Pretreatment periodontitis is predictive of a poorer prognosis after esophagectomy for esophageal cancer.

BACKGROUND: Poor oral health is an independent risk factor for upper-aerodigestive tract cancers, including esophageal cancer. Several studies have investigated short-term outcomes after esophagectomy and the impact of periodontal disease, but few have examined the impact of periodontal disease on long-term outcomes. The purpose of this study was to investigate the rate of periodontitis among esophagectomy patients and the prognostic value of periodontitis and its effect on prognosis after esophagectomy. METHODS: A total of 508 patients who underwent esophagectomy received oral health care from a dentist before cancer treatment at Akita University Hospital between January 2009 and December 2021. We assessed the presence and severity of the patients' periodontitis and divided them into no-periodontitis, mild periodontitis, severe periodontitis and edentulous jaw groups. We then assessed 10-year overall survival (OS) and disease-specific survival (DSS) and determined whether periodontitis was an independent prognostic factor affecting OS and DSS. RESULTS: We found that 101 (19.9%) patients had no periodontitis, 207 (40.8%) had mild periodontitis, 176 (34.6%) had severe periodontitis requiring tooth extraction, and 24 (4.7%) had edentulous jaw. Both OS and DSS were significantly poorer in the periodontitis than no-periodontitis group (p < 0.001). In detail, the edentulous jaw group had the poorest prognosis (p < 0.001). Multivariate analysis showed that periodontitis was an independent risk factor affecting OS and DSS. CONCLUSION: Esophageal cancer patients had a high prevalence of periodontitis. Moreover, the presence of periodontitis and severity of periodontitis are independent risk factors contributing to a poorer prognosis after esophagectomy.

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.

Preoperative inspiratory muscle weakness as a risk factor of postoperative pulmonary complications in patients with esophageal cancer.

OBJECTIVE: We examined whether preoperative inspiratory muscle weakness (IMW) is a risk factor for postoperative pulmonary complications (PPCs) in patients with esophageal cancer who underwent subtotal esophagectomy. METHODS: This single-center retrospective cohort study enrolled patients with esophageal cancer who underwent a scheduled subtotal esophagectomy between June 2020 and May 2022. Maximal inspiratory pressure (MIP) was measured as inspiratory muscle strength using a respiratory dynamometer, and we defined IMW as MIP < 80% of the predicted value. Our primary outcome comprised overall PPCs. We investigated the relationship between IMW and PPCs using the Bayesian logistic regression model. RESULTS: After exclusion, 72 patients were included in this study. IMW was identified in 26 patients (36%), and PPCs developed in 28 patients (39%). Among patients with IMW, 15 (58%) developed PPCs. Preoperative IMW was associated with PPCs (mean odds ratio [OR]: 3.58; 95% credible interval [95% CrI]: 1.29, 9.73) in the unweighted model. A similar association was observed in the weighted model adjusted for preoperative and intraoperative contributing factors (mean OR: 4.15; 95% CrI: 2.04, 8.45). CONCLUSIONS: Preoperative IMW was associated with PPCs in patients with esophageal cancer who underwent subtotal esophagectomy. This association remained after adjusting for preoperative and intraoperative contributing factors.

High TLR6 Expression Status Predicts a More Favorable Prognosis after Esophagectomy for Locally Advanced Thoracic Esophageal Squamous Cell Carcinoma.

Most so-called "beneficial bacteria" in gut microbiota are Gram-positive, and TLR6 recognizes the peptidoglycan (PGN) present in their cell walls. We hypothesized that a high TLR6 expression status predicts a more favorable prognosis after esophagectomy. We used an ESCC tissue microarray (TMA) to examine TLR6 expression status in ESCC patients and to determine whether TLR6 expression status correlates with prognosis after curative esophagectomy. We also examined whether PGN influences the cell proliferation activity of ESCC lines. Clinical ESCC samples from 177 patients tested for the expression of TLR6 were categorized as 3+ (n = 17), 2+ (n = 48), 1+ (n = 68), or 0 (n = 44). High TLR6 expression (3+ and 2+) correlated with significantly more favorable 5-year overall survival (OS) and disease-specific survival (DSS) after esophagectomy than a lower TLR6 expression (1+ and 0). Univariate and multivariate analyses showed that TLR6 expression status is an independent prognostic factor that affects 5-year OS. PGN significantly inhibited the cell proliferation activity of ESCC lines. This is the first study to show that high TLR6 expression status predicts a more favorable prognosis in locally advanced thoracic ESCC patients after curative esophagectomy. PGN released from "beneficial bacteria" seems to have potential to inhibit the cell proliferation activity of ESCC.

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.

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.

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.

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.

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.

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.

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).

Differences in treatment and survival between elderly patients with thoracic esophageal cancer in metropolitan areas and other areas.

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.

Robot-assisted thoracoscopic enucleation for a large esophageal leiomyoma: a case report.

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.

SUVmax reduction predicts long-term survival in patients of non-pCR both in the tumor and lymph nodes after neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma.

BACKGROUND: A pathological complete response (pCR) after neoadjuvant chemoradiotherapy (NACRT) ensures long-term survival in esophageal squamous cell carcinoma (ESCC) patients following esophagectomy, but pCR patients are a minority. The aim here was to identify prognostic factors in patients with non-pCR ESCC after NACRT. METHODS: This is a retrospective study. Investigated were 5-year overall survival (OS), disease-specific survival (DSS), and relapse-free survival (RFS) among non-pCR ESCC patients divided into pT0N0, primary site pCR (pT0N+), lymph node pCR (pT+N0), and non-pCR in both the tumor and lymph node (pT+N+) subgroups after NACRT and esophagectomy. Focusing on the SUVmax reduction rate in the primary tumor in 88 patients who underwent FDG-PET before and after NACRT, we used univariate and multivariate Cox proportional hazard models to identify prognostic factors. RESULTS: Although there were no significant survival differences among non-pCR ESCC patients with pT0N+, pT+N0, or pT+N+, survival rate among pT+N+patients was the poorest. After setting a 60% cutoff for the SUVmax reduction rate in the tumor, RFS curves for non-pCR patients significantly differed between patients above the cutoff and those below it. For pT+N+ patients, the SUVmax reduction rate (<60% vs ≥ 60%) was an independent prognostic factor of OS, DSS, and RFS. CONCLUSION: Because ESCC patients with SUVmax reduction rates of <60% in the tumor after NACRT and categorized as pT+N+ after NACRT had significantly poorer prognoses, even after esophagectomy, a change in treatment strategy may be an option to improve survival.

Lower local recurrence rate after robot-assisted thoracoscopic esophagectomy than conventional thoracoscopic surgery for esophageal cancer.

The oncological advantages of robot-assisted thoracoscopic esophagectomy (RATE) over conventional thoracoscopic esophagectomy (TE) for thoracic esophageal cancer have yet to be verified. In this study, we retrospectively analyzed clinical data to compare the incidences of recurrence within the surgical field after RATE and TE as an indicator of local oncological control. Among 121 consecutive patients with thoracic esophageal or esophagogastric junction cancers for which thoracoscopic surgery was indicated, 51 were treated with RATE while 70 received TE. The number of lymph nodes dissected from the mediastinum, duration of the thoracic portion of the surgery, and morbidity due to postoperative complications did not differ between the two groups. However, the rate of overall local recurrence within the surgical field was significantly (P = 0.039) higher in the TE (9%) than the RATE (0%) group. Lymph node recurrence within the surgical field occurred in left recurrent nerve, left tracheobronchial, left main bronchus and thoracic paraaortic lymph nodes, which were all difficult to approach to dissect. The other two local failures occurred around the anastomotic site. This study indicates that using RATE enabled the incidence of recurrence within the surgical field to be reduced, though there were some limitations.

Neoadjuvant Chemoradiotherapy Followed by Esophagectomy with Three-Field Lymph Node Dissection for Thoracic Esophageal Squamous Cell Carcinoma Patients with Clinical Stage III and with Supraclavicular Lymph Node Metastasis.

BACKGROUND: Neoadjuvant chemoradiotherapy (NACRT) followed by esophagectomy is now the standard treatment for patients with resectable advanced thoracic esophageal squamous cell carcinoma (ESCC) worldwide. However, the efficacy of NACRT followed by esophagectomy with three-field lymph node dissection for clinical Stage III patients and for clinical Stage IVB patients with supraclavicular LN metastasis has not yet been determined. METHODS: Between 2008 and 2018, 94 ESCC patients diagnosed as clinical Stage III and 18 patients diagnosed as clinical Stage IVB with supraclavicular LN metastasis as the only distant metastatic factor were treated with NACRT followed by esophagectomy with extended lymph node dissection at Akita University Hospital. Long-term survival and the patterns of recurrence in these 112 patients were analyzed. RESULTS: The median follow-up period of censored cases was 60 months. The five-year OS and DSS rates among the clinical Stage III patients were 57.6% and 66.6%, respectively. The five-year OS and DSS rates among the clinical Stage IVB patients were 41.3% and 51.6%, respectively. The most frequent recurrence pattern was distant metastasis (69.2%) in the Stage III patients and LN metastasis (75.0%) in the Stage IVB patients. CONCLUSION: NACRT followed by esophagectomy with three-field LN dissection is feasible and offers the potential for long-term survival of clinical Stage III ESCC patients and even clinical Stage IVB patients with supraclavicular LN metastasis as the only distant metastatic factor. At least in patients with upper and middle thoracic ESCC, treating supraclavicular LNs as regional LNs seems to be appropriate.

Effects of SLC31A1 and ATP7B polymorphisms on platinum resistance in patients with esophageal squamous cell carcinoma receiving neoadjuvant chemoradiotherapy.

The relationship between the SLC31A1 (protein: copper transporter 1) rs10981694 A > C and ATP7B (protein: P-type adenosine triphosphatase 7B) rs9535828 A > G polymorphisms on the overall survival and disease-free survival of 104 Japanese patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant chemoradiotherapy (CRT) was investigated. Chemotherapy consisted of protracted infusion of 5-fluoracil (800 mg/m2/day) on days 1-5 and cisplatin or nedaplatin (80 mg/m2/day) on day 1. The median (range) follow-up was 47 (6-127) months. The 5-year overall and disease-free survival rates were 71.2% and 60.6%, respectively. The 5-year overall survival rate was significantly higher in patients with the SLC31A1 rs10981694 C allele compared with the rs10981694 A/A genotype (91.7% vs. 65.0%, P = 0.018). The 5-year disease-free survival rate was significantly higher in patients with the SLC31A1 rs10981694 C allele compared with the rs10981694 A/A genotype (79.2% vs. 55.0%, P = 0.043). In addition, univariate and multivariate analyses showed the SLC31A1 rs10981694 A > C polymorphism to be a significant prognostic factor affecting 5-year overall survival after neoadjuvant CRT. However, the overall and disease-free survival rates after surgery did not differ significantly among the ATP7B rs9535828 genotypes. In conclusion, only the SLC31A1 rs10981694 A/A genotype was an independent predictor of a poorer 5-year overall survival. Therefore, in neoadjuvant CRT for ESCC patients, the effect of platinum was affected by the SLC31A1 rs10981694 A > C polymorphism. The presence of this polymorphism should be considered when devising neoadjuvant CRT regimens or treatment strategies for ESCC.

Verification of the Optimal Interval Before Esophagectomy After Preoperative Neoadjuvant Chemoradiotherapy for Locally Advanced Thoracic Esophageal Cancer.

BACKGROUND: The interval between preoperative chemoradiotherapy and surgery reportedly affects perioperative outcomes and survival; however, the optimal interval in esophageal cancer patients remains uncertain. OBJECTIVE: Our aim was to determine whether a prolonged interval between preoperative neoadjuvant chemoradiotherapy (NACRT) and esophagectomy affects the outcomes of esophageal cancer patients. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Approaches to resection of recurrent solitary mediastinal lymph nodes after esophagectomy.

Esophageal cancer recurrence in solitary mediastinal lymph node that may possibly been left behind in the first surgery differs from other recurrence patterns because it is still local disease and offers the possibility of complete cure through resection, but it is technically difficult. We resected recurrent mediastinal lymph nodes in six cases. A left transthoracic approach was used in three patients. Other approaches were left thoracoabdominal, right open transthoracic and transcervical. R0 resections were achieved in five patients without severe surgical stress or postoperative complications. Overall survival after resection of recurrent lymph nodes was 43 (16-82) months. Approaches to resection of recurrent solitary mediastinal lymph nodes after esophagectomy should be consider to perform curative treatment safely and less invasively.

IGF2BP3 Expression Correlates With Poor Prognosis in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Insulin-like growth factor-II mRNA binding protein 3 (IGF2BP3) is an oncofetal RNA-binding protein normally involved in cell growth and migration during the early stages of embryogenesis. However, it is also expressed in various cancers, and the relationship between IGF2BP3 and the clinicopathological features and prognosis of esophageal squamous cell carcinoma patients is not fully understood. Our aim in this study was to determine whether IGF2BP3 expression status correlates with prognosis in patients with advanced thoracic esophageal squamous cell carcinoma. METHODS: The IGF2BP3 expression statuses of 177 patients treated with esophagectomy without preoperative therapy were evaluated immunohistochemically using tissue microarray analysis. The relationships between IGF2BP3 expression status and clinicopathological features and survival were then assessed using appropriate statistics. RESULTS: Among 177 esophageal tumors, 122 (68.9%) expressed high levels of IGF2BP3. In patients undergoing surgery alone, IGF2BP3-high expression was significantly associated with a poorer prognosis. By contrast, there were no significant associations between IGF2BP3 expression and clinicopathological features or outcomes in patients treated with surgery plus postoperative adjuvant chemotherapy. CONCLUSIONS: IGF2BP3 positivity in advanced thoracic esophageal squamous cell carcinoma is associated with adverse clinical outcomes in patients treated with surgery alone.