribriform. Recently, ISUP experts published a consensus definition of cribriform pattern highlighting criteria that distinguish it from mimickers. The current study aimed to analyze morphologic features separately to identify those that define the essence of the cribriform pattern. Thirty-two selected photomicrographs were classified by 12 urologic pathologists as: definitely cribriform cancer, probably cribriform, unsure, probably not cribriform, or definitely not cribriform. Consensus was defined as 9/12 agree or disagree, with ≤1 strongly supporting the opposite choice. Final consensus was achieved in 21 of 32 cases. Generalized estimating equation (GEE) model with logit link was fitted to estimate effect of multiple morphologic predictors. Fisher exact test was used for categorical findings. Presence of intervening stroma precluded calling cribriform cancer (p = 0.006). Mucin presence detracted (p = 0.003) from willingness to call cribriform cancer (only 3 cases had mucin). Lumen number was associated with cribriform consensus (p = 0.0006), and all consensus cases had ≥9 lumens. Predominant papillary pattern or an irregular outer boundary detracted (p = NS). Invasive cribriform carcinoma should have absence of intervening stroma, and usually neither papillary pattern, irregular outer boundary, nor very few lumens. Setting the criteria for cribriform will help prevent over- or undercalling this important finding.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151733DOI Listing
June 2021

Association of Matrix Metalloproteinase-2 mRNA Expression with Subtypes of Pediatric Cholesteatoma.

Biomed Res Int 2021 10;2021:6644897. Epub 2021 Mar 10.

Department of Otorhinolaryngology, Aichi Medical University School of Medicine, 1-1, Yazakokarimata, Nagakute, Aichi 480-1195, Japan.

Objective: Cholesteatoma is a clinically heterogeneous disease, with some patients showing spontaneous regression, while others experiencing an aggressive, lethal disease. Cholesteatoma in children can be divided into two types: congenital and acquired. Identifying good prognostic markers is needed to help select patients who will require immediate surgical intervention. Matrix metalloproteinase-2 (MMP2) was previously reported to play an important role in cholesteatoma progression, by promoting bone destruction and keratinocyte infiltration. Herein, we analyzed mRNA expression level in cholesteatoma using RNA-in situ hybridization in formalin-fixed, paraffin-embedded (FFPE) tissue samples.

Methods: Sixty patients with cholesteatoma under 15 years old, who underwent their primary surgery at Aichi Medical University's Otolaryngology Department, were analyzed for MMP2 expression level, using RNA-in situ hybridization.

Results: There were no significant differences in mRNA expression level between congenital cholesteatoma and acquired cholesteatomas. In congenital cholesteatoma, higher MMP2 signals were observed in the open type than in the closed type ( < 0.001). In acquired cholesteatoma, higher MMP2 signals were observed in the pars tensa than in the pars flaccida ( < 0.001). mRNA expression level was almost exclusively found in the fibroblasts or in the inflammatory cells in the stroma, but not in the epithelium.

Conclusion: Our study reveals that mRNA expression level is strongly associated with the subtypes of cholesteatoma. The findings suggest that the level of expression of mRNA may be related to the pathogenesis and aggressive features of cholesteatoma.
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http://dx.doi.org/10.1155/2021/6644897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972836PMC
May 2021

Spontaneous regression of multiple pulmonary metastases accompanied by normalization of serum immune markers following cytoreductive nephrectomy in a patient with clear-cell renal cell carcinoma.

IJU Case Rep 2021 Mar 26;4(2):95-99. Epub 2020 Dec 26.

Department of Urology Dokkyo Medical University Shimotsuga Tochigi Japan.

Introduction: The spontaneous regression of metastases, which mostly occurs after surgical resection of the primary tumor, has been described in various malignancies, including renal cell carcinoma. The involvement of the host immune system is currently postulated as the underlying mechanism.

Case Presentation: We present a case of metastatic clear-cell renal cell carcinoma that achieved complete spontaneous regression of multiple pulmonary metastases preceded by normalization of serum immune markers after cytoreductive nephrectomy. The patient remained disease free for 3 years without any systemic therapy, suggesting that postoperative normalization of serum immune markers may indicate recovery of the host immune system, which prevents tumor recurrence.

Conclusion: Monitoring of serum immune markers may be useful to identify patients with recovered immune function and, therefore, may not require systemic therapy. Similarly, the case suggests a potential role of cytoreductive nephrectomy in the contemporary management of metastatic renal cell carcinoma.
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http://dx.doi.org/10.1002/iju5.12252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924083PMC
March 2021

A Case of Low-Grade Oncocytic Tumor/Chromophobe Renal Cell Carcinoma (Oncocytic Variant) of the Kidney.

Case Rep Pathol 2021 18;2021:6684777. Epub 2021 Feb 18.

Department of Pathology, Shonan Fujisawa Tokushukai Hospital, 1-5-1 Tsujido-kandai, Fujisawa, Kanagawa 251-0041, Japan.

The oncocytic variant of chromophobe renal cell carcinoma (oChRCC) and low-grade oncocytic tumor (LOT) is introduced as new renal disease entity. Both of these tumors are low-grade malignancies consisting of cells with eosinophilic cytoplasm. Distinguishing between eosinophilic variant of chromophobe renal cell carcinoma (eCRCC) and oncocytoma is often a diagnostic challenge in routine surgical pathology. However, oChRCC and LOT might be independent disease entities that might not fit completely into any of these categories. Histologically, these tumors have greater morphological similarity with oncocytoma than with ChRCC. However, immunohistochemically, they exhibit diffuse and dense positivity for CK7 and are negative for CD117. In the present case, we initially had difficulty distinguishing among oncocytoma, eCRCC, and type 2 papillary renal cell carcinoma (2-pRCC). However, after learning about new disease entities such as oChRCC and LOT, we were able to diagnose this tumor.
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http://dx.doi.org/10.1155/2021/6684777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906815PMC
February 2021

Editorial Comment to Prognostic significance of tertiary Gleason pattern in the contemporary era of Gleason grade grouping: A narrative review.

Authors:
Toyonori Tsuzuki

Int J Urol 2021 06 28;28(6):621-622. Epub 2021 Feb 28.

Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute, Aichi, Japan.

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http://dx.doi.org/10.1111/iju.14535DOI Listing
June 2021

High phospho-histone H3 expression uniquely predicts favorable survival among four markers of cellular proliferation in colorectal cancer.

Pathol Int 2021 May 25;71(5):316-324. Epub 2021 Feb 25.

Department of Pathology, Aichi Medical University School of Medicine, Aichi, Japan.

Colorectal cancer (CRC) is one of the most frequent gastrointestinal cancers worldwide, with high morbidity and mortality rates. Despite numerous attempts to identify prognostic markers for the CRC patients, the significance of the association of cellular proliferation markers with survival is controversial. Here we used immunohistochemistry to detect four markers of cellular proliferation expressed in primary CRC tissue specimens (n = 269) to assess their potential to serve as prognostic factors. CRC cells variably expressed phospho-histone H3 (PHH3) (range, 0-76 per high-powered field (HPF); median, 7 per HPF), cyclin A (CCNA) (range, 11.3-73.7%; median, 32%), geminin (GMNN) (range, 7.8-82.0%; median, 37.1%), and marker of proliferation Ki-67 (MKI67) (range, 4.9-96.6%; median, 49.6%). Among them, patients with PHH3-high (≥7 per HPF) tumors uniquely experienced significantly longer 5-year survival than those with PHH3-low (≤6 per HPF) (81.8% vs. 65.5%; P = 0.0047). Multivariable Cox hazards regression analysis identified PHH3-high (hazard ratio, 0.54; 95% confidence interval, 0.31-0.92; P = 0.025) as potential favorable factors. PHH3 levels inversely associated with pT stage (P < 0.0001) and were significantly and inversely associated with tumor diameter (ρ = -0.314, P < 0.0001). These findings support the use of PHH3 immunohistochemistry for predicting the prognoses of patients with CRC.
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http://dx.doi.org/10.1111/pin.13084DOI Listing
May 2021

Primary cutaneous methotrexate-associated B-cell lymphoproliferative disorders other than EBV-positive mucocutaneous ulcer: clinical, pathological, and immunophenotypic features.

Pathology 2021 Aug 19;53(5):595-601. Epub 2021 Feb 19.

Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute, Japan.

Methotrexate (MTX)-associated B-cell lymphoproliferative disorders (B-LPD) may first present in the skin. Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is now a well known disease listed in the 2017 World Health Organization classification. However, primary cutaneous MTX-associated B-LPD (pcMTX B-LPD), other than EBVMCU, appear to be underestimated, and their distinctiveness remains unproven. This study aimed to document the clinicopathological characteristics of nine patients with pcMTX B-LPD that were not EBVMCU to extend our understanding of this peculiar disease. The cohort included three males and six females, with a median age of 74 years (range 54-83 years). All patients were treated with MTX for RA. Of nine patients, four presented with a solitary lesion, and five had multiple lesions. Histologically, five cases showed a polymorphic pattern, and four showed a monomorphic pattern. Immunohistochemically, four cases showed positive EBER staining, and one showed positive CD5 staining. In eight cases, once pcMTX B-LPD was diagnosed, methotrexate was immediately withdrawn. All eight of these patients experienced spontaneous regression and achieved complete remission (CR), without relapse. The patient with CD5 positivity received cytotoxic chemotherapy as the initial treatment. This patient achieved a CR after the initial treatment, but eventually experienced disease relapse resulting in death. We also revealed that pcMTX B-LPD and MTX-associated EBVMCU exhibited similar biological behaviours. We concluded that most pcMTX B-LPD cases could be cured by stopping MTX treatment. We also highlighted the fact that pcMTX B-LPD and MTX-EBVMCU had overlapping features. This finding suggested that pcMTX B-LPD and MTX-EBVMCU might share an underlying mechanism.
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http://dx.doi.org/10.1016/j.pathol.2020.10.019DOI Listing
August 2021

Bladder preservation therapy in combination with atezolizumab and radiation therapy for invasive bladder cancer (BPT-ART) - A study protocol for an open-label, phase II, multicenter study.

Contemp Clin Trials Commun 2021 Mar 21;21:100724. Epub 2021 Jan 21.

Department of Urology, Faculty of Medicine, University of Tsukuba, Japan.

Radical cystectomy (RC) is recommended for muscle-invasive bladder cancer (MIBC) or highest-risk non-muscle-invasive bladder cancer (NMIBC). Trimodal therapy (TMT) is the most favorable strategy among bladder preservation therapies (BPT) for patients who are ineligible for or refuse RC. However, referrals for TMT, especially following chemotherapy, are limited by the patient's condition. Therefore, new BPT approaches are needed. Atezolizumab inhibits programmed death-ligand 1, is well-tolerated in patient populations heavily dominated by renal insufficiency, and is expected to have synergistic anti-tumor effects in combination with radiation therapy (RT). Therefore, we have conducted this open-label phase II multicenter study to evaluate the efficacy and safety of RT in combination with atezolizumab for T2-3 MIBC and highest-risk T1 NMIBC patients. This study was initiated in January 2019, and we aimed to enroll a total of 45 patients. The study is registered in the Japan Registry of Clinical Trials (Identifier: RCT2031180060).
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http://dx.doi.org/10.1016/j.conctc.2021.100724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878176PMC
March 2021

Loss-of-function mutation of c-Ret causes cerebellar hypoplasia in mice with Hirschsprung disease and Down's syndrome.

J Biol Chem 2021 Jan-Jun;296:100389. Epub 2021 Feb 6.

Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Aichi, Japan. Electronic address:

The c-RET proto-oncogene encodes a receptor-tyrosine kinase. Loss-of-function mutations of RET have been shown to be associated with Hirschsprung disease and Down's syndrome (HSCR-DS) in humans. DS is known to involve cerebellar hypoplasia, which is characterized by reduced cerebellar size. Despite the fact that c-Ret has been shown to be associated with HSCR-DS in humans and to be expressed in Purkinje cells (PCs) in experimental animals, there is limited information about the role of activity of c-Ret/c-RET kinase in cerebellar hypoplasia. We found that a loss-of-function mutation of c-Ret Y1062 in PCs causes cerebellar hypoplasia in c-Ret mutant mice. Wild-type mice had increased phosphorylation of c-Ret in PCs during postnatal development, while c-Ret mutant mice had postnatal hypoplasia of the cerebellum with immature neurite outgrowth in PCs and granule cells (GCs). c-Ret mutant mice also showed decreased numbers of glial fibers and mitogenic sonic hedgehog (Shh)-positive vesicles in the external germinal layer of PCs. c-Ret-mediated cerebellar hypoplasia was rescued by subcutaneous injection of a smoothened agonist (SAG) as well as by reduced expression of Patched1, a negative regulator for Shh. Our results suggest that the loss-of-function mutation of c-Ret Y1062 results in the development of cerebellar hypoplasia via impairment of the Shh-mediated development of GCs and glial fibers in mice with HSCR-DS.
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http://dx.doi.org/10.1016/j.jbc.2021.100389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950328PMC
February 2021

Interobserver reproducibility of perineural invasion of prostatic adenocarcinoma in needle biopsies.

Virchows Arch 2021 Jun 3;478(6):1109-1116. Epub 2021 Feb 3.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Numerous studies have shown a correlation between perineural invasion (PNI) in prostate biopsies and outcome. The reporting of PNI varies widely in the literature. While the interobserver variability of prostate cancer grading has been studied extensively, less is known regarding the reproducibility of PNI. A total of 212 biopsy cores from a population-based screening trial were included in this study (106 with and 106 without PNI according to the original pathology reports). The glass slides were scanned and circulated among four pathologists with a special interest in urological pathology for assessment of PNI. Discordant cases were stained by immunohistochemistry for S-100 protein. PNI was diagnosed by all four observers in 34.0% of cases, while 41.5% were considered to be negative for PNI. In 24.5% of cases, there was a disagreement between the observers. The kappa for interobserver variability was 0.67-0.75 (mean 0.73). The observations from one participant were compared with data from the original reports, and a kappa for intraobserver variability of 0.87 was achieved. Based on immunohistochemical findings among discordant cases, 88.6% had PNI while 11.4% did not. The most common diagnostic pitfall was the presence of bundles of stroma or smooth muscle. It was noted in a few cases that collagenous micronodules could be mistaken for a nerve. The distance between cancer and nerve was another cause of disagreement. Although the results suggest that the reproducibility of PNI may be greater than that of prostate cancer grading, there is still a need for improvement and standardization.
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http://dx.doi.org/10.1007/s00428-021-03039-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203540PMC
June 2021

Prevalence and Clinicopathologic Features of Intestinal Perforation Caused by Segmental Absence of the Intestinal Musculature in Adults.

Am J Surg Pathol 2021 06;45(6):803-811

Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute.

Segmental absence of the intestinal musculature (SAIM) can cause intestinal perforation in adults. However, its prevalence and clinicopathologic features have not been well-described. This study aimed to determine the prevalence of SAIM-associated perforation and characterize its clinicopathologic features. We retrospectively examined 109 cases of intestinal perforation that underwent surgical resection from January 2009 to December 2019. SAIM was defined as the complete absence of the muscularis propria without extensive inflammation and fibrinous exudation around the perforation. SAIM was the second most frequent cause of perforation (26 cases: 24%), the most frequent cause being related to diverticulitis (39 cases: 36%). The most common site was the sigmoid colon (12 cases: 46.2%). The younger group (aged below 65 y) exhibited more frequent perforation of the upper segments of the gastrointestinal tract (from the duodenum to the descending colon) than the older group (65 y and above) (P=0.0018). No patients developed recurrence. The most common gross features were well-defined circular or small punched-out lesions, and the histologic features were complete absence of the muscularis propria and absence of hemorrhage and necrosis around the area of perforation. The characteristic features of SAIM were unique and their prevalence was higher than previously reported. The precise recognition of SAIM can aid in understanding the cause of perforation and avoiding further unnecessary examinations.
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http://dx.doi.org/10.1097/PAS.0000000000001671DOI Listing
June 2021

Perineal recurrence of prostate ductal adenocarcinoma after transperineal brachytherapy: a case report and literature review.

J Contemp Brachytherapy 2020 Dec 16;12(6):612-617. Epub 2020 Dec 16.

Department of Surgical Pathology, Aichi Medical University, Nagakute, Aichi, Japan.

Perineal recurrence after brachytherapy is an exceedingly rare complication. Moreover, ductal adenocarcinoma is a rare histological variant of prostate cancer. Herein, we describe a case of perineal recurrence from ductal adenocarcinoma of prostate after low-dose-rate brachytherapy (LDR-BT) in a 65-year-old male patient. The patient had localized prostate cancer, for which he received LDR-BT; however, he experienced perineal recurrence 2 years after receiving LDR-BT. Surgical excision was attempted, but we were unable to remove the whole tumor, owing to invasion to surrounding tissue. Pathological examination of resected tumor showed ductal adenocarcinoma of the prostate. External beam radiation therapy and high-dose-rate brachytherapy (HDR-BT) were performed for residual tumor. Mild mediastinal lymph node swelling was observed during clinical course of the disease. Hence, androgen deprivation therapy was administered with abiraterone after radiation therapy, and prostate-specific antigen level decreased to undetectable level. Biochemical failure after transperineal brachytherapy for prostate cancer should be considered as a perineal recurrence.
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http://dx.doi.org/10.5114/jcb.2020.101696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787201PMC
December 2020

Thyroid Gland Flap for Minimally Invasive Reconstructive Head and Neck Surgery.

Plast Reconstr Surg Glob Open 2020 Dec 17;8(12):e3297. Epub 2020 Dec 17.

Department of Anatomy, Aichi Medical University, Aichi, Japan.

Head and neck surgery sometimes causes small defects, and salvage surgery after chemoradiotherapy poses some risk because of damage to the surgical site from the previous treatment. We have developed a novel thyroid gland flap for head and neck surgical reconstruction and here we describe elevating the flap, including arc rotation, size, and suture technique, and our outcomes to date.

Methods: Thyroid gland flap reconstruction was performed in 13 cases (11 patients) between July 2009 and May 2020. The clinical importance and adverse effects of the procedure were examined. Thyroid function and blood flow of the flap were assessed, and the status of the flap and irradiated recipient tissue was examined histopathologically.

Results: Median age at surgery was 64.6 years (range 49-77 years). Two of the patients underwent reconstruction with a thyroid gland flap twice. There were 4 cases of primary head and neck cancer resection with neck dissection in which the flap was harvested from the thyroid gland as reinforcement. In 1 case, surgery was performed for cervical esophageal diverticulum. In all cases, the arc was limited to 6 cm and suturing was basic. There were no complications of the surgical procedure, and the postoperative course was uneventful. Contrast-enhanced computed tomography revealed adequate enhancement of the flap. Postoperative thyroid function was normal. The thyroid gland flap was firmly adapted and fused with the irradiated recipient tissue.

Conclusion: The thyroid gland flap could be an effective tissue flap fed by the superior thyroid arteriovenous pedicle for head and neck reconstruction.
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http://dx.doi.org/10.1097/GOX.0000000000003297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787277PMC
December 2020

pT3 subclassification of renal pelvic cancer considering the tumor location improves the patients' prognostic accuracy.

Virchows Arch 2021 Jun 9;478(6):1089-1097. Epub 2021 Jan 9.

Department of Surgical Pathology, Aichi Medical University Hospital, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.

Whether pT3 urothelial carcinoma of the renal pelvis (UCRP) and urothelial carcinoma of the ureter (UCU) have the same prognosis is controversial, this study compared the prognosis of pT3 UCRP with that of pT3 UCU. We retrospectively evaluated 954 patients who underwent nephroureterectomy at our institutions between January 1983 and December 2017. All surgical specimens were reviewed by a single genitourinary pathologist. Cases of pT3 UCRP were subclassified as pT3a (urothelial carcinomas extending only to the renal medulla) and pT3b (urothelial carcinomas extending into the renal cortex and/or peripelvic adipose tissue). Fine and Gray's model was used to predict recurrence-free survival (RFS) and cancer-specific survival (CSS). A total of 493 (51.7%) had UCRP and 461 (48.3%) had UCU. Within this group, 202 patients had pT3 UCRP and 146 had pT3 UCU. The pT3 subclassification of UCRP resulted in 79 cases of pT3a and 120 of pT3b. The difference in 5-year CSS among the pT3a UCRP, pT2 UCRP, and pT2 UCU subgroups was not statistically significant (pT3a UCRP vs pT2 UCRP, HR = 0.69, p = 0.56; pT3a UCRP vs pT2 UCU, HR = 0.66, p = 0.31) However, RFS and CSS were significantly higher in the pT3a UCRP group than in the pT3b group (pT3a vs pT3b, HR = 2.59, p = 0.0038 and pT3a vs pT3b, HR = 3.10, p = 0.001). The results suggest that our proposed pT3 subclassification better predicts the prognosis of UCRP patients than does the pT3 of the current AJCC/UICC classification.
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http://dx.doi.org/10.1007/s00428-020-02973-8DOI Listing
June 2021

Increased expression of adenosine 2A receptors in metastatic renal cell carcinoma is associated with poorer response to anti-vascular endothelial growth factor agents and anti-PD-1/Anti-CTLA4 antibodies and shorter survival.

Cancer Immunol Immunother 2021 Jul 8;70(7):2009-2021. Epub 2021 Jan 8.

Department of Urology, Dokkyo Medical University, 880 Kitakobayashi Mibu, Tochigi, 321-0293, Japan.

Background: Adenosine and its adenosine 2A receptors (A2AR) mediate the immunosuppressive mechanism by which tumors escape immunosurveillance and impede anti-tumor immunity within the tumor microenvironment. However, we do not know whether the adenosine pathway (CD39/CD73/A2AR) plays a role in renal cell carcinoma (RCC). Therefore, we studied the role of immunosuppression in RCC by assessing the adenosine pathway in patients with RCC treated with anti-vascular endothelial growth factor (anti-VEGF) agents or immune checkpoints inhibitors (ICIs) or both.

Methods: In 60 patients with metastatic RCC, we examined the expression of CD39, CD73, A2AR, and programmed cell death 1 ligand 1 (PD-L1) immunohistochemically in surgically resected tumor tissues and studied the clinicopathological characteristics of these patients. Patients were treated by cytoreductive nephrectomy with systemic therapy with anti-VEGF agent or a combination of the ICIs anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody and programmed cell death 1 (PD-1) antibody.

Results: Increased expression of A2AR in the primary tumors was associated with metastatic profiles. Patients treated with anti-PD-1 antibody in monotherapy, a combination of anti-PD-1 and anti-CTLA4 antibodies, or anti-VEGF agents showed better response and longer overall survival if the primary tumor had higher PD-L1 expression and lower A2AR expression. In Cox multivariate regression analysis, higher expression of A2AR was associated with shorter overall survival.

Conclusions: Our findings suggest that the expression of A2AR and PD-L1 in the primary tumors in RCC might predict the outcomes of treatment with anti-VEGF agents and ICIs and that the A2AR pathway might be a molecular target for immunotherapy.
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http://dx.doi.org/10.1007/s00262-020-02843-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195893PMC
July 2021

Grade group 2 (10% ≥ GP4) patients have very similar malignant potential with grade group 1 patients, given the risk of intraductal carcinoma of the prostate.

Int J Clin Oncol 2021 Apr 1;26(4):764-769. Epub 2021 Jan 1.

Department of Surgical Pathology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, Japan.

Background: It has been argued that grade group 2 (GG2) with a low Gleason pattern 4 (GP4) proportion should be an indication for active surveillance (AS) of prostate cancer (PCa). However, the cut-off GP4 proportion for AS remains unclear. Here, we evaluated the effect of GP4 proportion and IDC-P on cancer recurrence following radical prostatectomy (RP) in GG1 and GG2 patients, and identified candidates for AS.

Methods: We retrospectively evaluated 646 patients with PCa who underwent RP between 2005 and 2014, and whose specimens were of GG1 or GG2 status.

Results: The GGs were as follows: GG1, 25.2% (n = 163); GG2 (5% ≥ GP4), 11.4% (n = 74); GG2 (5% < GP4 ≤ 10%), 25.9% (n = 167); and GG2 (20% ≤ GP4), 37.5% (n = 242). IDC-P was detected in 26 patients (4%), i.e., in 2/167 GG2 (5% < GP4 ≤ 10%; 1%) cases and 24/242 GG2 (20% ≤ GP4; 10%) cases. GG2 patients with IDC-P exhibited a significantly poorer prognosis than did those without IDC-P (P < 0.0001), as did GG2 (20% ≤ GP4) patients without IDC-P (P < 0.05). The GG2 (5% ≥ GP4) and (5% < GP4 ≤ 10%) groups exhibited prognoses similar to those of the GG1 patients. In multivariate analysis, GG2 (20% ≤ GP4) without IDC-P, the presence of IDC-P, and the prostate-specific antigen level at diagnosis significantly predicted prognosis (P < 0.05, < 0.0001, and < 0.0001, respectively).

Conclusion: Our findings suggest that GG2 (GP4 ≤ 10%) patients could be indicated for AS, similar to GG1 patients, given the risk of IDC-P tumors.
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http://dx.doi.org/10.1007/s10147-020-01841-4DOI Listing
April 2021
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