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For patients with T1a muscularis mucosae (MM) esophageal squamous cell carcinoma (ESCC) with lymphovascular invasion (LVI) or T1b submucosal (SM) ESCC, endoscopic resection is non-curative, and adjuvant treatment entailing esophagectomy or definitive chemoradiotherapy is necessary. This is because about 30% of these cases have lymph node (LN) metastasis. The purpose of this study was to test the utility of a CRP genetic polymorphism test kit for determining the risk of LN metastasis with the aim of eliminating additional invasive adjuvant therapy.This is a retrospective, multi-institutional, observational study. The CRP 1846CT genetic polymorphisms were identified using a fully automated genotyping system. The primary end points were an 85% negative predictive value (NPV) for diagnosis of LN metastasis in pT1a (MM) and 80% NPV in pT1b (SM1) patients.A total of 742 ESCC (105 pMM, 166 pSM1 and 471 pSM2-3) patients who had received esophagectomy with 2- or 3-field LN dissection at 65 institutions were enrolled. According to this test, patients with the C/C and C/T genotypes were considered to be low risk. The NPVs using this test were 82.8% in pMM and 71.7% in pSM1 patients.CRP 1846CT genetic polymorphism is not a useful diagnostic indicator for determining the risk of LN metastasis; however, the possibility that CRP gene polymorphisms are involved in the mechanism of lymph node metastasis in solid tumors still remains.

Metastasis predicts poor prognosis in cancer patients. It has been recognized that specific tumor microenvironment defines cancer cell metastasis, whereas the underlying mechanisms remain elusive. Here we show that Galectin-7 is a crucial mediator of metastasis associated with immunosuppression. In a syngeneic mouse squamous cell carcinoma (SCC) model of NR-S1M cells, we isolated metastasized NR-S1M cells from lymph nodes in tumor-bearing mice and established metastatic NR-S1M cells in in vitro culture. RNA-seq analysis revealed that interferon gene signature was markedly downregulated in metastatic NR-S1M cells compared with parental cells, and in vivo NR-S1M tumors heterogeneously developed focal immunosuppressive areas featured by deficiency of anti-tumor immune cells. Spatial transcriptome analysis (Visium) for the NR-S1M tumors revealed that various pro-metastatic genes were significantly upregulated in immunosuppressive areas when compared to immunocompetent areas. Notably, Galectin-7 was identified as a novel metastasis-driving factor. Galectin-7 expression was induced during tumorigenesis particularly in the microenvironment of immunosuppression, and extracellularly released at later stage of tumor progression. Deletion of Galectin-7 in NR-S1M cells significantly suppressed lymph node and lung metastasis without affecting primary tumor growth. Therefore, Galectin-7 is a crucial mediator of tumor metastasis of SCC, which is educated in the immune-suppressed tumor areas, and may be a potential target of cancer immunotherapy.

The prognosis of advanced colorectal cancer (aCRC) remains poor, and development of new therapeutic approaches, including immunotherapy, is needed urgently. Herein we report on our phase II study of personalized peptide vaccination (PPV) in 60 previously treated patients with aCRC, who had failed at least one regimen of standard chemotherapy and/or targeted therapy. For PPV, a maximum of four HLA-matched peptides were individually selected from a pool of 31 different peptide candidates based on preexisting host immunity, and administered subcutaneously without severe adverse events. Boosting of IgG and cytotoxic T lymphocyte (CTL) responses specific to the administered peptides was observed in 49% and 63%, respectively, of the patients, who completed the first cycles of six vaccinations. Median overall survival (OS) time was 498 days, with 1- and 2-year survival rates of 53% and 22%, respectively. Multivariate Cox regression analysis of prevaccination factors showed that plasma IL6, IP-10, and BAFF levels were significantly prognostic for OS [hazard ratio (HR), 1.508, P = 0.043; HR, 1.579, P = 0.024; HR, 0.509, P = 0.002, respectively]. In addition, increased peptide-specific CTL responses after vaccination were significantly predictive of favorable OS (HR, 0.231; P = 0.021), suggesting a causal relationship between biologic and clinical efficacy of PPV. On the basis of the safety profile and potential clinical efficacy, we believe that clinical trials of PPV would be warranted for previously treated patients with aCRC. Cancer Immunol Res; 2(12); 1154–62. ©2014 AACR.

Immunohistochemical analysis of vaccine antigen expressions in CRC tissues.

Immune responses to the administered peptides.

Supplementary Methods

The purpose of this study was to obtain basic data regarding the difference among medical area within Akita prefecture with which to formulate policies to reduce cancer mortality. We enrolled all cancer patients in Akita prefecture registered in “the population-based cancer register” between 2013 and 2017. The cancer standardized mortality rate, cancer standardized incidence rate, and early detection rate for gastric cancer, colorectal cancer, liver cancer, lung cancer, female breast cancer, and cervical cancer were analyzed in 8 medical areas within Akita prefecture (Daisen, Yokote, Yuzawa, Ohdate, Kita-akita, Noshiro, Akita, and Yuri-Honjo). This revealed that the cancer mortality, incidence rates and early detection differed among the medical areas evaluated. Low early detection rates were correlated with high cancer standardized mortality rates in nearly all areas. The immediate challenge differed among these areas, depending upon the cancer involved. In several medical areas the early lung cancer detection rate among men was only 20%. Early detection of cervical cancer was high, exceeding 80% in several areas. Based on these results, we suggest that implementing detailed cancer controls targeted to each medical area would be an effective way to reduce the cancer mortality rate in Akita prefecture.

Disruption of cancer screening programs and diagnoses of gastrointestinal cancers by the COVID-19 pandemic has been reported; however, little attention has been paid to the situation in depopulated areas with low infection rates. Akita Prefecture is one of the most depopulated areas of Japan and has the lowest COVID-19 infection rate per capita; at the same time, the prefecture has been top-ranked for mortality due to gastrointestinal cancer for years. In this population-based study in Akita Prefecture, we investigated the occurrence of gastrointestinal cancers and the number of cancer screening procedures over the five-year period of 2016-2020, employing a database from the collaborative Akita Prefecture hospital-based registration system of cancers. The occurrence of gastrointestinal cancers, especially esophago-gastric cancers, declined by 11.0% in 2020, when the COVID-19 pandemic affected the overall healthcare system, compared with the average of 2016-2019. Nonetheless, the occurrence of advanced-stage (stage IV) esophago-gastric cancers increased by 7.2% in 2020. The decrease in the gastrointestinal cancer diagnosis rate in 2020 coincided with a 30% decline in the total number of regular population-based screening programs. Under the ongoing COVID-19 pandemic, cancer screening was uniformly suspended throughout Japan. Accordingly, the COVID-19 pandemic has substantially disrupted the cancer screening system, leading to delays in diagnoses of gastrointestinal cancer, even in depopulated areas (Akita Prefecture) of Japan with a low prevalence of infection. Suspension of cancer screening procedures during an infectious disease pandemic should be thoroughly considered for each region based on the cancer incidence and infection status in that area.

To address the major issue of regional disparity in the treatment for elderly cancer patients in an aging society, we compared the treatment strategies used for elderly patients with thoracic esophageal cancer and their survival outcomes in metropolitan areas and other regions. Using the national database of hospital‐based cancer registries in 2008‐2011, patients aged 75 years or older who had been diagnosed with thoracic esophageal cancer were enrolled. We divided the patients into two groups: those treated in metropolitan areas (Tokyo, Kanagawa, Osaka, Aichi, Saitama, and Chiba prefectures) with populations of 6 million or more and those treated in other areas (the other 41 prefectures). Compared were patient backgrounds, treatment strategies, and survival curves at each cancer stage. In total, 1236 (24%) patients from metropolitan areas and 3830 (76%) patients from nonmetropolitan areas were enrolled. Patients in metropolitan areas were treated at more advanced stages. There was also a difference in treatment strategy. The 3‐year survival rate among cStage I patients was better in metropolitan areas (71.6% vs. 63.7%), and this finding mainly reflected the survival difference between patients treated with radiotherapy alone. For cStage II‐IV patients, there were no differences. Multivariable Cox proportional hazard analysis including interaction terms between treatment areas, cStage, and the first‐line treatments revealed that treatments in the metropolitan areas were significantly associated with better survival among patients treated with radiotherapy alone for cStage I cancer. Treatment strategies for elderly patients with thoracic esophageal cancer and its survival outcomes differed between metropolitan areas and other regions., We compared the treatment strategies used for elderly patients with thoracic esophageal cancer and their survival outcomes in metropolitan areas and other regions. The 3‐year survival rate among cStage I patients was better in metropolitan areas (71.6% vs. 63.7%), and this finding mainly reflected the survival difference between patients treated with radiotherapy alone. Treatment strategies for elderly patients with thoracic esophageal cancer and its survival outcomes differed between metropolitan areas and other regions.

For thymic epithelial tumors, simple contact with adjacent structures does not necessarily mean invasion. The purpose of our study was to develop a simple noninvasive technique for evaluating organ invasion using routine pretreatment computed tomography (CT).This retrospective study analyzed the pathological reports on 95 mediastinal resections performed between January 2003 and June 2020. Using CT images, the length of the interface between the primary tumor and neighboring structures (arch distance; Adist) and maximum tumor diameter (Dmax) was measured, after which Adist/Dmax (A/D) ratios were calculated. Receiver operating characteristic (ROC) curves were used to analyze the Adist and A/D ratios.An Adist cut-off of 37.5 mm best distinguished between invaded and non-invaded mediastinal great veins based on ROC curves. When Adist 37.5 mm was used for diagnosis of invasion of the brachiocephalic vein (BCV) or superior vena cava (SVC), the sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and area under the ROC curve for diagnosis of invasion were 61.9%, 92.5%, 81.25%, 82.2%, 81.97%, and 0.76429, respectively. Moreover, there were significant differences between BCV/SVC Adist 37.5 mm and ≤ 37.5 mm for 10-year relapse-free survival and 10-year overall survival (p 0.01).When diagnosing invasion of the mediastinal great veins based on Adist 37.5 mm, we achieved a higher performance level than the conventional criteria such as irregular interface with an absence of the fat layer. Measurement of Adist is a simple noninvasive technique for evaluating invasion using CT. Key Points • Simple contact between the primary tumor and adjacent structures on CT does not indicate direct invasion. • Using CT images, the length of the interface between the primary tumor and neighboring structures (arch distance; Adist) is a simple noninvasive technique for evaluating invasion. • Adist 37.5 mm can be a supportive tool to identify invaded mediastinal great veins and surgical indications for T3 and T4 invasion by thymic epithelial tumors.

Well known risk factors of Esophageal squamous cell carcinoma (ESCC) are habit of alcoholic drinking, smoking and poor diet. Moreover, recent reports showed that poor oral health is associated with upper aerodigestive tract malignancies including ESCC. We previously reported that among 232 ESCC patients who had preoperative assessment of oral function by dentist, about 70% of patients were diagnosed with periodontitis and about half of those patients were needed dental extraction. Toll-like receptors (TLRs), a family of pattern recognition receptors, are able to recognize pathogen-associated molecular patterns (PAMPs) associated with a wide range of viruses, bacteria, fungi and parasites and thus play key roles in innate immune responses. Among these TLRs, TLR4 recognizes LPS, which construct the cell wall of gram-negative bacteria. Based on these findings, it is supposed that continuous exposure of LPS from gram-negative periodontal bacteria induces chronic inflammation caused by inflammatory cytokines from TLR4 signals, then carcinogenesis and progression of ESCC occurs. Among these TLRs, TLR4 recognizes LPS, which construct the cell wall of gram-negative bacteria. We reported that ESCC patients who had higher TLR4 expression status in resected main tumor specimen showed significantly poor overall survival compared to lower patients after esophagectomy. (Sato Y, et al. Esophagus 2020) On the other hand, TLR3 recognizes dsRNA released form cell invading viruses. We previously reported that ESCC patients who had higher TLR3 expression status in resected main tumor specimen showed significantly better overall survival compared to lower patients after esophagectomy. (Sato Y, et al. Am J Surg. 2018). Though TLR3 and TLR4 are in the same TLR family, those functional mechanism and relationships to prognosis in ESCC are totally different. Because TLR4 signaling is stimulatory on proliferative ability of ESCC, it is supposed that improvement of oral health inhibits carcinogenesis and progression of ESCC. On the other hand, because TLR3 signaling is suppressive, TLR3 agonist should be a possible candidate of therapeutic agent.

The results of the JCOG1109 trial indicate that the standard preoperative neoadjuvant therapy is Docetaxel-cisplatin-fluorouracil (DCF) combined chemotherapy. However, appropriate preoperative treatment for borderline resectable cases is still controversial. Preoperative CF-RT therapy with more substantial local control continues to be an option for tumors with a high risk of invading adjacent organs. The study participants were 163 cT3 locally advanced thoracic esophageal cancer patients who underwent preoperative CF-RT therapy followed by radical esophagectomy. The patients were partitioned into 58 borderline resectable cases (cT3.5 group) and 105 resectable cases (cT3 group). We compared the clinicopathological features, surgical results, and survival between the two groups to verify the effectiveness of preoperative CF-RT therapy for cT3.5 cases. SCC was the predominant cancer histological type. Significantly more upper and middle mediastinum cases and fewer lower mediastinum cases in the cT3.5 group (p Borderline resectable esophageal cancer (cT3.5) treated with preoperative CF-RT therapy showed a comparable survival rate even though the pCR rate was lower than that of resectable esophageal cancer (cT3). Preoperative CF-RT therapy may still be a promising treatment for locally advanced thoracic esophageal cancer with suspected invasion of adjacent organs.

Background Video-assisted thoracoscopic surgery (VATS) is being used to treat esophageal submucosal tumors (SMTs) all over the world. However, this technique is difficult when the tumor is large and located on the left side wall of the esophagus, within the upper mediastinum. This is because, with VATS, the surgical forceps have a limited range of motion. Robot-assisted thoracoscopic surgery (RATS) using the da Vinci surgical system may be extremely useful for enucleation of esophageal SMTs within the narrow upper mediastinum. Case presentation A female in her thirties experiencing epigastric pain visited our hospital and was diagnosed with a large esophageal leiomyoma within the upper mediastinum. From its size (10 cm), it was judged to have malignant potential. We performed SMT enucleation using RATS with a da Vinci surgical system Xi. This was our second case using this system. The patient was placed in the left lateral position. Four da Vinci trocars (8 mm) were inserted into the 10th, 7th, 5th and 3rd intercostal spaces (ICS), and an assist port was added in the 5th ICS. We opened the superior mediastinal pleura cranially and caudally from the arch of the azygos vein and expanded the superior mediastinum after dividing the azygos vein. We made an incision in the muscular layer of the esophagus and, using a monopolar hook and monopolar scissors, enucleated the esophageal tumor in a protective manner so as not to damage its capsule or mucosa while applying appropriate robot-specific counter traction. We then sewed up the muscularis using 4–0 Vicryl, inserting the endoscope into the thoracic esophagus to substitute for a bougie. In addition, the pleura was sutured using barbed suture. The surgical procedure was straightforward and smooth. The patient was discharged on postoperative day 4 with no surgical complications. The tumor was definitively diagnosed pathologically from paraffin sections as a benign esophageal leiomyoma. Conclusions RATS enables more delicate and precise esophageal SMT enucleation without surgical complications, though various challenges remain to be overcome.

Background Immune checkpoint inhibitors (ICIs) are a promising advance in the treatment of patients with lung cancer. However, each ICI has been tested with an independently designed companion diagnostic assay that is based on a unique antibody. Consequently, the different trial‐validated programmed death ligand 1 (PD‐L1) immunohistochemistry (IHC) assays should not be considered interchangeable. Our aim was to compare the performance of each available PD‐L1 antibody for its ability to accurately measure PD‐L1 expression and to investigate the possibility of harmonization across antibodies through the use of a new rapid IHC system, which uses noncontact alternating current (AC) mixing to achieve more stable staining. Methods First, 58 resected non‐small cell lung cancer (NSCLC) specimens were stained using three PD‐L1 IHC assays (28–8, SP142, and SP263) to assess the harmonization achieved with AC mixing IHC. Second, specimens from 27 patients receiving ICIs for postoperative recurrent NSCLC were stained using the same IHC method to compare the clinical performance of ICIs to PD‐L1 scores. All patients received a tumor proportion score (TPS) with the 22C3 companion diagnostic test. Results Better staining was achieved with the new AC mixing IHC method than the conventional IHC in PD‐L1‐positive cases, and the interchangeability of some combinations of assays was increased in PD‐L1‐positive. In addition, AC mixing IHC provided more appropriate overall response rates for ICIs in all assays. Conclusions Stable PD‐L1 IHC driven by AC mixing helped to improve TPS scoring and patient selection for ICIs through interchangeable assays., In lung cancer, each immune checkpoint inhibitors have been tested with an independently designed companion diagnostic assay. Better PD‐L1 staining was achieved with novel immunohistochemistry using noncontact alternating current mixing, and the interchangeability with any antibody was improved in PD‐L1‐positive.

Background Programmed cell death 1 (PD-1)-based treatments are approved for several cancers. CheckMate 648, a global, phase 3 trial, showed that first-line nivolumab (anti-PD-1 antibody) plus ipilimumab (NIVO + IPI) or nivolumab plus chemotherapy (NIVO + Chemo) significantly increased survival in advanced esophageal squamous cell carcinoma (ESCC) without new safety signals versus chemotherapy alone (Chemo). Methods We evaluated the Japanese subpopulation of CheckMate 648 (n = 394/970), randomized to receive first-line NIVO + IPI, NIVO + Chemo, or Chemo. Efficacy endpoints included overall survival (OS) and progression-free survival assessed by blinded independent central review in Japanese patients with tumor-cell programmed death-ligand 1 (PD-L1) expression ≥ 1% and in all randomized Japanese patients. Results In the Japanese population, 131, 126, and 137 patients were treated with NIVO + IPI, NIVO + Chemo, and Chemo, and 66, 62, and 65 patients had tumor-cell PD-L1 ≥ 1%, respectively. In patients with tumor-cell PD-L1 ≥ 1%, median OS was numerically longer with NIVO + IPI (20.2 months; hazard ratio [95% CI], 0.46 [0.30–0.71]) and NIVO + Chemo (17.3 months; 0.53 [0.35–0.82]) versus Chemo (9.0 months). In all randomized patients, median OS was numerically longer with NIVO + IPI (17.6 months; 0.68 [0.51–0.92]) and NIVO + Chemo (15.5 months; 0.73 [0.54–0.99]) versus Chemo (11.0 months). Grade 3–4 treatment-related adverse events were reported in 37%, 49%, and 36% of all patients in the NIVO + IPI, NIVO + Chemo, and Chemo arms, respectively. Conclusion Survival benefits with acceptable tolerability observed for NIVO + IPI and NIVO + Chemo treatments strongly support their use as a new standard first-line treatment in Japanese patients with advanced ESCC. ClinicalTrials.gov ID NCT03143153.

We herein report on a male with primary accessory breast cancer in an axilla. A 75-year-old man first noticed a subcutaneous nodule about 2 cm in diameter in the area of his right axilla. The patient underwent extirpation of the mass in a public hospital. Histological examination revealed invasive breast carcinoma of no special type associated with mucinous carcinoma, invasive micropapillary carcinoma and intraductal components. Immunohistochemical analysis showed that the tumor cells were positive for Gross cystic disease fluid protein (GCDFP)-15, mammaglobin and GATA3. Staining for estrogen receptor (ER) and progesterone receptor (PR) was positive, and human epidermal growth factor receptor 2 (HER2) was negative. The Ki67 labeling index (LI) was 33.6%. Imaging revealed no evidence of a primary tumor in any other organ or in the bilateral mammary gland. We performed radical resection of the right axilla, including the scar, and axillary lymph node dissection. The final pathological examination of the surgical specimen showed normal mammary gland tissue that was not connected to the proper mammary gland, and no residual cancer or metastatic lymph nodes. Based on our clinical and pathological findings, this tumor was diagnosed as breast cancer originating from the accessory mammary gland in the right axilla. After surgery, tamoxifen was administered as adjuvant therapy. Since the surgery, 2 years ago, there has been no evidence of recurrence. Hereditary Breast and Ovarian Cancer syndrome was suspected in this case because the patient was a male with breast cancer, and he had two first-degree relatives with breast cancer. This patient had no BRCA mutations on genetic testing. Nonetheless, in cases of male breast cancer, it is necessary to obtain genetic information due to the possibility of hereditary breast cancer, including cancers associated with BRCA gene mutation.

Background Human epidermal growth factor receptor 2‐in situ hybridization (HER2‐ISH) is widely approved for diagnostic, prognostic biomarker testing of formalin‐fixed paraffin‐embedded tissue blocks. However, cytologic ISH analysis has a potential advantage in tumor samples such as pleural effusion and ascites that are difficult to obtain the histological specimens. Our aim was to evaluate the clinical reliability of a novel rapid cytologic HER2 fluorescence ISH protocol (rapid‐CytoFISH). Materials and Methods Using a new device, we applied a high‐voltage/frequency, noncontact alternating current electric field to tissue imprints and needle rinses, which mixed the probe within microdroplets as the voltage was switched on and off (AC mixing). Cytologic samples (n = 143) were collected from patients with immunohistochemically identified HER2 breast cancers. The specimens were then tested using standard dual‐color ISH using formalin‐fixed paraffin‐embedded tissue (FFPE‐tissue DISH) for HER2‐targeted therapies, CytoFISH, and rapid‐CytoFISH (completed within 4 h). Results All 143 collected cytologic specimens (50 imprinted cytology specimens from resected tumors and 93 liquid‐based cytology specimens from needle rinses) were suitable for FISH analysis. The HER2/chromosome enumeration probe (CEP) 17 ratios did not significantly differ between FFPE‐tissue DISH and either CytoFISH protocol. Based on HER2 scoring criteria, we found 95.1% agreement between FFPE‐tissue DISH and CytoFISH (Cohen's kappa coefficient = 0.771 and 95% confidence interval (CI): 0.614–0.927). Conclusion CytoFISH could potentially serve as a clinical tool for prompt determination of HER2 status in breast cancer cytology. Rapid‐CytoFISH with AC mixing will enable cancer diagnoses and HER2 status to be determined on the same day a patient comes to a clinic or hospital., Rapid in situ hybridization device used to apply an alternating current electric field analysis of cytologic specimens (Rapid CytoFISH) has a potential advantage in tumor samples such as pleural effusion and ascites that are difficult to obtain the histological specimens. Rapid‐CytoFISH will enable cancer diagnoses and Human epidermal growth factor receptor 2 (HER2) status to be determined on the same day a patient comes to a clinic or hospital.

290 Background: NIVO + chemo and NIVO + IPI demonstrated superior overall survival (OS) vs chemo in CheckMate 648 (NCT03143153), leading to approvals in the US, EU, Japan, and other countries. We report longer follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR). Hierarchical testing was done first in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%, then in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 29-mo minimum follow-up, NIVO + chemo and NIVO + IPI continued to show improvement in OS vs chemo, including higher 24-mo OS rates, in pts with tumor cell PD-L1 ≥ 1% and all randomized pts. Responses were more durable and a larger proportion of responders had a duration of response (DOR) ≥ 24 mo with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (22%, 36%, 13%, respectively) and all randomized pts (21%, 29%, 13%). Additional efficacy data by PD-L1 status will be presented. Any-grade treatment-related adverse events (TRAEs) occurred in 96% (grade 3/4, 49%) of pts with NIVO + chemo, 80% (33%) with NIVO + IPI, and 90% (36%) with chemo. Any-grade TRAEs leading to discontinuation occurred in 35% of pts with NIVO + chemo, 19% with NIVO + IPI, and 21% with chemo. Treatment-related deaths occurred in 2% of pts in each arm. Conclusions: NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit vs chemo, durable objective responses, and acceptable safety profiles with longer follow-up. This further supports each regimen as a new 1L treatment option for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]

OBJECTIVE To determine whether esophagectomy provides a survival advantage in octogenarians with resectable thoracic esophageal cancer. SUMMARY BACKGROUND DATA Elderly patients with thoracic esophageal cancer do not always receive the full standard treatment; however, advanced age alone should not preclude the use of effective treatment that could meaningfully improve survival. METHODS We retrieved the 2008-2011 data from the National Database of Hospital-based Cancer Registries from the National Cancer Center in Japan, divided the patients into a ≥75 group (75-79 years; n = 2,935) and a ≥80 group (80 years or older; n = 2,131), and then compared the patient backgrounds and survival curves. A multivariable Cox proportional hazards regression model was developed to compare the effects of esophagectomy and chemoradiotherapy in the two groups. RESULTS A significantly greater percentage of patients were treated with esophagectomy in the ≥75 group (34.6%) than the ≥80 group (18.4%). Among patients who received esophagectomy, the 3-year survival rate was 51.1% in the ≥75 group and 39.0% in the ≥80 group (P < 0.001). However, among patients who received chemoradiotherapy, there was no difference in survival curve between the two groups (P = 0.17). Multivariable Cox proportional hazard analysis revealed that esophagectomy for clinical Stage II-III patients was significantly associated to better survival (adjusted HR: 0.731) (95%CI: 0.645-0.829, p < 0.001) in the ≥75 group but not the ≥80 group when compared with CRT. CONCLUSIONS Many octogenarians do not necessarily get a survival benefit from esophagectomy. However, patients should be evaluated based on their overall health before ruling out surgery based on age alone.

Background The efficacy and safety of nivolumab versus chemotherapy was evaluated in the Japanese subpopulation from the overall intent-to-treat (ITT) population of the ATTRACTION-3 trial conducted in patients with advanced esophageal squamous cell carcinoma (ESCC) as second-line treatment. Methods Data from Japanese patients enrolled in the multicenter, randomized, open-label, phase 3 ATTRACTION-3 trial were analyzed. The primary endpoint was overall survival (OS). Secondary endpoints included duration of response (DOR), objective response rate (ORR), disease control rate (DCR), and safety. Exploratory subgroup analyses evaluated the association between OS and stratification factors/baseline variables. Results Overall, 274 (nivolumab, 136; chemotherapy, 138) of the 419 patients in ATTRACTION-3 were enrolled from Japan: response-evaluable population (107; 108) and safety population (135; 138). OS tended to be longer in the nivolumab group versus the chemotherapy group (median: 13.4 months vs. 9.4 months; HR, 0.77; 95% CI 0.59–1.01). Median DOR was longer in the nivolumab group (7.6 months) versus the chemotherapy group (3.6 months). ORRs were similar between the nivolumab [22.4% of patients (24/107)] and chemotherapy groups [22.2% (24/108); odds ratio, 0.98; 95% CI 0.52–1.87]. DCR was lower in the nivolumab group [41.1% (44/107)] versus the chemotherapy group [66.7% (72/108)]. OS in the exploratory analysis consistently favored the nivolumab group versus the chemotherapy group. Overall, nivolumab demonstrated favorable efficacy and safety versus chemotherapy in the Japanese subpopulation, and the trend was similar to that observed in the overall ATTRACTION-3 ITT population. Conclusion Nivolumab represents a new standard second-line treatment option for Japanese patients with advanced ESCC.

The interval between preoperative chemoradiotherapy and surgery reportedly affects perioperative outcomes and survival; however, the optimal interval in esophageal cancer patients remains uncertain. Our aim was to determine whether a prolonged interval between preoperative neoadjuvant chemoradiotherapy (NACRT) and esophagectomy affects the outcomes of esophageal cancer patients. A total of 131 patients with esophageal cancer received curative surgery following NACRT at Akita University Hospital between 2009 and 2017. We divided these patients into two groups based on the median interval from NACRT to esophagectomy, and compared the rates of pathological complete response (pCR), surgical outcomes, and survival. The median interval from NACRT to esophagectomy was 39 days (range 21–95). Of the 131 patients, 70 (53%) received esophagectomy after 39 days or more from completion of NACRT. There were no significant differences in the clinicopathological features, including pCR rates, between the two groups. Prolongation of the interval from NACRT to esophagectomy was significantly associated with an increased rate of anastomotic leakage and recurrent laryngeal nerve palsy (p = 0.0225 and p = 0.0022, respectively); however, no association with overall survival was detected. A prolonged interval between NACRT and esophagectomy had no impact on pCR rates or survival. However, delaying esophagectomy may increase the likelihood of surgical complications such as anastomotic leakage and recurrent laryngeal nerve palsy.

Background Although lobectomy is considered the standard surgery for any non‐small cell lung cancer (NSCLC), recent evidence indicates that for early NSCLCs segmentectomy may be equally effective. For segmentectomy to be oncologically safe, however, adequate intraoperative lymph node staging is essential. The aim of this study was to compare the results of a new rapid‐IHC system to the HE analysis for intraoperative nodal diagnosis in lung cancer patients considered for segmentectomy. Methods This retrospective study analyzed the pathological reports from NSCLC resections over a six‐year period between 2014 and 2020. Using a new device for rapid‐IHC, we applied a high‐voltage, low‐frequency alternating current (AC) field, which mixes the antipancytokeratin antibody as the voltage is switched on/off. Rapid‐IHC can provide a nodal diagnosis within 20 minutes. Results Frozen sections from 106 resected lymph nodes from 70 patients were intraoperatively evaluated for metastasis. Of those, five nodes were deemed positive based on both HE staining and rapid‐IHC. In addition, rapid‐IHC alone detected isolated tumor cells in one hilar lymph node. Three cStage IA patients with nodal metastasis detected with HE staining and rapid‐IHC received complete lobectomies. Five‐year relapse‐free survival and overall survival among patients receiving segmentectomy with rapid‐IHC were 88.77% and 88.79%, respectively. Conclusions Rapid‐IHC driven by AC mixing is simple, highly accurate, and preserves nodal tissue for subsequent tests. This system can be used effectively for intraoperative nodal diagnosis. Rapid immunohistochemistry based on alternating‐current field mixing (completed within 20 minutes) is simple and highly accurate. This system will assist clinicians when making intraoperative diagnoses of lymph node metastasis and deciding upon the appropriate surgical procedure in segmentectomy for lung cancer. Key points Significant findings of the study Rapid immunohistochemistry driven by alternating‐current field mixing (completed within 20 minutes intraoperatively) is simple, highly accurate, and preserves lymph node tissue for subsequent pathological examination, including molecular assessments. What this study adds Segmentectomy for lung cancer is oncologically safe, but only when there is adequate intraoperative node staging. Rapid immunohistochemistry will assist clinicians when making intraoperative nodal diagnoses., Rapid immunohistochemistry based on alternating‐current field mixing (completed within 20 minutes) is simple and highly accurate. This system will assist clinicians when making intraoperative diagnoses of lymph node metastasis and deciding upon the appropriate surgical procedure in segmentectomy for lung cancer.

BACKGROUND: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma. METHODS: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients). RESULTS: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P

Breast cancer is the most commonly diagnosed cancer in females worldwide. If diagnosed early, patients generally have good outcomes. However, approximately 20% to 30% of all women diagnosed with breast cancer develop metastatic disease. Metastatic breast cancer is incurable, but there is growing evidence that resection or other local therapy for breast cancer liver metastases (BCLM) may improve survival. We aimed to review indications for and outcomes of perioperative liver resection and other local therapies for BCLM. In this series, we reviewed 11 articles (605 patients) focusing on surgical resection and 7 articles (266 patients) describing radiofrequency ablation (RFA) for BCLM. Median disease-free survival (DFS) after surgical resection was 23 months (range, 14–29 months) and median overall survival (OS) was 39.5 months (range, 26–82 months). One, 3- and 5-year survivals were 89.5%, 70%, and 38%, respectively. The factors favoring better outcomes are hormone receptor positive primary breast cancer status, R0 resection, no extrahepatic metastases (EHM), small BCLM, and solitary liver metastases. On the other hand, the median DFS with RFA was 11 months, median OS was 32 months, and the 3- and 5-year OS were 43% and 27%, respectively. The clinical features that are indications for RFA are smaller tumor and higher EHM rate than those favoring surgical resection (2.4 vs. 4.0 cm and 46% vs. 27%). The merits of RFA are its high technical success rate, low morbidity, short hospital stay, and that it can be repeated. Although results are as yet limited, in carefully selected patients, resection or other local therapies such as RFA, render BCLM potentially provide prognostic improvement.

Esophageal squamous cell carcinoma (ESCC) is one of the most fatal types of malignant tumors worldwide. Epitranscriptome, such as N6 -methyladenosine (m6 A) of mRNA, is an abundant post-transcriptional mRNA modification and has been recently implicated to play roles in several cancers, whereas the significance of m6 A modifications is virtually unknown in ESCC. Analysis of tissue microarray of the tumors in 177 ESCC patients showed that higher expression of m6 A demethylase ALKBH5 correlated with poor prognosis and that ALKBH5 was an independent prognostic factor of the survival of patients. There was no correlation between the other demethylase FTO and prognosis. siRNA knockdown of ALKBH5 but not FTO significantly suppressed proliferation and migration of human ESCC cells. ALKBH5 knockdown delayed progression of cell cycle and accumulated the cells to G0/G1 phase. Mechanistically, expression of CDKN1A (p21) was significantly up-regulated in ALKBH5-depleted cells, and m6 A modification and stability of CDKN1A mRNA were increased by ALKBH5 knockdown. Furthermore, depletion of ALKBH5 substantially suppressed tumor growth of ESCC cells subcutaneously transplanted in BALB/c nude mice. Collectively, we identify ALKBH5 as the first m6 A demethylase that accelerates cell cycle progression and promotes cell proliferation of ESCC cells, which is associated with poor prognosis of ESCC patients.

β-1,4-N-Acetyl-galactosaminyltransferase 4 (B4GALNT4), an enzyme involved in ganglioside synthesis, is upregulated in many cancers. We examine B4GALNT4 expression and its relationship to prognosis in esophageal squamous cell carcinoma (ESCC). Expression of B4GALNT4 mRNA and B4GALNT4 protein was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry, respectively, in 17 human ESCC cell lines and/or clinical specimens from two independent cohorts of 147 and 159 ESCC patients. The contributions of B4GALNT4 to proliferation, invasion, migration, and adhesion was evaluated in ESCC cells subjected to siRNA-mediated gene knockdown. Correlations between clinicopathological parameters and B4GALNT4 expression in clinical specimens were analyzed in both patient cohorts. B4GALNT4 mRNA expression levels varied widely in ESCC cell lines, regardless of differentiation status or the originating tissue. Knockdown of B4GALNT4 significantly suppressed the proliferation, invasion, migration, and adhesion of ESCC cell lines compared with control cells. B4GALNT4 mRNA was overexpressed in ESCC tissues compared with adjacent normal esophageal tissues. High mRNA expression was significantly associated with poor disease-free survival and hematogenous recurrence, and high B4GALNT4 protein expression was also significantly related to poor disease-specific survival. On multivariable analysis, high B4GALNT4 expression was an independent predictor of poor prognosis. In both patient cohorts, high B4GALNT4 expression did not correlate with known prognostic factors, such as disease stage, lymphovascular invasion, or squamous cell-carcinoma-related antigen level. B4GALNT4 influences the malignant behavior of ESCC cells. B4GALNT4 expression may serve as a novel prognostic marker, independent of established risk factors, for ESCC patients.

Poor oral health is an independent risk factor for upper aerodigestive tract cancers, including esophageal squamous cell carcinoma (ESCC). The pattern recognition receptor Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide in the cell walls of Gram-negative periodontal pathogens associated with the development and progression of ESCC. It is, therefore, plausible that TLR4 plays a crucial role in the pathogenesis of ESCC. We used an ESCC tissue microarray to confirm expression of TLR4 in patients with ESCC and to determine whether TLR4 expression status correlates with the clinicopathological features of these patients or their prognosis after esophagectomy. We also tested whether the combined expression statuses of TLR4 and TLR3 better correlate with prognosis in these patients than either parameter alone. Clinical ESCC samples from all 177 patients tested showed expression of TLR4. Moreover, high TLR4 expression (3 + and 2 +) correlated with poorer 5-year overall survival after esophagectomy than lower TLR4 expression (1 +) (p = 0.0491). Patients showing high TLR4 expression tended to have a poorer prognosis whether treated with surgery alone or with surgery and adjuvant chemotherapy. Univariate and multivariate analyses showed TLR4 expression status to be an independent prognostic factor affecting 5-year overall survival. Patients exhibiting high TLR4 expression with low TLR3 expression had a much poorer prognosis than other patients (p =