Neoadjuvant Chemoradiotherapy Upregulates the Immunogenicity of Cold to Hot Tumors in Esophageal Cancer Patients.

Objective: To test the hypothesis that neoadjuvant chemoradiotherapy (NACRT) is more effective against hot esophageal squamous cell carcinoma (ESCC) and that it may upregulate tumor immunogenicity. Background: There have been several recent reports showing the efficacy of immune check-point inhibitors (ICIs) against esophageal cancer, especially immunologically hot tumors. In addition, several studies have suggested that chemotherapy and radiotherapy may convert cold tumors to hot tumors. Methods: Of 105 ESCC patients who underwent surgery after NACRT between 2010 and 2018 at our hospital, 99 whose biopsy tissue samples were obtained were enrolled. Based on immunohistochemical analysis, tumors that were FOXA1 (+) and/or EYA2 (+) were defined as hot tumors, others were cold tumors. We then investigated the association between tumor immunogenicity and clinicopathological features. Results: The 29 patients with hot tumors before NACRT had a significantly better 5-year disease-specific survival (DSS) rate than the remaining 70 patients with cold tumors (85% vs 64%; P = 0.036). In a multivariate analysis, tumor immunogenicity was a significant independent predictor of DSS. Of 68 patients without a pathological complete response (non-pCR) in their primary tumor, 51 (75%) had hot tumors after NACRT. Moreover, 75% (36/48) of tumors that were cold before NACRT were converted to hot tumors after NACRT. Conclusions: Patients with hot ESCC tumors treated with NACRT plus esophagectomy had a better prognosis than those with cold tumors. NACRT upregulated cold tumor immunogenicity to hot tumors, suggesting NACRT may increase the sensitivity of ESCC to adjuvant ICIs.

Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial.

BACKGROUND: First-line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab-containing regimens in many countries. We report longer-term follow-up data. METHODS: This open-label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression-free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD-L1) expression of ≥1% and then in the overall population. RESULTS: A total of 970 patients were randomly assigned. After 29 months of minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46-0.76]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65-0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48-0.80]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65-0.92]). In patients with tumor cell PD-L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51-0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79-1.36]). Among all treated patients (n = 936), Grade 3-4 treatment-related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients. CONCLUSIONS: Nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow-up, further supporting use as first-line standard treatment options for patients with advanced ESCC.

Preoperative neoadjuvant chemoradiotherapy provides borderline resectable thoracic esophageal cancer with equivalent treatment results as clinically T3 thoracic esophageal cancer.

Aim: Because the optimal treatment strategy for borderline resectable (cT3br) thoracic esophageal cancer patients remains unclear, it is of great interest whether preoperative neoadjuvant therapy for cT3br could achieve results comparable to those seen with resectable T3 cancer (cT3r). We speculated that preoperative neoadjuvant chemoradiotherapy (NACRT) would be particularly effective in cT3br thoracic esophageal cancer patients and compared to cT3br and cT3r. Methods: Of 186 cT3 thoracic esophageal cancer patients treated with intended NACRT, 162 received radical esophagectomy. More than 97% were squamous cell carcinomas. Patients were partitioned into two groups according to whether invasion of adjacent organs was suspected (cT3br and cT3r). Treatment outcomes and survival were analyzed. Results: Sixty-eight patients (36.6%) were classified as cT3br and 118 (63.4%) as cT3r. The cT3br group had significantly more tumors in the upper and middle mediastinum (p < 0.0001) and more cases with cM1 (lymph node) (p = 0.0104) than the cT3r group. In addition, the cT3br patients receiving esophagectomy exhibited a significantly lower pathological complete response rate than the cT3r patients (p = 0.0374). However, the R0 resection rate did not differ between the cT3br and cT3r patients (p = 0.0978), and the two groups treated with intended NACRT had similar 5-year overall (OS) and disease-specific survival (DSS) (p = 0.3831 and p = 0.9020). In addition, the incidence and patterns of recurrence did not differ between the cT3br and cT3r patients receiving esophagectomy (p = 0.8109 and p = 0.3128). Conclusions: Preoperative neoadjuvant chemoradiotherapy appears to be a promising treatment for patients with borderline resectable thoracic esophageal squamous cell carcinoma.

OPLAH Protein Expression Stratifies the Prognosis of Patients With Squamous Cell Carcinoma of the Esophagus.

BACKGROUND/AIM: Squamous cell carcinoma is one of the major subtypes of esophageal carcinoma, and the 5-year overall survival rate of esophageal squamous cell carcinoma patients who underwent curative treatment remains below 40%. We aimed to detect and validate the prognosticators of esophageal squamous cell carcinoma in patients who underwent radical esophagectomy. MATERIALS AND METHODS: Comprehensive analysis of transcriptome and clinical data from The Cancer Genome Atlas revealed OPLAH as one of the differentially expressed genes between esophageal squamous cell carcinoma tissues and normal esophageal mucosa. OPLAH expression changes were significantly associated with a patient prognosis. OPLAH protein levels were further evaluated by immunohisto-chemistry in esophageal squamous cell carcinoma tissues (n=177) as well as in serum samples (n=54) using ELISA. RESULTS: OPLAH mRNA was significantly overexpressed in esophageal squamous cell carcinoma tissues compared to normal esophageal mucosa, and patients with high OPLAH mRNA expression have a significantly poorer prognosis, according to The Cancer Genome Atlas data. The high staining intensity of OPLAH protein in esophageal squamous cell carcinoma tissue clearly stratified patient prognosis. According to multivariable analysis, high OPLAH protein expression was an independent prognostic factor for survival after surgery. Pre-neoadjuvant chemotherapy serum OPLAH protein concentrations were significantly associated with clinical tumor depth and node positivity and, consequently, with advanced clinical stage. The serum OPLAH protein concentration was significantly decreased by neoadjuvant chemotherapy. CONCLUSION: OPLAH protein expression in cancerous tissue and serum may have clinical utility towards stratifying prognosis of patients with esophageal squamous cell carcinoma.

Squamous cell carcinoma-derived G-CSF promotes tumor growth and metastasis in mice through neutrophil recruitment and tumor cell proliferation, associated with poor prognosis of the patients.

Tumor-derived G-CSF is a well-known factor to aggravate disease progression in various types of cancers. In this study, we investigated a role of G-CSF in squamous cell carcinoma (SCC). High expression of G-CSF in the tumor tissues of esophageal SCC (ESCC) patients correlated with poor prognosis. Murine SCC NR-S1M cells produce considerable amount of G-CSF, which expression is correlated with its metastatic potentials. Deletion of G-CSF in NR-S1M cells mitigated tumor growth and metastasis to lymph node and lung of subcutaneous NR-S1M tumors in the mice. Mechanistically, G-CSF enhanced cell proliferation in autocrine manner in vitro, whereas in NR-S1M tumor-bearing mice, accumulation of plasma G-CSF was associated with expansion of peripheral neutrophils, which led to a decreased proportion of CD8+ T cells. Antibody depletion of neutrophils restored the number of CD8+ T cells and modestly suppressed tumor outgrowth, albeit no changes in distant metastasis. We propose that G-CSF produced by NR-S1M cells facilitates tumor progression in mice through bi-functional effects to promote neutrophil recruitment and tumor cell proliferation, which may render poor prognosis to the ESCC patients with high G-CSF expression.

First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50).

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. GOV ID: NCT03143153.

Salvage Robotic-Assisted Thoracoscopic Esophagectomy after Definitive Chemoradiotherapy for Clinical T4b Esophageal Cancer: A Case Report.

The advantages of salvage esophagectomy through robotic-assisted surgery for patients with clinically diagnosed tumor invasion of adjacent vital organs (cT4b) or patients with scar tissue from definitive chemoradiotherapy (dCRT) are still only rarely reported. A man in his 60s with middle thoracic esophageal cancer (cT4b [left main bronchus] N1 M0 cStage IIIC) received dCRT (60 Gy). After the chemoradiotherapy, upper gastrointestinal endoscopy revealed a residual primary tumor, and we performed robotic-assisted thoracoscopic subtotal esophagectomy and gastric tube reconstruction via a retrosternal route with three-field lymphadenectomy. Although it was difficult to dissect the tumor from adjacent organs, especially the left main bronchus and left inferior pulmonary vein, due to loss of the dissecting layer and scarring, R0 surgery was achieved. With robot-assisted thoracoscopic surgery, the high-magnification, high-resolution, and three-dimensional images; the stable surgical field with full countertraction made with the robotic arm forceps, which were readily adjusted; and the stable motion of the robotic arm without physiological tremor are considerable advantages for salvage esophagectomy for cT4b tumors. It goes without saying that sufficient experience with robot-assisted surgery and sufficient understanding and surgical skill in esophageal cancer surgery under suitable surgical indications and timing are required to make use of these advantages.

Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors.

Introduction: Clinical roles of plasma IL-6 levels have been reported in patients with various cancers, including non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (ICIs). However, the roles of other IL-6 signaling components, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130), in the plasma have not been elucidated. Methods: Blood was collected from 106 patients with NSCLC before initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Plasma levels of IL-6, sIL-6R, sgp130, and their complexes were assessed by Cox regression hazard model to evaluate their clinical significance. The clinical role of IL-6 or IL-6R genetic polymorphisms was also analyzed. Results: Cox regression analysis showed that higher plasma IL-6 levels significantly predicted unfavorable overall survival (OS; hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.05-1.68, p = 0.012) in NSCLC patients treated with ICIs. However, plasma sIL-6R and sgp130 levels showed no prognostic significance (p = 0.882 and p = 0.934, respectively). In addition, the estimated concentrations of binary IL-6:sIL-6R and ternary IL-6:sIL-6R:sgp130 complexes and their ratios (binary/ternary complex) were not significantly associated with OS (p = 0.647, p = 0.727, and p = 0.273, respectively). Furthermore, the genetic polymorphisms of IL-6 (-634G>C) and IL-6R (48892A>C) showed no clinical role by Kaplan-Meier survival analysis (p = 0.908 and p = 0.639, respectively). Discussion: These findings demonstrated the clinical significance of plasma levels of IL-6, but not of other IL-6 signaling components, sIL-6R and sgp130, suggesting that classical IL-6 signaling, but not trans-signaling, may be related to anti-tumor immune responses in cancer patients treated with ICIs.

A Multi-institutional Study to Diagnose the Risk of Lymph Node Metastasis Using a CRP Genetic Polymorphism Test Kit in pT1, cN0 Thoracic Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIM: 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. PATIENTS AND METHODS: This is a retrospective, multi-institutional, observational study. The CRP 1846C>T 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. RESULTS: 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. CONCLUSION: CRP 1846C>T 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.

Identification of Galectin-7 as a crucial metastatic enhancer of squamous cell carcinoma associated with immunosuppression.

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.

Disturbance of Gastrointestinal Cancers Diagnoses by the COVID-19 Pandemic in a Depopulated Area of Japan: A Population-Based Study 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.

Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.

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<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. CONCLUSIONS: Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.).

Peritumoral CD16b positive-neutrophil accumulation strongly correlates with regional lymph node metastasis in thoracic esophageal squamous cell cancer.

BACKGROUND: The mechanism underlying cancer cell metastasis from the tumor to regional lymph nodes is not yet fully understood. We hypothesized that peritumoral neutrophil accumulation promotes regional lymph node metastasis in thoracic esophageal squamous cell cancer. METHODS: Between 2010 and 2019, 126 thoracic esophageal squamous cell cancer patients received curative (R0) esophagectomy without preoperative treatment in our hospital. Using paraffin-embedded resected tumors, we performed immunohistochemical analysis of CD16b-positive neutrophil accumulation in the peritumoral area, which was defined as a 1-mm region centered on the border separating the malignant cell nests from the host tissue. The relationship between the density of peritumoral CD16b staining and pathological lymph node metastasis or 5-year overall survival was evaluated. RESULTS: Although the clinicopathological characteristics of CD16b-high and CD16b-low patients did not differ, greater pathological lymph node metastasis (P < .001) and lymphatic invasion by the tumor (P = .024) and a poorer 5-year survival (P = .010) were seen in CD16b-high patients. Moreover, CD16b-positive neutrophil density was generally higher in the peritumoral area than within the tumor itself. Univariate and multivariate analyses showed that CD16b-positive neutrophil accumulation was an independent factor for lymph node metastasis with an odds ratio >25 (P < .001). On the other hand, blood neutrophil counts did not correlate with lymph node metastasis. CONCLUSION: Peritumoral accumulation of CD16b-positive neutrophils is an independent factor strongly correlated with lymph node metastasis in thoracic esophageal squamous cell cancer.

New PET/CT criterion for predicting lymph node metastasis in resectable advanced (stage IB-III) lung cancer: The standard uptake values ratio of ipsilateral/contralateral hilar nodes.

BACKGROUND: The aim of the present study was to use surgical and histological results to develop a simple noninvasive technique to improve nodal staging using preoperative PET/CT in patients with resectable lung cancer. METHODS: Preoperative PET/CT findings (pStage IB-III 182 patients) and pathological diagnoses after surgical resection were evaluated. Using PET/CT images to determine the standardized uptake value (SUV) ratio, the SUVmax of a contralateral hilar lymph node (on the side of the chest opposite to the primary tumor) was measured simultaneously. The I/C-SUV ratio was calculated as ipsilateral hilar node SUV/contralateral hilar node SUV. Receiver operating characteristic (ROC) curves were then used to analyze those data. RESULTS: Based on ROC analyses, the cutoff I/C-SUV ratio for diagnosis of lymph node metastasis was 1.34. With a tumor ipsilateral lymph node SUVmax ≥2.5, an IC-SUV ratio ≥1.34 had the highest accuracy for predicting N1/N2 metastasis; the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of nodal staging were 60.66, 85.11, 84.09, 62.5 and 71.29%, respectively. CONCLUSIONS: When diagnosing nodal stage, a lymph node I/C-SUV ratio ≥1.34 can be an effective criterion for determining surgical indications in advanced lung cancer.

PET-Uptake Reduction into Lymph Nodes After Neoadjuvant Therapy is Highly Predictive of Prognosis for Patients Who have Thoracic Esophageal Squamous Cell Carcinoma Treated with Chemoradiotherapy Plus Esophagectomy.

BACKGROUND: Patients with 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET)-positive lymph nodes before treatment have a poor prognosis after esophagectomy. This study investigated whether FDG uptake into lymph nodes on FDG-PET (PET-N) during the pre- or posttreatment stage is more predictive of survival for thoracic esophageal squamous cell carcinoma (TESCC) patients who received neoadjuvant chemoradiotherapy (NACRT) followed by esophagectomy. METHODS: Of 129 TESCC patients with clinical lymphatic metastasis who underwent curative-intent esophagectomy after NACRT between 2010 and 2018, 97 who received PET before and after NACRT were enrolled in the study. The study defined lymph nodes with a maximum standardized uptake value (SUVmax) greater than 2.5 on FDG-PET before NACRT as cPET-N(+) and after NACRT as CRT-cPET-N(+). Both the cPET-N(+) and CRT-cPET-N(-) patients were defined as PET-N responders. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: No significant difference in survival was detected between the cPET-N(+) and cPET-N(-) patients. However, the CRT-cPET-N(-) patients had significantly better 5-year overall survival (OS) and disease-specific survival (DSS) than the CRT-cPET-N (+) patients. The PET-N responders had significantly better 5-year OS and DSS than the PET-N non-responders, and PET-N response was an independent prognostic factor for 5-year DSS. CONCLUSION: The PET-N response is a highly predictive prognostic marker for TESCC patients who undergo NACRT followed by esophagectomy. The PET-N response may help clinicians to establish a strategy for perioperative treatments that improves survival for patients with lymph node metastasis in TESCC.

Does Esophagectomy Provide a Survival Advantage to Patients Aged 80 Years or Older? Analyzing 5066 Patients in the National Database of Hospital-based Cancer Registries in Japan.

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 to 2011 data from the National Database of Hospital-based Cancer Registries from the National Cancer Centerin Japan, divided the patients into a ≥75 group (75-79 years; n = 2935) and a ≥80 group (80 years or older; n = 2131), 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 2 groups. RESULTS: A significantly greater percentage of patients were treated with esoph-agectomy 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 2 groups (P = 0.17). Multivariable Cox proportional hazard analysis revealed that esoph-agectomy 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 chemoradiotherapy. 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.

Using CT to evaluate mediastinal great vein invasion by thymic epithelial tumors: measurement of the interface between the tumor and neighboring structures.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Association between ABCC2 polymorphism and hematological toxicity in patients with esophageal cancer receiving platinum plus 5-fluorouracil therapy.

BACKGROUND: Platinum agents are taken up into cells by copper transporter (CTR) 1 (gene code: SLC31A1) and are excreted from cells by copper-transporting P-type adenosine triphosphatase (ATP7B) and multidrug resistance-associated protein (MRP) 2 (gene code: ABCC2). In addition, glutathione S transferase (GST) P1 is involved in the metabolism of platinum agents. The present study aimed to determine whether the rate of grade 3-4 hematological toxicity associated with platinum plus 5-fluorouracil (5-FU) therapy in 239 patients with esophageal cancer was affected by the SLC31A1 rs10981694A>C and rs12686377G>T, ATP7B rs9535828A>G, GSTP1 rs1695A>G, and ABCC2 -24C>T polymorphisms. METHODS: Chemotherapy consisted of protracted infusion of 5-FU (800 mg/m2/day) on days 1-5 and cisplatin or nedaplatin (80 mg/m2/day) on day 1. RESULTS: A total of 82 of 239 patients developed grade 3-4 hematological toxicity after chemotherapy. Univariate analysis showed that ABCC2 -24C/T + T/T genotypes (P = 0.038), radiation therapy (P = 0.013), baseline white blood cell count < 6000/µL (P = 0.003), and baseline neutrophil count < 3900/µL (P = 0.021) were statistically significant predictors of grade 3-4 hematological toxicity. Multivariate analysis revealed that ABCC2 -24C/T + T/T genotypes (P = 0.036), radiation therapy (P = 0.005), and baseline white blood cell count < 6000/µL (P < 0.001) were significant risk factors. CONCLUSIONS: We determined that ABCC2 -24C>T is significantly associated with grade 3-4 hematological toxicity after platinum plus 5-FU therapy. These findings might contribute to improved treatment strategies for patients with esophageal cancer.

Patterns and timing of recurrence in esophageal squamous cell carcinoma patients treated with neoadjuvant chemoradiotherapy plus esophagectomy.

BACKGROUND: Tumor regression grade (TRG) after neoadjuvant therapy is reportedly predictive of prognosis in esophageal cancer patients, as lack of a response to neoadjuvant therapy is associated with a poor prognosis. However, there is little information available on the timing and pattern of recurrence after esophagectomy for thoracic esophageal squamous cell carcinoma (TESCC) that takes into consideration TRG after neoadjuvant chemoradiotherapy (NACRT). Here, in an effort to gain insight into a treatment strategy that improves the prognosis of NACRT non-responders, we evaluated the patterns and timing of recurrence in TESCC patients, taking into consideration TRG after NACRT. METHODS: A total of 127 TESCC patients treated with NACRT and esophagectomy between 2009 and 2017 were enrolled in this observational cohort study. TRGs were assigned based on the proportion of residual tumor cells in the area (TRG1, ≥1/3 viable cancer cells; 2, < 1/3 viable cancer cells; 3, no viable cancer cells). We retrospectively investigated the timing and patterns of recurrence and the prognoses in TESCC patients, taking into consideration TRG after NACRT. RESULTS: The 127 participating TESCC patients were categorized as TRG1 (42 patients, 33%), TRG2 (56 patients, 44%) or TRG3 (29 patients, 23%). The locoregional recurrence rate was higher in TRG1 (36.4%) patients than combined TRG2-3 (7.4%) patients. Patients with TRG3 had better prognoses, though a few TRG3 patients experienced distant recurrence. There were no significant differences in median time to first recurrence or OS among patients with locoregional or distant recurrence. There was a trend toward better OS in TRG2-3 patients with recurrence than TRG1 patients with recurrence, but the difference was not significant. CONCLUSIONS: NACRT non-responders (TRG1 patients) experienced higher locoregional recurrence rates and earlier recurrence with distant or locoregional metastasis. TRG appears to be useful for establishing a strategy for perioperative treatments to improve TESCC patient survival, especially among TRG1 patients. (303 words).