Prevention of Sarcopenia and Maintenance of Exercise Tolerance by Individualized Prehabilitation in a Patient With Esophageal Cancer During Preoperative Adjuvant Therapy: A Case Report.

Preoperative adjuvant therapy for esophageal cancer increases sarcopenia and decreases exercise tolerance, which are risk factors for postoperative pneumonia. Preoperative rehabilitation for patients undergoing esophagectomy effectively reduces the incidence of postoperative pneumonia. Therefore, the risk factors should be optimized by preoperative rehabilitation. Our patient had several risk factors for postoperative pneumonia, including low exercise tolerance, presarcopenia, and low respiratory muscle strength. However, because of the patient's advanced age, multiple comorbidities, and poor nutritional status, we struggled to determine the appropriate exercise intensity. Furthermore, there was a concern that chemotherapy-related adverse events could prevent adequate exercise from being performed. However, with individualized measures such as adjustable exercise intensity settings based on treatment status and nutritional management through multidisciplinary collaboration, it was possible to prevent sarcopenia and maintain exercise tolerance during preoperative adjuvant therapy. Individualized support in preoperative rehabilitation was suggested to contribute to the prevention of sarcopenia and maintenance of exercise tolerance during preoperative adjuvant therapy.

Lipopolysaccharide induces CCL2 through TLR4 signaling and promotes esophageal squamous cell carcinoma cell proliferation.

Poor oral health is an independent risk factor for upper-aerodigestive tract cancers, including esophageal squamous cell carcinoma (ESCC). Our previous findings suggest that high expression of toll-like receptor (TLR) 4, which recognizes lipopolysaccharide (LPS) released from periodontal pathogens, correlates with a poor prognosis after esophagectomy for ESCC. We therefore hypothesized that LPS influences cancer cell proliferation and disease progression in ESCC. We used 8 ESCC cell lines to investigate how LPS affects ESCC cell proliferation and migration activity. We also assessed mRNA and protein expression to determine how LPS affects cytokine production and whether blocking TLR4 signaling attenuates that effect. We also used a mouse xenograft model to investigate whether LPS upregulates ESCC tumor progression in vivo. We then determined whether C-C motif chemokine ligand 2 (CCL2) expression in clinical samples correlates with 5-year overall survival (OS) and disease-specific survival (DSS) in ESCC patients after esophagectomy. LPS significantly upregulated cell proliferation and migration in all ESCC lines. It also upregulated CCL2 production. In vivo, subcutaneous LPS administration significantly increased ESCC tumor volume in mice. In clinical samples, high CCL2 expression significantly correlated with 5-year OS and DSS. There was also a significant correlation between CCL2 and TLR4 expression status, suggesting the involvement of an LPS-TLR4-CCL2 cascade in clinical settings. LPS significantly upregulates cell proliferation and tumor progression through an LPS-TLR4-CCL2 cascade and influences prognosis after esophagectomy for ESCC. This suggests improving the oral environment has the potential to improve the prognosis of ESCC patients after esophagectomy.

Does clinical T1N0 GGN really require checking for distant metastasis during initial staging for lung cancer?

BACKGROUND: Accurate clinical staging is crucial for selection of optimal oncological treatment strategies in non-small cell lung cancer (NSCLC). Although brain MRI, bone scintigraphy and whole-body PET/CT play important roles in detecting distant metastases, there is a lack of evidence regarding the indication for metastatic staging in early NSCLCs, especially ground-grass nodules (GGNs). Our aim was to determine whether checking for distant metastasis is required in cases of clinical T1N0 GGN. METHODS: This was a retrospective study of initial staging using imaging tests in patients who had undergone complete surgical R0 resection for clinical T1N0 Stage IA NSCLC. RESULTS: A total of 273 patients with cT1N0 GGNs (n = 183) or cT1N0 solid tumors (STs, n = 90) were deemed eligible. No cases of distant metastasis were detected on initial routine imaging evaluations. Among all cT1N0M0 cases, there were 191 incidental findings on various modalities (128 in the GGN). Most frequently detected on brain MRI was cerebral leukoaraiosis, which was found in 98/273 (35.9%) patients, while cerebral infarction was detected in 12/273 (4.4%) patients. Treatable neoplasms, including brain meningioma and thyroid, gastric, renal and colon cancers were also detected on PET/CT (and/or MRI). Among those, 19 patients were diagnosed with a treatable disease, including other-site cancers curable with surgery. CONCLUSIONS: Extensive staging (MRI, scintigraphy, PET/CT etc.) for distant metastasis is not required for patients diagnosed with clinical T1N0 GGNs, though various imaging modalities revealed the presence of adventitious diseases with the potential to increase surgical risks, lead to separate management, and worsen patient outcomes, especially in elderly patients. If clinically feasible, it could be considered to complement staging with whole-body procedures including PET/CT.

Multiplex Intraoperative Rapid Immunohistochemistry with Noncontact Antibody Mixing for Distinguishing the Histologic Phenotype of Lung Cancer.

INTRODUCTION: Determining a surgical strategy for early-stage lung cancer requires an accurate histologic diagnosis. Immunohistochemistry (IHC) enables reliable diagnosis of histological types but requires more time and more tumor tissue slides than hematoxylin and eosin staining. We aimed to assess the clinical validity of a new rapid multiplex IHC technique utilizing alternating current (AC) mixing for intraoperative lung cancer diagnosis. METHODS: Forty-three patients who underwent radical resection of lung cancers were enrolled in a retrospective observational study. Frozen sections were prepared from lung tumor samples, and rapid IHC employing AC mixing was implemented alongside a multiplex IHC protocol targeting thyroid transcription factor-1 + cytokeratin 5, desmoglein 3 + Napsin A, and p63 + tripartite motif containing 29. We then evaluated the concordance between intraoperative diagnoses derived from rapid multiplex IHC and final pathology. RESULTS: The concordance rate between the pathological diagnosis made with added rapid multiplex IHC and the final pathology was 93.0% (Cohen's 𝜅 coefficient = 0.860 and 95% CI: 0.727-0.993). When considering only adenocarcinoma and squamous cell carcinoma, the diagnoses were in agreement for all cases. CONCLUSIONS: We suggest rapid multiplex IHC as a promising tool for determining surgical strategies for lung tumors.

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.

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.

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.

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.

Validity of the 30-Second Chair-Stand Test to Assess Exercise Tolerance and Clinical Outcomes in Patients with Esophageal Cancer: A Retrospective Study with Reference to 6-Minute Walk Test Results.

This retrospective study aimed to investigate the validity of a 30-sec chair stand test (CS-30) as a simple test to assess exercise tolerance and clinical outcomes in 53 Japanese patients with esophageal cancer. There was a strong correlation between the results of CS-30 and the 6-min walk test (6MWT), the gold standard for assessing exercise tolerance (r=0.759). Furthermore, fewer patients whose CS-30 score was greater than 16 (the cutoff value defined based on 6MWT) experienced pneumonia in their postoperative course. These results suggest that exercise tolerance could be assessed using CS-30, and its cutoff value may be useful in predicting postoperative pneumonia risk.

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.

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.

Changes in Serum Trace Element Concentrations Before and After Surgery in Resectable Breast Cancer.

BACKGROUND/AIM: Minerals and trace elements (TEs) play vital roles in normal biological functions and in all cancers. Breast carcinoma is the most commonly occurring cancer in women. The aim of this study was to evaluate changes in TE levels before and after breast cancer surgery and the clinical utility and reliability of TE levels assayed using inductively coupled plasma mass spectrometry (ICP-MS). PATIENTS AND METHODS: Thirteen patients with ductal carcinoma in situ (DCIS) and 34 with invasive ductal carcinoma (IDC) treated with planned surgery were enrolled between August 2017 and February 2019. Blood samples were collected before and the day after resection of the primary tumor. All enrolled patients received mastectomy or quadrantectomy and axillary lymph node dissection/biopsy. Serum TE concentrations were determined using ICP-MS. RESULTS: Changes in boron, titanium, vanadium, chromium, copper, zinc, and selenium levels from before to after surgery differed between IDC and DCIS patients. Boron and copper levels before surgery and changes in titanium, vanadium, and chromium before and after surgery are potential predictors distinguishing DCIS from IDC. Subset analysis showed that chromium is a potential biomarker for luminal subtype, while titanium and chromium are potential biomarkers for pathological staging. CONCLUSION: Changes in serum TEs before and after surgery may help with diagnosis and staging of breast cancer and in establishing TE supplementation protocols.

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.

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.

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.

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.

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.