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Purpose: The purpose of this study was to examine the prognostic and oxaliplatin predictive value of mismatch repair (MMR) status and common hot spot mutations, which we previously identified in stage II and III colon cancer.Experimental Design: Mutations in BRAF, KRAS, NRAS, MET, and PIK3CA were profiled in 2,299 stage II and III colon tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials C-07 (n = 1,836) and C-08 (n = 463) with Type Plex chemistry and mass spectrometry. C-07 tested the worth of adding oxaliplatin to 5-fluorouracil plus leucovorin, and C-08 tested the worth of adding bevacizumab to FOLFOX. Cox proportional hazard models were used to assess prognostic or oxaliplatin predictive value of mutations for tumor recurrence, overall survival (OS), and survival after recurrence (SAR).Results:BRAF mutations were associated with MMR-deficient tumors (P < 0.0001), poor OS [HR, 1.46; 95% confidence interval (CI), 1.20–1.79; P ≤ 0.0002], and poor SAR (HR, 2.31; 95% CI, 1.83–2.95; P < 0.0001). Mutations in KRAS, NRAS, MET, and PIK3CA were not associated with recurrence, OS, or SAR. MMR-deficient tumors were associated with an improved prognosis based on recurrence (HR, 0.48; 95% CI, 0.33–0.70; P < 0.0001). Mutations and MMR status were not predictive for oxaliplatin benefit.Conclusions: This study shows that BRAF mutations profiled from stage II and III colon cancer tumors were associated with poor SAR and validates and explains, at least in part, previous observations associating it with poor OS. Profiling of all of these mutations is warranted for future clinical trials testing new targeted therapies that block relevant signaling pathways. Such clinical trials are under development at NSABP. Clin Cancer Res; 18(23); 6531–41. ©2012 AACR.

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XLS file - 154K, Freqeuncy of Mutations in NSABP C-07 and C-08 and in COSMIC

Murine double minute 2 (MDM2) is well known to inhibit p53 function and its over-expression is associated with poor prognosis in several human malignancies. Nutlin-3, a small-molecule inhibitor of MDM2, exerts antitumor effects on various solid tumors harboring wild-type p53. We aimed to clarify its effects on esophageal cancer.We first examined the potential antitumor effects of nutlin-3 according to MDM2 status using esophageal carcinoma cell lines (KYSE 170/180). We then immunolocalized MDM2 immunoreactivity in 62 surgical cases of esophageal squamous cell carcinoma undergoing neoadjuvant chemotherapy followed by esophagectomy and correlated the findings with clinicopathological variables.MDM2 mRNA expression in KYSE 170 was significantly higher than that in KYSE 180 cells. No significant changes were detected in both cell lines when nutlin-3 was added. However, cell proliferation was significantly decreased in KYSE 170 cells treated with nutlin-3 and cisplatin compared to cisplatin alone but not in KYSE 180. MDM2 immunoreactivity was also significantly associated with poor sensitivity to neoadjuvant chemotherapy in the cases examined.The combination of nutlin-3 with chemotherapeutic agents may become a novel therapeutic strategy in esophageal cancer over-expressing MDM2.

Definitive chemoradiotherapy (dCRT) is widely considered as a treatment option for cervical esophageal squamous cell carcinoma (ESCC) toward preserving the larynx. We have reported favorable outcomes, including the treatment response rate and short-term survival of dCRT concomitant with docetaxel, cisplatin, and 5-fluorouracil (DCF-RT) for advanced cervical ESCC. The aim of this paper was to report the subsequent progress of the study.We assessed 18 patients with advanced (clinical stage II-IV, including T4b and/or M1 lymph node) cervical ESCC at our department who received DCF-RT as the first-line treatment between December 2010 and June 2020.A total of 14 men and 4 women underwent the study regimen. The pretreatment clinical stage included stage II, stage III, stage IVA, and stage IVB cases (including 9 patients with T4b) [8 trachea and 2 thyroids] and 7 patients with the M1 lymph node. The complete response (CR) was achieved in 15 patients, stable disease in 2, and progressive disease in 1. Of 15 patients with CR, 7 experienced recurrence, and 8 had continued CR. Frequent cases of grade ≥3 adverse effects included leucopenia, neutropenia, febrile neutropenia, and pharyngeal pain. The 3-year overall survival rate, disease-free survival rate, and disease-specific survival rate were 44.2%, 47.7%, and 48.6%, respectively.DCF-RT for advanced cervical esophageal cancer could achieve a favorable prognosis with larynx preservation. Further observations are warranted to establish the long-term prognosis, late complications of radiotherapy, and the significance of salvage surgery.

Background Thioredoxin reductase 1 (TXNRD1) and heme oxygenase-1 (HO-1) are both involved in the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and play key roles in antioxidant responses. In patients with esophageal squamous cell carcinoma (ESCC), the correlation between the expression of these two proteins and the therapeutic response to neoadjuvant chemoradiation therapy (NACRT), as well as the difference in their expression after chemoradiotherapy, remains unknown. Methods Proteins involved in the Nrf2 pathway were immunolocalized in carcinoma cells in ESCC patients on NACRT with 5-fluorouracil and cisplatin, followed by esophagectomy. The 8-hydroxydeoxyguanosine (8-OHdG) levels were used to quantify reactive oxygen species. The changes in immunoreactivity before and after NACRT (Δ) were assessed. Results Tumor reduction following NACRT was significantly attenuated in pre-therapeutic biopsy specimens associated with high HO-1 status. TXNRD1Δ, HO-1Δ, and 8-OHdGΔ were significantly different in the ineffective and effective groups. The overall survival was significantly lower in high Nrf2 and TXNRD1 groups. In addition, high TXNRD1 expression was an independent prognostic factor in the multivariate analysis of overall survival. Conclusions The study findings indicate that HO-1 status in pre-therapeutic biopsy specimens could predict response to NACRT, and TXNRD1 status could predict overall survival of ESCC patients.

Background Evaluating the effect on primary lesions is important in determining treatment strategies for esophageal cancer. The Response Evaluation Criteria in Solid Tumors system, which employs the longest diameter for measuring tumors, is commonly used for evaluating treatment effects. However, the usefulness of these criteria in assessing primary esophageal tumors remains controversial. Thus, we evaluated this issue by measuring not only the longest diameter but also the shorter axis of the tumor. Methods We retrospectively reviewed data from 313 patients with esophageal cancer treated with neoadjuvant chemotherapy followed by esophagectomy at three major high-volume centers in Japan. All patients underwent contrast-enhanced computed tomography before and after chemotherapy. The longest and shortest tumor diameters were measured in each case. Treatment effects were adapted to the Response Evaluation Criteria in Solid Tumors system. Correlations between pathological and survival data were also analyzed. Results Inter-observer discrepancies were examined for changes in the longest diameter and shorter axis of the tumor (the intraclass correlation coefficients were 0.550 and 0.624, respectively). The shorter axis was correlated with the pathological response in the multivariate analysis (p Conclusions This multicenter study demonstrated that the Response Evaluation Criteria in Solid Tumors system is useful for predicting pathological response and survival by incorporating the shorter axis of the primary esophageal tumor.

Esophageal intramural pseudodiverticulosis (EIPD) is a rare disease. A 78-year-old man with dysphagia presented to our hospital. The presence of diffuse esophageal spasm was suspected by his primary-care doctor. High-resolution manometry (HRM) showed no abnormal findings. The patient was diagnosed with EIPD and Candida esophagitis, by esophagogastroduodenoscopy (EGD) and esophagography. His symptoms improved after symptomatic treatment for Candida esophagitis with oral administration of an antifungal drug. EIPD should be considered in patients with dysphagia; EGD and esophagography should be performed when diagnosing EIPD.

A number of elderly esophageal cancer patients who have eligibility for radical esophagectomy are increasing. However, we have no clearly evidence of treating strategy for these population because mostly high evidential clinical studies doesn’t include over 75-year-old patients. In this study, we retrospectively assessed efficacy of neoadjuvant chemotherapy using CDDP +5-FU in over 75-year-old patient in our hospital. We extracted total 105 over 75-year-old esophageal cancer patients who underwent radical esophagectomy from 2007 to 2020 in our hospital. We classified them Group A (surgery alone) and Group B (neo-FP(±RT) + surgery) and analyzed perioperative surgical risk, surgical outcomes, and adverse events or effectiveness for neoadjuvant therapy. Furthermore, long-term survival was assessed by using matched cohort from propensity score matching. Preoperative risk score calculated by E-pass scoring system was significantly higher in group A while surgical score was similar between two groups. Among group B, 86% of patients were underwent neoadjuvant chemotherapy (NAC) and its completion rate was 78.9%. Number of the patients occurred adverse events during NAC were 8/7/12/3 in the G1/2/3/4 respectively. Postoperative complications decided by Clavien-Dindo classification weren’t seen significant difference between two groups. Postoperative in hospital days were significantly shorter in group A. Survival analysis showed significantly worse overall survival and disease-free survival in group A in both all cohort and matched cohort. The level of preoperative risk score was different between two different treatment strategies. Although this study has several limitations including low number population, difference of preoperative risk, and short follow up period, neoadjuvant therapy using FP may safety and effective treatment for elderly esophageal cancer patients.

Radiochemotherapy (CRT) is one of the curative treatment options next to surgery in the treatment of esophageal squamous cell carcinoma. However, CRT may cause esophageal stenosis or obstruction during the healing process. Therefore, in such cases, follow up of early recurrence detection becomes an issue for those patients. We report a case of severe stenosis after CRT, in which recurrence could not detected until advanced cancer developed on the anal side of stenosis. The case is a 73-year-old male. He was diagnosed with upper thoracic esophageal cancer (T4N2M0StageIVa) and had undergone radical chemoradiotherapy 5 years ago. The treatment effect achieved a complete response, but the primary tumor site caused severe esophageal stenosis. Therefore, biannual CT follow up had been done instead of endoscopic follow up. During follow-up, CT revealed a new neoplastic lesion in the lower thoracic esophagus, and endoscopy inserted through a gastrostomy revealed a bulky tumor on the anorectal side of the stenotic lesion. Biopsy revealed carcinosarcoma and robot-assisted thoracoscopic esophagectomy was performed. Malignant neoplasms can be developed not only the same site of primary tumor after CRT. Especially in case of carcinosarcoma, detection would be delayed because of rapid growing. But when the severe esophageal stenosis occurred after CRT, the examination of anal side become difficult. Therefore, it is necessary to observe by frequent CT or PET examination, or endoscopy from gastrostomy for early detection of recurrence or newly malignant neoplasm.

Esophageal basaloid squamous cell carcinoma may resemble small cell carcinoma biopsy specimens and cause difficulties in pathology diagnosis. We aimed to explore the pathological features of basaloid squamous cell carcinomas in biopsy specimens that mimic small cell carcinoma and to clarify their diagnostic and prognostic features. This study will contribute to draw attention to an important pitfall in pathology diagnosis in endoscopic biopsy specimens of the esophagus. Thirty biopsy specimens of esophageal basaloid squamous cell carcinoma were reviewed and compared with 13 matched surgical specimens. A small cell carcinoma-like feature was defined as, when at least one of the three following findings was observed: 1) diffuse growth pattern, 2) nuclear molding and 3) nuclear crush artifact. Immunohistochemistry of synaptophysin, chromogranin A, CD56 (neuroendocrine markers) and p16 were performed in all cases. Small cell carcinoma-like features, such as diffuse growth, nuclear molding, or nuclear crush artifact, were identified in 80% (24/30) of the biopsies and in 77% (10/13) of the surgery specimens, but in a proportionally much smaller area in the surgical specimens than in the biopsy samples. The presence of a small cell carcinoma-like feature had no impact on patients´ outcome. Immunohistochemically, synaptophysin and chromogranin A were consistently negative, while CD56 was expressed in 42% (10/24) basaloid squamous cell carcinomas with small cell carcinoma-like features. p16, a highly sensitive marker for small cell carcinoma, was also expressed in 8% (2/24). In conclusion, small cell carcinoma-like features are frequent and conspicuous in biopsies, which may probably be caused by exogenous factors such as friction and external pressure that occur in biopsy procedure and in the tumor environment. Small cell carcinoma-like features may lead to a misinterpretation of a true small cell carcinoma, if CD56 is an only neuroendocrine marker expressed. p16 expression may be also detected in basaloid squamous cell carcinoma.

Nrf2 is a transcription factor that regulates cytoprotective genes in response to oxidative and electrophilic stresses. The activity of Nrf2 is mainly controlled by the protein degradation by Keap1, a ubiquitin E3 ligase adaptor. Most of esophageal squamous cell carcinomas (ESCC) exhibit constitutive Nrf2 activation by Keap1 dysfunction, resulting in the poor prognosis. However, it has not been clarified whether Nrf2 activation serves as the initiation in tumorigenesis of ESCC. We generated tamoxifen-inducible and squamous epithelium-specific Keap1 conditional knockout (Keap1-cKO) mice in which Nrf2 is activated segmentally in esophageal epithelium at the adult stage. Using Nqo1 that is a representative Nrf2 target gene as the marker of Nrf2-acitivated cells, we distinguished Keap1-deleted/Nrf2-activated cells and Nrf2-normal cells in immunohistochemical analysis and gene expression analysis. Single-cell RNA-seq (scRNA-seq) analysis was conducted to compare the gene expression of Nrf2-activated cells and Nrf2-normal cells from Keap1-cKO mice, and control cells from control mice. In Keap1-cKO mice, Nrf2-activated cells accounted for 35% at 1 week and 20% at 4 weeks after induction of Keap1 deletion. This decrease was based on observations that Nrf2-activated cells were eliminated from the epithelium due to the weakened attachment to the basement membrane. In contrast, DNA damage accumulated in Nrf2-normal cells neighboring Nrf2-activated cells. To clarify the cell fate in the esophagus, we compared Nrf2-normal cells to Nrf2-activated cells or control cells in scRNA-seq analysis. Gene sets of G2/M checkpoint and E2F targets, which regulate cell proliferation, were enriched in Nrf2-normal cells. Constitutive Nrf2 activation renders esophageal epithelial cells able to be selectively eliminated via cell competition. Nrf2-normal cells suffered from DNA damage, but not Nrf2-activated cells, have a potency to be an origin of ESCC. These results suggest that Nrf2 activation serves as a tumor promoter of ESCC, but not the initiator. We speculate that the other gene mutations such as Tp53 are needed for the initiation to form ESCC prior to Nrf2 activation.

Recently, the selection rate of definitive chemoradiotherapy (CRT) as a treatment option for cervical esophageal squamous cell carcinoma (ESCC) has increased to preserve the larynx. However, many things about the regimen, irradiation field, or which is better treatment have not been determined. We have started definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-RT) for advanced cervical esophageal squamous cell carcinoma. We evaluated 20 advanced cervical ESCC patients (clinical stage II–IV, including T4b and/or M1 lymph node) in our department who received DCF-RT as the first-line treatment between December 2010 and August 2021. 16 males and 4 females. The pretreatment clinical stage included one stage II, five stage III, six stage IVa, and eight stage IVb cases (including 10 with T4b and 8 with M1 lymph node. Grade 3 or more adverse events included leucopenia (95%), neutropenia (90%), febrile neutropenia (55%). We attained CR in 17 patients (85%), SD in 2 patients, and PD in 1 patient. Of 17 patients with CR, 8 experienced recurrence and 9 continued exhibiting CR. Two patients who underwent salvage surgery. While the 2−/3-year overall survival rate was 60.2%/46.4%, the 2−/3-year recurrent-free survival rate was 51.4%/45.7%, respectively. DCF-RT for advanced cervical ESCC could be completed by the careful administration, and although a strong blood toxicity might occur, a favorable prognosis can be obtained with larynx preservation. Further observations are warranted to establish the long-term prognosis, late complications of radiotherapy, and the significance of salvage surgery.

Recently, effectiveness of robot-assisted minimally invasive esophagectomy (RAMIE) has been reported however, there are some issues specific to RAMIE which may lead to major complications. The issues include 1) interference with the right shoulder, 2) compression of vertebral bodies and blood vessels, 3) energy devices, and 4) education to young surgeons. In this study, we evaluated the short-term outcome of RAMIE in our department, and show the ideas for improving those issues. For 1), the assistant gives instructions to the surgeon, and uses a protector on right shoulder. In 2), port arrangement depending on the cases and switching the camera port is useful. 3) Because those devices are still under developing, careful procedure is required while using energy device, 4) Double console and extra thoracoscopic camera is useful in operating under the education. We conducted a comparative study of 81 cases of RAMIE performed at our institution from 2014 to January 2022 and 392 cases of prone thoracoscopic esophagectomy performed at about the same time, to evaluate the short-term outcomes including complications. RAMIE showed an increase in thoracic operation time (median 286 min vs 260 min), but amount of thoracic bleeding tended to be smaller (median 13 mL vs 19 mL). Recurrent laryngeal nerve palsy (G1) was about 40%, and pneumonia was about 18%, which was about the same. One case encountered to in-hospital death from RAMIE group by aspiration pneumonia and one cardiac tamponade by thoracoscopic surgery, respectively, Also, there was no difference in short-term outcomes between experienced and non-experienced surgeons, except operation time. It is difficult to educate young surgeons who cannot afford to pay attention to the surroundings because there is a possibility that the surrounding organs will be damaged without resistance. Therefore, experienced surgeon should observe and understand the situation using double console or an additional scope. Also, many other knacks and tricks are important to reduce the complications arises from robotic surgery.

Background Esophageal achalasia causes dysphagia following impaired relaxation of the lower esophageal sphincter due to the degeneration of Auerbach’s plexus in the esophageal smooth muscle. Recently, peroral endoscopic myotomy (POEM) has become one of the preferred treatment options for esophageal achalasia. However, pathomorphological changes after POEM have not been well examined. Case presentation A 65-year-old man with a history of POEM for esophageal achalasia was diagnosed with clinical stage II (cT2-N0-M0) thoracic esophageal squamous cell carcinoma and was consequently treated with neoadjuvant chemotherapy followed by thoracoscopic esophagectomy. Intraoperatively, the esophagus appeared dilated, reflecting esophageal achalasia; however, fairly slight fibrous adhesions were observed between the esophagus and the pericardial surface despite previously performed POEM via an anterior incision. Histopathological examination revealed esophageal wall thickening, edema, and fibrosis extending from the lamina propria to the submucosa. Besides, the majority of the inner layer and some proportion of the outer layer of the muscularis propria were found to be missing or atrophic at the esophagogastric junction (EGJ). No ganglion cells could be detected at the Auerbach’s plexus. Conclusions The previous history of POEM did not affect circumferential mediastinal periesophageal dissection during thoracoscopic esophagectomy. Nevertheless, a large proportion of the inner layer of the muscularis propria at the EGJ level seemed to have become lost or atrophic because of the POEM procedure.

An appropriate strategy is needed to determine the therapeutic effect of chemotherapy on primary lesions in esophageal cancer. This multicenter cohort study aimed to examine the usefulness of a novel criterion obtained by multiplying the lengths of the major and minor esophageal axes from helical computed tomography as a tool to evaluate the therapeutic effect of neoadjuvant chemotherapy and to predict prognosis after surgery in locally advanced esophageal cancer. A first investigation evaluated the reproducibility of the new criterion between two independent examiners. In a second investigation, we examined the association of the novel criterion with pathological tumor regression grade and long-term outcomes. Pretreatment primary lesions less than 20 mm on computed tomography were excluded. In an initial cohort of 81 patients, the intraclass correlation coefficient for the novel criterion was higher than that for the tumor major axis both before and after neoadjuvant chemotherapy. In the second cohort of 255 patients, the novel criterion significantly correlated with tumor regression grade (p = 0.0003), overall survival (p < 0.0001), and disease-free survival (p < 0.0001). It was also an independent predictor for overall survival (p = 0.0023), along with age, tumor regression grade, and pathological stage. The measurement derived by multiplying the esophageal major and minor axes on computed tomography is easy to obtain and has better objectivity and reproducibility for tumors of any shape. This novel criterion may be clinically useful because it can estimate therapeutic effect, tumor regression grade, and prognosis after neoadjuvant chemotherapy followed by surgery for esophageal cancer.

As the population ages, the proportion aged ≥75 years is expected to increase. Many studies on peroral endoscopic myotomy (POEM) as treatment for esophageal achalasia have already been reported; however, few studies have been designed on patients aged ≥75 years. The purpose of this study is to describe the characteristics of esophageal achalasia in patients75 years and to evaluate the outcomes of POEM.This study included 121 patients who underwent POEM for esophageal achalasia, which was divided into the geriatric (n = 18) group aged ≥75 and the young (n = 103) group ≤74 years. The characteristics of esophageal achalasia and the short-term outcomes after POEM in the geriatric group compared with the young group were retrospectively investigated.The median age of the geriatric group was 78 years, and two patients were initially diagnosed with refractory pneumonia, and esophageal achalasia was initially overlooked. The preoperative Eckardt score of the geriatric group was significantly lower than that of the young group (4 vs. 6, P = 0.007), particularly in the regurgitation score. The Eckardt score and integrated relaxation pressure of both groups were significantly improved after POEM (P 0.001). There were no cases of perioperative complications in the geriatric group.POEM for esophageal achalasia is a safe and effective treatment even in geriatric patients75 years of age. In geriatric patients with recurrent or intractable pneumonia, it is important to rule out esophageal achalasia. Geriatr Gerontol Int 2021; 21: 788-793.

Esophageal basaloid squamous cell carcinoma may resemble small cell carcinoma biopsy specimens and cause difficulties in pathology diagnosis. We aimed to clarify the clinicopathological significance of small cell carcinoma-like morphologies in basaloid squamous cell carcinoma. Thirty biopsy specimens of esophageal basaloid squamous cell carcinoma were reviewed and compared with 13 matched surgical specimens. Small cell carcinoma-like features, such as diffuse growth, nuclear molding, or nuclear crush artifact, were identified in 80% (24/30) of the biopsies and in 77% (10/13) of the surgery specimens, but in a proportionally much smaller area in the surgical specimens than in the biopsy samples. The presence of a small cell carcinoma-like feature had no impact on patients´ outcome. Immunohistochemically, synaptophysin and chromogranin A were consistently negative, while CD56 was expressed in 42% (10/24) of basaloid squamous cell carcinomas with small cell carcinoma-like features. p16, a highly sensitive marker for small cell carcinoma, was also expressed in 8% (2/24). p40 was expressed in all cases of basaloid squamous cell carcinoma. In conclusion, small cell carcinoma-like features are frequent and conspicuous in biopsies, which are probably caused by exogenous factors such as friction and external pressure that occur in biopsy procedure and in the tumor environment. Small cell carcinoma-like features may lead to a misinterpretation of a true small cell carcinoma, if CD56 is the only neuroendocrine marker expressed. p16 expression may also be detected in basaloid squamous cell carcinoma.

A 63-year-old man with protein C deficiency underwent thoracoscopic esophagectomy and digestive reconstruction using a gastric tube for thoracic esophageal cancer. On postoperative day 3, the gastric tube was removed because of anastomotic leakage and gastric tube necrosis. Digestive reconstruction using a free jejunal graft was attempted 140 days after the first surgery. However, thrombus formation in the artery and vein of the jejunal graft resulted in a failed reconstruction. Ten days after this surgery, digestive reconstruction using the colon was performed with intraoperative heparin administered for anticoagulation control. The surgery was successful, with no thrombus formation afterward. When performing digestive reconstruction in patients with conditions predisposing to thrombus formation, perioperative management should be completed with careful attention toward preventing thrombus formation. In particular, appropriate anticoagulation control, such as the administration of intraoperative heparin, is recommended in patients with protein C deficiency because necrosis of the reconstructed organ is likely.

The immune microenvironment plays a pivotal role in cancer development and progression. Therefore, we studied the status of immune cells in esophageal adenocarcinoma (EAC) and adjacent Barrett's esophagus (BE) and their association with the clinical course of patients. We included 87 patients with EAC who underwent surgical resection or endoscopic submucosal dissection. CD3, CD8, Foxp3, p53, and Ki-67 were immunolocalized in EAC and adjacent BE (N = 87) and BE without EAC (N = 13). BE adjacent to EAC exhibited higher CD3+ lamina propria lymphocyte (LPL) numbers than BE without EAC. Abundant Foxp3+ LPLs in BE were associated with dysplasia and increased Ki-67 labeling index (LI) in BE glandular cells and tended to link to aberrant p53 expression. Abundant CD8+ LPLs in adjacent BE were associated with worse prognosis of EAC patients (P = 0.019). Results of our present study firstly revealed the potential influence of the tissue immune microenvironment of BE adjacent to EAC on cancer development and eventual clinical outcome of EAC patients. T cell infiltration could play pivotal roles in facilitating the dysplasia-adenocarcinoma sequence in BE. The number of Foxp3+ T cells is increased at the early stage of carcinogenesis and could help identify patients harboring dysplastic and highly proliferating cells. CD8+ T cells could reflect unfavorable inflammatory response in adjacent tissue microenvironment and help predict worse prognosis of EAC patients.

Previous studies have evaluated the clinicopathological significance of carcinoembryonic antigen (CEA) of esophageal cancer in relatively small numbers of patients. Therefore, this study aimed to clarify the prognostic significance of CEA in 1822 patients with esophageal squamous cell carcinoma (SCC).Based on the Japanese Esophageal Society nationwide multi-institutional retrospective study, a total of 1,748 surgically treated ESCC from 15 hospitals were enrolled to evaluate prognostic impact of preoperative CEA values. Among them, 605 patients were categorized to up-front surgery group, and 1,217 patients were categorized to neoadjuvant therapy group. The CEA threshold for positivity was 3.7 ng/ml. The clinicopathological and prognostic impact of CEA was evaluated by univariate and multivariate analysis in each treatment modality groups.In total, the CEA positive rate was 25.8% (470/1822). CEA-positive status was significantly associated with distant metastasis (P = 0.004) but not associated with other factors. CEA-positive status was associated with poor overall survival (P 0.001) in univariate analysis as well as multivariate analysis (P = 0.003).CEA was an independent prognostic determinant of overall survival in esophageal SCC. Based on the subgroup analysis, regardless of the treatment modality, patients with high pretreatment CEA showed poor overall survival.

With de novo cancer, esophagectomy after lung transplantation (LTx) can be challenging because of intrathoracic adhesions, delayed wound healing, and postoperative pulmonary complications, which might be lethal.A 52-year-old woman with esophageal cancer had undergone bilateral LTx for end-stage diffuse panbronchiolitis at 50 years of age. Thoracoscopic esophagectomy was performed. Bilateral bronchial arteries and subcarinal and bilateral bronchial lymph nodes were preserved to maintain blood supply to the transplanted bronchi. No ischemic changes were observed in either bronchi. The patient's postoperative course was uneventful. Although she underwent chemoradiation therapy for recurrence at the left cervical paraesophageal lymph node, she remains alive with good disease control and well-maintained respiratory function.Minimally invasive surgery with careful attention to blood supply to the transplanted bronchi was useful for treating esophageal cancer after LTx.

Neoadjuvant chemotherapy (NAC) followed by esophagectomy can improve the prognosis of locally advanced esophageal cancer (LAEC). However, LAEC reportedly recurred in 17-21% of patients within 6 months post surgery. Thus, current treatment strategies may be inadequate for LAECs with poor prognosis. Preoperative identification of patients with poor prognosis might aid in modification of treatment strategies. This study aimed to evaluate the usefulness of the maximum standardized uptake value change rate (ΔSUVThis study involved 220 esophageal cancer patients who underwent esophagectomy after NAC at three facilities in Japan. The optimal cut-off point for ΔSUVThe optimal cut-off point for ΔSUVΔSUV

Although previous reports showed clinicopathological and diagnostic significance of serum p53 antibody in esophageal squamous cell carcinoma, all those reports analyzed only 100 to 200 patients at single institute. This study was designed as a multi-institutional study promoted by the Japan Esophageal Society to elucidate the clinical significance of serum p53 antibody in esophageal cancer treatment. Methods A total of 1,487 patients, from 15 hospitals of Japan, with esophageal carcinoma surgically treated between 2008 and 2016 were enrolled in this retrospective study. We used 1.30 U/ml as a cutoff for classifying patients into positive and negative groups. And we attempted to analyze only positive cases. A receiver operating characteristic curve was constructed to assess serum p53 antibody cutoff levels to differentiate poor prognosis. We used 9.82 U/ml as a cutoff for classifying patients into low and high groups. Univariate and multivariate analyses were used to evaluate the clinicopathological and prognostic significance of pretreatment level of serum p53 antibody. Results There were significant relationships between serum p53 antibody level and tumor depth (p = 0.002), nodal status (p = 0.027) and pathological stage (p = 0.002). The positive serum p53 antibody group had a no significantly worse overall survival than that of the negative group (p = 0.699). The high serum p53 antibody group had a significantly worse overall survival than that of the low group (p = 0.024). However, the difference was not significant in the multivariate analysis (p = 0.137). Conclusion Although high level (>9.82 U/ml) of pretreatment serum p53 antibody might be associated with poor prognosis for patients with esophageal cancer, high serum p53 antibody was not an independent risk factor.

Necroptosis is a pivotal process in cancer biology, however, the clinical significance of necroptosis in esophageal squamous cell carcinoma (ESCC) has remained unknown. Therefore, in this study, we aimed to verify the potential involvement of necroptosis in the clinical outcome, chemotherapeutic resistance, and tumor microenvironment of ESCC. Mixed lineage kinase domain-like protein (MLKL) and phosphorylated MLKL (pMLKL) were immunohistochemically examined in 88 surgically resected specimens following neoadjuvant chemotherapy (NAC) and 53 pre-therapeutic biopsy specimens, respectively. Tumor-infiltrating lymphocytes (TILs) were also evaluated by immunolocalizing CD3, CD8, and forkhead box protein 3 (FOXP3) in the residual tumors after NAC. High pMLKL status in the post-NAC resected specimens was significantly correlated with worse prognosis in ESCC patients. Multivariate analysis demonstrated that a high pMLKL status was an independent prognostic factor. In pre-NAC biopsy specimens, a high pMLKL status was significantly associated with a lower therapeutic efficacy. CD8+ TILs were significantly lower in the high-pMLKL group. FOXP3+ TILs were significantly higher in both high-MLKL and high-pMLKL groups. We first demonstrated pMLKL status as an independent prognostic factor in ESCC patients. Our study revealed the possible involvement of necroptosis in the immunosuppressive microenvironment, resulting in the attenuated therapeutic efficacy of NAC and eventual adverse clinical outcomes in ESCC.