Batf3 DCs and the 4-1BB/4-1BBL axis are required at the effector phase in the tumor microenvironment for PD-1/PD-L1 blockade efficacy.

The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL is a major positive co-stimulatory signal provided by these DCs within the TME that translates to CD8 T cell functional reinvigoration and tumor regression.

Wilms tumor reveals DNA repair gene hyperexpression is linked to lack of tumor immune infiltration.

Background: A T cell-rich tumor microenvironment has been associated with improved clinical outcome and response to immune checkpoint blockade therapies in several adult cancers. Understanding the mechanisms for lack of immune cell infiltration in tumors is critical for expanding immunotherapy efficacy. To gain new insights into the mechanisms of poor tumor immunogenicity, we turned to pediatric cancers, which are generally unresponsive to checkpoint blockade.

Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial.

Purpose: KEYNOTE-224 cohort 1 demonstrated that pembrolizumab was efficacious and tolerable in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. We report results from KEYNOTE-224 (NCT02702414) cohort 2, which enrolled patients with advanced HCC and no prior systemic therapy.

Patients And Methods: KEYNOTE-224 was an open-label, multicountry phase II trial.

Severe COVID-19 infection is associated with aberrant cytokine production by infected lung epithelial cells rather than by systemic immune dysfunction.

The mechanisms explaining progression to severe COVID-19 remain poorly understood. It has been proposed that immune system dysregulation/over-stimulation may be implicated, but it is not clear how such processes would lead to respiratory failure. We performed comprehensive multiparameter immune monitoring in a tightly controlled cohort of 128 COVID-19 patients, and used the ratio of oxygen saturation to fraction of inspired oxygen (SpO2 / FiO2) as a physiologic measure of disease severity.

Immune cell and tumor cell-derived CXCL10 is indicative of immunotherapy response in metastatic melanoma.

A T cell-inflamed tumor microenvironment is characterized by the accumulation and local activation of CD8 T cells and Bat3-lineage dendritic cells, which together are associated with clinical response to anti-programmed cell death protein 1 (anti-PD-1)-based immunotherapy. Preclinical models have demonstrated a crucial role for the chemokine CXCL10 in the recruitment of effector CD8 T cells into the tumor site, and a chemokine gene signature is also seen in T cell-inflamed tumors from patients. However, the cellular source of CXCL10 in human solid tumors is not known.

Efficacy evaluation of anticancer agents in single-arm clinical trials: analysis of review reports from Pharmaceuticals and Medical Devices Agency.

Background: Comparative studies often cannot be conducted for cancer types with a small patient population. We reviewed the efficacy evaluations of new drug approvals in Japan based on the results of single-arm clinical trials.

Methods: We reviewed review reports on anticancer agents approved in Japan between 2006 and 2019 that are publicly available on the website of the Pharmaceuticals and Medical Devices Agency, Japan.

Review of early endoscopic findings in patients with local recurrence after definitive chemoradiotherapy for esophageal squamous cell carcinoma.

Backgrounds: Local recurrence after definitive chemoradiotherapy, if diagnosed early, can be cured by salvage endoscopic therapy, which allows organ preservation and contributes to maintaining patient quality of life. This study aimed to investigate early endoscopic findings of local recurrence in post-definitive chemoradiotherapy patients.

Methods: Between January 2008 and June 2012, 17 esophageal squamous cell carcinoma patients with no metastasis but local recurrence after definitive chemoradiotherapy were enrolled.

The Tumor Microenvironment of Bladder Cancer.

Bladder cancer has been well known as immunotherapy-responsive disease as intravesical therapy with BCG has been the standard of care for non-muscle invasive disease for several decades. In addition, immune checkpoint inhibitors have dramatically changed the treatment of metastatic bladder cancer. However, only a small fraction of patients with bladder cancer can benefit from these therapies.

Relationship between the immune microenvironment of different locations in a primary tumour and clinical outcomes of oesophageal squamous cell carcinoma.

Background: Tumour microenvironments can differ according to intratumoural locations. We investigated the immune status at different locations in primary tumours and its clinical significance in oesophageal squamous cell carcinoma (ESCC).

Methods: The number of CD8 tumour-infiltrating immune cells (TIICs) and PD-1 TIICs, and PD-L1 expression on tumour cells (PD-L1) were immunohistochemically examined in the surface (Surf), centre (Cent) and invasive front (Inv) of tumours surgically resected from 192 patients with ESCC.

Risk factors for febrile neutropenia in neoadjuvant docetaxel, cisplatin, and 5-fluorouracil chemotherapy for esophageal cancer.

Purpose: The aim of the present study was to evaluate the incidence and explore the risk factors of febrile neutropenia (FN) in patients with esophageal cancer receiving neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy in real-world settings.

Methods: We retrospectively reviewed clinical data of 128 consecutive patients with esophageal cancer. Specifically, these patients underwent neoadjuvant DCF chemotherapy with prophylactic antibiotic administration at our institution between July 2009 and January 2015.

Complete response of renal cell carcinoma vena cava tumor thrombus to neoadjuvant immunotherapy.

Background: Clinically localized renal cell carcinoma is treated primarily with surgery followed by observation or adjuvant sunitinib in selected high-risk patients. The checkpoint inhibitor immunotherapeutic agents nivolumab and ipilimumab have recently shown a survival benefit in the first-line metastatic setting. To date, there have been no reports on the response of localized renal cancer to modern immunotherapy.

Global Development of Anticancer Therapies for Rare Cancers, Pediatric Cancers, and Molecular Subtypes of Common Cancers.

Advances in genetic sequencing and other diagnostic technologies have enabled the use of precision medicine in clinical cancer care, as well as the development of novel therapies that are targeted to specific molecular drivers of cancer. Developing these new agents and making them accessible to patients requires global clinical studies and regulatory review and approval by different national regulatory agencies. Whereas these global trials present challenges for drug developers who conduct them and regulatory agencies who oversee them, they also raise practical issues about patients with low-frequency cancers who need these therapies.

Pathological tumor regression grade of metastatic tumors in lymph node predicts prognosis in esophageal cancer patients.

Tumor regression grade of the primary tumor (TRG-PT) and residual lymph node metastasis have been pathologically determined in esophageal squamous cell carcinoma (ESCC) patients who had received neoadjuvant chemotherapy (nCT) followed by surgery; however, TRG of the metastatic tumor involving lymph nodes (LN) has not yet been determined. The aim of the present study was to clarify the impact of TRG on the prognosis of ESCC patients. ESCC patients (n = 110) who had received nCT followed by surgery were enrolled.

Salvage endoscopic resection (ER) after chemoradiotherapy for esophageal squamous cell carcinoma: What are the risk factors for recurrence after salvage ER?

Background And Aim: Salvage endoscopic resection (ER) is among the curative treatments for superficial local failure after chemoradiotherapy (CRT) for esophageal squamous cell carcinoma (ESCC). The present study aimed to clarify risk factors for recurrence after salvage ER.

Methods: This study enrolled consecutive ESCC patients treated with salvage ER for local failure after CRT between 1998 and 2013.

Large-scale comprehensive immunohistochemical biomarker analyses in esophageal squamous cell carcinoma.

Background: Esophageal squamous cell carcinoma (ESCC) is a heterogeneous disease in the sense that the biological behavior is regulated by the activation of various signaling pathways. The aim of this study was to investigate the relationships between the expressions of various targetable proteins and the clinicopathological characteristics of ESCC patients.

Methods: A total of 286 patients with ESCC who had undergone curative surgical resection without neoadjuvant therapy were enrolled in this study.

Concordance between PIK3CA mutations in endoscopic biopsy and surgically resected specimens of esophageal squamous cell carcinoma.

Background: PIK3CA mutations are expected to be potential therapeutic targets for esophageal squamous cell carcinoma (ESCC). We aimed to clarify the concordance between PIK3CA mutations detected in endoscopic biopsy specimens and corresponding surgically resected specimens.

Methods: We examined five hotspot mutations in the PIK3CA gene (E542K, E545K, E546K, H1047R, and H1047L) in formalin-fixed and paraffin-embedded tissue sections of paired endoscopic biopsy and surgically resected specimens from 181 patients undergoing curative resection for ESCC between 2000 and 2011 using a Luminex technology-based multiplex gene mutation detection kit.

Comprehensive immunohistochemical analysis of tumor microenvironment immune status in esophageal squamous cell carcinoma.

Immunotherapy with anti-PD-1 antibody preliminarily showed promising efficacy for treating esophageal squamous cell carcinoma (ESCC). Herein, we used tissue microarrays and immunohistochemically analyzed PD-L1 and various tumor infiltrating immune cells (TIICs) in specimens from 196 ESCC patients who had undergone curative resection without preoperative therapy. PD-L1 expressions in tumor cells (TCs) and TIICs, as well as infiltration of lymphocytes (CD4+, CD8+, FOXP3+, and PD- 1+) and macrophages (CD68+ and CD204+), were evaluated.

Prognostic significance of tumor regression grade for patients with esophageal squamous cell carcinoma after neoadjuvant chemotherapy followed by surgery.

Background And Objectives: To clarify prognostic factors for the patients with esophageal squamous cell carcinoma (ESCC) through an assessment of surgically resected specimens modified by neoadjuvant chemotherapy (nCT).

Methods: We retrospectively reviewed the clinicopathological data of 143 consecutive patients with ESCC who underwent nCT followed by surgery between 2008 and 2012 at our institution and conducted survival analysis. The tumor regression grade (TRG) was classified based on the proportion of residual tumor cells in the area where the tumor was thought to have existed before nCT as follows: Grade 0 (no therapeutic effect), Grade 1a (residual tumor cells ≥2/3), Grade 1b (1/3≤ residual tumor cells <2/3), Grade 2 (residual tumor cells <1/3), and Grade 3 (no residual tumor).

[Molecular Subtypes of Gastric Cancer].

Gastric cancer has been classified based on the pathological characteristics including microscopic configuration and growth pattern. Although these classifications have been used in studies investigating prognosis and recurrence pattern, they are not considered for decisions regarding the therapeutic strategy. In the ToGA study, trastuzumab, an anti-HER2 monoclonal antibody, demonstrated clinical efficacy for gastric cancer with HER2 overexpression or HER2 gene amplification.

Local efficacy and survival outcome of salvage endoscopic therapy for local recurrent lesions after definitive chemoradiotherapy for esophageal cancer.

Background: Salvage endoscopic therapy (SET), such as endoscopic mucosal resection (EMR) and photodynamic therapy (PDT), is a less-invasive treatment for local failure at the primary site after chemoradiotherapy (CRT) for esophageal squamous cell carcinoma (ESCC). We conducted this retrospective study to clarify the risk factors for local recurrence along with the long term results after SET for recurrent lesions after definitive CRT for ESCC.

Methods: We enrolled 77 consecutive patients who underwent EMR or PDT for local recurrence without any metastasis after definitive CRT at our institution.

Salvage photodynamic therapy for local failure after chemoradiotherapy for esophageal squamous cell carcinoma.

Background And Aims: Photodynamic therapy (PDT) is a less-invasive salvage treatment option for local failure at the primary site after chemoradiotherapy (CRT) for esophageal squamous cell carcinoma. The objective of this study was to clarify the long-term outcomes and prognostic factors of salvage PDT.

Methods: One hundred thirteen consecutive patients treated in our institution with PDT for local failure limited to within T2 without any metastases after definitive CRT performed between 1998 and 2008 were retrospectively enrolled.

Photodynamic therapy for esophageal cancer.

Photodynamic therapy (PDT) is a treatment that uses a photosensitizing drug that is administered to the patient, localized to a tumor, and then activated with a laser to induce a photochemical reaction to destroy the cell. PDT using porfimer sodium followed by excimer dye laser irradiation is approved as a curative treatment for superficial esophageal cancer in Japan. While endoscopic submucosal dissection (ESD) is currently more popular for esophageal cancer, there is evidence to support PDT as an alternative treatment and as a salvage treatment for local failure after chemoradiotherapy (CRT).

[Timely colonoscopy leads to faster identification of bleeding diverticulum].

We conducted a retrospective study of the efficacy of a polyethylene glycol purge before colonoscopic examination in 110 patients with colonic diverticular bleeding. The patients' data were assessed for the timing of colonoscopy and the methods used to stop bleeding. The rate at which bleeding diverticula were identified was markedly higher when a purge was used than when it was not (28.

Unexpected endoscopic full-thickness resection of a duodenal neuroendocrine tumor.

A 57-year-old man underwent endoscopy for investigation of a duodenal polyp. Endoscopy revealed a hemispheric submucosal tumor, about 5 mm in diameter, in the anterior wall of the duodenal bulb. Endoscopic biopsy disclosed a neuroendocrine tumor histologically, therefore endoscopic mucosal resection was conducted.