Minimally Invasive Esophagectomy Provides Better Short- and Long-Term Outcomes Than Open Esophagectomy in Locally Advanced Esophageal Cancer.

BACKGROUND: Minimally invasive esophagectomy (MIE) has been increasingly performed for locally advanced esophageal cancer in place of open transthoracic esophagectomy (OE). This study explored the significance of MIE for esophageal squamous cell carcinoma (ESCC), focusing mainly on the depth of primary esophageal tumors. METHODS: This study retrospectively assessed short- and long-term outcomes of patients who underwent esophagectomy for ESCC from 2005 through 2021. The inverse probability of the treatment-weighting (IPTW) method was used to compare the outcomes between OE and MIE. The outcomes also were evaluated in the subgroups stratified by cT category. RESULTS: Among 1117 patients, 447 (40%) underwent OE and 670 (60%) underwent MIE. After IPTW adjustment, the incidence of any postoperative complications was significantly higher in the OE group than in the MIE group (60.8% vs 53.7%; p = 0.032), whereas the R0 resection rate was significantly higher in the MIE group (98.6% vs 92.7%; p < 0.001). The MIE group showed better 3 year overall and cancer-specific survival than the OE group (p < 0.001). The incidence of locoregional recurrence within the surgical field was significantly more frequent in the OE group (p < 0.001). In the subgroup analysis stratified by cT category, the R0 resection rate was significantly higher and the incidence of locoregional recurrence was lower in the MIE group among the patients with cT3-4 tumors. In the patients with cT1-2 tumors, MIE showed no significant benefit over OE. CONCLUSIONS: For the patients with cT3-4 tumors, MIE showed fewer postoperative complications, better locoregional control, and better prognosis than OE. Compared with OE, MIE is beneficial, especially for locally advanced ESCC.

Induction of Kallikrein-Related Peptidase 13 and TET2/3 by Anticancer Drugs and Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma After Preoperative Treatment.

BACKGROUND: Preoperative chemotherapy/chemoradiotherapy has been generally considered for the treatment of esophageal squamous cell carcinoma (ESCC) to improve prognosis. We examined the effects of anticancer drugs on the expression of kallikrein-related peptidase 13 (KLK13), a potential ESCC prognostic marker, and its clinical relevance in patients who received chemotherapy/chemoradiotherapy for ESCC. METHODS: Overall, 105 patients with ESCC who received chemotherapy or chemoradiotherapy before esophagectomy were enrolled. The expression of KLK13 in biopsy samples obtained before chemotherapy/chemoradiotherapy and resected ESCC tumors was assessed by immunohistochemical staining. The effects of 5-fluorouracil (5-FU) and/or cisplatin (CDDP) exposure on the expressions of KLK13 and ten-eleven translocation dioxygenases (TET) in ESCC cells were examined by reverse transcription-polymerase chain reaction. RESULTS: Immunohistochemical staining of paired ESCC specimens before (biopsy samples) and after (resected specimens) chemotherapy/chemoradiotherapy demonstrated a change in KLK13 expression. KLK13 and TET2/3 transcriptions were induced when human ESCC cell lines were treated with 5-FU and/or CDDP. Among patients with KLK13-negative status before chemotherapy/chemoradiotherapy, those with KLK13-positive resected tumors had a significantly poorer prognosis than those with KLK13-negative resected tumors (p = 0.0477). By using tumor cells isolated from ESCC biopsy tissues obtained before chemotherapy/chemoradiotherapy, we established a primary culture system and detected the induction of KLK13 expression by anticancer drugs. CONCLUSIONS: Preoperative treatments alter KLK13 expression in ESCC. The conversion of KLK13 expression from a negative status in biopsy samples to a positive status in resected tumor samples is a predictor of poor prognosis. KLK13 status is a potential marker for decision making to avoid harmful chemotherapy/chemoradiotherapy in patients with ESCC.

Anatomical factor associated with thoracic procedural difficulty in robot-assisted minimally invasive esophagectomy.

BACKGROUND: Robotic surgical systems with full articulation of instruments, tremor filtering, and motion scaling can potentially overcome the procedural difficulties in endoscopic surgeries. However, whether robot-assisted minimally invasive esophagectomy (RAMIE) can overcome anatomical difficulties during thoracoscopic esophagectomy remains unclear. This study aimed to clarify the anatomical and clinical factors that influence the difficulty of RAMIE in the thoracic region. METHODS: Forty-five patients who underwent curative-intent RAMIE with upper mediastinal lymph node dissection for esophageal cancer were included. Using preoperative computed tomography images, we calculated previously reported anatomical indices to assess the upper mediastinal narrowness and vertebral body projections in the middle thoracic region. The factors influencing thoracic operative time were then investigated. RESULTS: During the thoracic procedure, the median operative time was 215 (124-367) min and the median blood loss was 20 (5-190) mL. Postoperatively, pneumonia, anastomotic leakage, and recurrent laryngeal nerve palsy occurred in 17.8%, 2.2%, and 6.7% of the patients, respectively. The multiple linear regression model revealed that a narrow upper mediastinum and greater blood loss during the thoracic procedure were significant factors associated with a prolonged thoracic operative time (P = 0.025 and P < 0.001, respectively). Upper mediastinal narrowing was not associated with postoperative complications. CONCLUSIONS: A narrow upper mediastinum was significantly associated with a prolonged thoracic operative time in patients with RAMIE.

Gastric conduit reconstruction after esophagectomy.

A high risk of complications still accompanies gastric conduit reconstruction after esophagectomy. In this narrative review, we summarize the technological progress and the problems of gastric conduit reconstruction after esophagectomy. Several types of gastric conduits exist, including the whole stomach and the narrow gastric tube. The clinical outcomes are similar between the two types of conduits. Sufficient blood supply to the conduit is mandatory for a successful esophageal reconstruction. Recently, due to the availability of equipment and its convenience, indocyanine green angiography has been rapidly spreading. When the blood perfusion of the planning anastomotic site is insufficient, several techniques, such as the Kocher maneuver, pedunculated gastric tube with duodenal transection, and additional microvascular anastomosis, exist to decrease the risk of anastomotic failure. There are two different anastomotic sites, cervical and thoracic, and mainly two reconstructive routes, retrosternal and posterior mediastinal routes. Meta-analyses showed no significant difference in outcomes between the anastomotic sites as well as the reconstructive routes. Anastomotic techniques include hand-sewn, circular, and linear stapling. Anastomoses using linear stapling is advantageous in decreasing anastomosis-related complications. Arteriosclerosis and poorly controlled diabetes are the risk factors for anastomotic leakage, while a narrow upper mediastinal space and a damaged stomach predict leakage. Although standardization among the institutional team members is essential to decrease anastomotic complications, surgeons should learn several technical options for predictable or unpredictable intraoperative situations.

A continuous muscle-sparing advantage of pylorus-preserving gastrectomy for older patients with cT1N0M0 gastric cancer in the middle third of the stomach.

In older patients with cT1N0M0 gastric cancer in the middle third of the stomach, LPPG has advantages over LDGB1 in maintaining skeletal muscle mass. BACKGROUND: Laparoscopic pylorus-preserving gastrectomy (LPPG) for early gastric cancer in the middle third of the stomach is expected to be an alternative procedure to laparoscopic distal gastrectomy (LDG). However, whether LPPG is safe and more useful than LDG in older patients is unclear because of their comorbidities and organ dysfunctions. METHODS: We retrospectively analyzed the data of consecutive patients aged 75 or over who underwent LDG with Billroth I reconstruction (LDGB1) or LPPG for cT1N0M0 gastric cancer in the middle third of the stomach between 2005 and 2019. After propensity score matching was used to improve the comparability between the LDGB1 and LPPG groups, we compared surgical and postoperative nutritional outcomes, including the postoperative trends of bodyweight (%BW) and skeletal muscle index (%SMI). RESULTS: A total of 132 patients who underwent LDGB1 (n = 88) and LPPG (n = 44) were collected for this study. No significant difference in postoperative complications was observed. The total protein levels after LPPG were significantly higher than those after LDGB1 for 4 postoperative years. Both %BW and %SMI after LPPG were significantly maintained compared with those after LDGB1 during the first year after surgery. For the subsequent years, %BW after LPPG became similar to that after LDGB1, while %SMI after LPPG was significantly larger than LDGB1 continuously. CONCLUSIONS: LPPG has a great advantage in maintaining the postoperative skeletal muscle mass as well as the nutritional parameters of older patients. LPPG is expected to be an alternative to LDG in older patients.

Loss of GSTO2 contributes to cell growth and mitochondria function via the p38 signaling in lung squamous cell carcinoma.

Glutathione S-transferase omega 2 (GSTO2) lacks any appreciable GST activity, but it exhibits thioltransferase activity. The significance of GSTO2 in lung function has been reported; however, the precise expression and molecular function of GSTO2 in the lungs remain unclear. In the present study, we found that GSTO2 is expressed in airway basal cells, non-ciliated, columnar Clara cells, and type II alveolar cells, which have self-renewal capacity in the lungs. Contrastingly, no GSTO2 expression was observed in 94 lung squamous cell carcinoma (LSCC) samples. When human LSCC cell lines were treated with 5-aza-2'-deoxycytidine, a DNA-methyltransferase inhibitor, GSTO2 transcription was induced, suggesting that aberrant GSTO2 hypermethylation in LSCC is the cause of its downregulation. Forced GSTO2 expression in LSCC cell lines inhibited cell growth and colony formation in vitro. In a subcutaneous xenograft model, GSTO2-transfected cells formed smaller tumors in nude mice than mock-transfected cells. Upon intravenous injection into nude mice, the incidence of liver metastasis was lower in mice injected with GSTO2-transfected cells than in those injected with mock-transfected cells. In addition, GSTO2 induction suppressed the expression of ß-catenin and the oxygen consumption rate, but it did not affect the extracellular acidification rate. Furthermore, GSTO2-transfected cells displayed lower mitochondrial membrane potential than mock-transfected cells. When GSTO2-transfected cells were treated with a p38 inhibitor, ß-catenin expression and mitochondrial membrane potential were recovered. Our study indicated that the loss of GSTO2 via DNA hypermethylation contributes to the growth and progression of LSCC, probably by modulating cancer metabolism via the p38/ß-catenin signaling pathway.

Expression Status of Serine Protease 27: A Prognostic Marker for Esophageal Squamous Cell Carcinoma Treated with Preoperative Chemotherapy/Chemoradiotherapy.

BACKGROUND: A previous study conducted a transcriptome analysis of paired normal and esophageal squamous cell carcinoma (ESCC) tissue samples. The results showed that the expression of serine protease 27 (PRSS27) was perturbed in tumor samples. Hence, this retrospective study aimed to validate the prognostic significance of PRSS27 in patients with preoperative treatment for ESCC. METHODS: We enrolled 86 patients who received preoperative treatment before esophagectomy for ESCC. The expression of PRSS27 in resected ESCC and biopsy tissue samples obtained before preoperative treatment was evaluated via immunostaining, and its relationship with clinicopathological features and prognosis was analyzed. RESULTS: In normal esophageal mucosa tissue samples, PRSS27 was expressed in the cytoplasm of spinous cells in the suprabasal layer and basal cells in the basal layer. Of 64 resected ESCC tissue samples, 35 (54.7%) expressed PRSS27 and 29 (45.3%) did not. Moreover, ectopic nuclear expression of PRSS27 was observed. Based on multivariate analysis, PRSS27 expression in resected tumor samples was a predictor of poor prognosis. In cases in which PRSS27 expression was observed in biopsy samples, patients with PRSS27-negative resected tumors had a better postoperative prognosis than those with PRSS27-positive resected tumors. CONCLUSIONS: PRSS27 expression in resected ESCC tissue samples is a poor prognostic factor in ESCC patients with preoperative treatment. Furthermore, conversion of PRSS27 expression from positive in biopsy samples to negative in resected tumor samples is a predictor of good prognosis in these patients. Hence, PRSS27 status is an effective tool for decision making regarding adjuvant treatment in ESCC patients.

Glutathione S-transferase omega 2 regulates cell growth and the expression of E-cadherin via post-transcriptional down-regulation of ß-catenin in human esophageal squamous cells.

Glutathione S-transferase omega 2 (GSTO2), which belongs to the superfamily of GST omega class, lacks any appreciable GST activity. Although GSTO2 exhibits thioltransferase and glutathione dehydrogenase activities, its precise expression and physiological functions are still unclear. In the present study, we found that GSTO2 is exclusively expressed in the basal cell layer in Ki67-negative non-proliferative cells in the human esophageal mucosa. GSTO2 overexpression in esophageal squamous cell carcinoma (ESCC) cell lines inhibited cell growth and colony formation, and GSTO2-transfected cells formed smaller tumors in nude mice compared with mock-transfected cells. Interestingly, GSTO2 induction suppressed the expressions of E-cadherin and ß-catenin at the cell-cell contact site. We quantified the phosphorylation levels of key proteins of MAPK signaling pathway and identified phosphorylation of p38. Additionally, HSP27, a downstream molecule of p38, was accelerated in GSTO2-transfected cells, unlike in mock-transfected cells. When GSTO2-transfected cells were treated with a p38 inhibitor, the expression of ß-catenin and the membrane localization of E-cadherin was recovered. We next examined GSTO2 expression in 61 ESCC tissues using quantitative reverse transcription polymerase chain reaction and immunostaining. The results showed that GSTO2 mRNA and protein were significantly reduced in ESCC compared with normal tissues. When human ESCC cell lines were treated with 5-aza-2'-deoxycytidine, a DNA-methyltransferase inhibitor, GSTO2 transcription was induced, suggesting that aberrant hypermethylation is the cause of the down-regulated expression. Our results indicate that GSTO2 expression inhibits the membrane localization of E-cadherin, probably by modulation of the p38 signaling pathway. Down-regulation of GSTO2 by DNA hypermethylation contributes to the growth and progression of ESCC.

Fully robotic side-to-side stapled anastomosis provides less anastomotic leakage than conventional minimally invasive approach in Ivor Lewis esophagectomy.

INTRODUCTION: This study evaluates surgical outcomes of minimally invasive Ivor Lewis esophagectomy (ILE) for esophageal and esophagogastric cancer, with the comparison of the robotic approach (RA) and the conventional minimally invasive approach (CA). METHODS: Selected patients who underwent minimally invasive ILE for esophageal cancer were included between January 2017 and December 2023. We retrospectively investigated the patients' background characteristics and the short-term surgical outcomes. RESULTS: In this period, among a total of 840 esophagectomies, 81 patients (9.6%) underwent minimally invasive ILE, consisting of 24 cases with RA and 57 with CA. The major indications for ILE were adenocarcinoma of the distal esophagus or esophagogastric junction and patients with prior head and neck cancer treatment. Among these thoracic approaches, there were no significant differences in the patients' indications and characteristics, including age, histology, tumor location, clinical TNM stage, and preoperative therapy. Compared with the CA group, no anastomotic leakage was observed in the RA group (17.5% vs. 0, p = .035). Rates of total postoperative complications and length of hospital stay also tended to be reduced in the RA group but did not reach significance. CONCLUSION: In the Ivor Lewis esophagectomy with a side-to-side linear-stapled anastomosis, the fully robotic approach has the potential to powerfully reduce anastomotic leakage compared to the conventional minimally invasive approach.

Robotic-Assisted Esophagectomy: Current Situation and Future Perspectives.

Robotic-assisted minimally invasive esophagectomy (RAMIE) has been rapidly spreading worldwide as a novel minimally invasive approach for esophageal cancer. This narrative review aimed to elucidate the current situation and future perspectives of RAMIE for esophageal cancer. References were searched using PubMed and Embase for studies published up to 8 April 2023. Search terms included "esophagectomy" or "esophageal cancer" and "robot" or "robotic" or "robotic-assisted." There are several different uses for the robot in esophagectomy. Overall complications are equivalent or may be less in RAMIE than in open esophagectomy and conventional (thoracoscopic) minimally invasive esophagectomy. Several meta-analyses demonstrated the possibility of RAMIE in reducing pulmonary complications, although the equivalent incidence was observed in two randomized controlled trials. RAMIE may increase the number of dissected lymph nodes, especially in the left recurrent laryngeal nerve area. Long-term outcomes are comparable between the procedures, although further research is required. Further progress in robotic technology combined with artificial intelligence is expected.

Advantages of Function-Preserving Gastrectomy for Older Patients With Upper-Third Early Gastric Cancer: Maintenance of Nutritional Status and Favorable Survival.

PURPOSE: The incidence of early gastric cancer is increasing in older patients alongside life expectancy. For early gastric cancer of the upper third of the stomach, laparoscopic function-preserving gastrectomy (LFPG), including laparoscopic proximal gastrectomy (LPG) and laparoscopic subtotal gastrectomy (LSTG), is expected to be an alternative to laparoscopic total gastrectomy (LTG). However, whether LFPG has advantages over LTG in older patients remains unknown. MATERIALS AND METHODS: We retrospectively analyzed data of consecutive patients aged ≥75 years who underwent LTG, LPG, or LSTG for cT1N0M0 gastric cancer between 2005 and 2019. Surgical and nutritional outcomes, including blood parameters, percentage body weight (%BW) and percentage skeletal muscle index (%SMI) were compared between LTG and LPG or LSTG. Survival outcomes were also compared between LTG and LFPG groups. RESULTS: A total of 111 patients who underwent LTG (n=39), LPG (n=48), and LSTG (n=24) were enrolled in this study. To match the surgical indications, LTG was further categorized into "LTG for LPG" (LTG-P) and "LTG for LSTG" (LTG-S). No significant differences were identified in the incidence of postoperative complications among the procedures. Postoperative nutritional parameters, %BW and %SMI were better after LPG and LSTG than after LTG-P and LTG-S, respectively. The survival outcomes of LFPG were better than those of LTG. CONCLUSIONS: LFPG is safe for older patients and has advantages over LTG in terms of postoperative nutritional parameters, body weight, skeletal muscle-sparing, and survival. Therefore, LFPG for upper early gastric cancer should be considered in older patients.

Optimal resection of gastric bronchogenic cysts based on anatomical continuity with adherent gastric muscular layer: A case report.

BACKGROUND: Bronchogenic cysts are congenital lesions requiring radical resection because of malignant potential. However, a method for the optimal resection of these cysts has not been completely elucidated. CASE SUMMARY: Herein, we presented three patients with bronchogenic cysts that were located adjacent to the gastric wall and resected laparoscopically. The cysts were detected incidentally with no symptoms and the preoperative diagnosis was challenging to obtain via radiological examinations. Based on laparoscopic findings, the cyst was attached firmly to the gastric wall and the boundary between the gastric and cyst walls was difficult to identify. Consequently, resection of cysts alone caused cystic wall injury in Patient 1. Meanwhile, the cyst was resected completely along with a part of the gastric wall in Patient 2. Histopathological examination revealed the final diagnosis of bronchogenic cyst and revealed that the cyst wall shared the muscular layer with the gastric wall in Patients 1 and 2. In Patient 3, the cyst was located adjacent to the gastric wall but histopathologically originated from diaphragm rather than stomach. All the patients were free from recurrence. CONCLUSION: The findings of this study state that a safe and complete resection of bronchogenic cysts required the adherent gastric muscular layer or full-thickness dissection, if bronchogenic cysts are suspected via pre- and/or intraoperative findings.

Long-term impact of sarcopenia in older patients undergoing gastrectomy for gastric cancer: a systematic review and meta-analysis.

Background: Sarcopenia is an inevitable problem in older patients. After gastrectomy, patients often have an inadequate dietary intake and easily fall into sarcopenia. However, the impact of preoperative sarcopenia on long-term outcomes after gastrectomy has not been analyzed. Methods: A systematic review was conducted for all relevant articles identified on PubMed, the Cochrane Library, Web of Science, and ClinicalTrials.gov until April 2023. Adjusted hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the fixed or random effects model according to the heterogeneity. The Newcastle-Ottawa Scale was used to quantify study quality. Results: Seven studies involving 1,831 patients aged ≥65 years who underwent gastrectomy for gastric cancer were analyzed. Four hundred twelve patients (22.5%) were diagnosed with sarcopenia. The analysis showed that preoperative sarcopenia was significantly associated with poor overall survival (OS) (HR =1.93; 95% CI:1.60-2.34; P<0.001). Two of the included studies also showed that preoperative sarcopenia was significantly correlated with disease-related survival: one with disease-specific survival (DSS) (HR =4.00; 95% CI: 1.20-13.3, P=0.024) and the other with non-cancer specific survival (HR =3.27; 95% CI: 1.61-6.67; P=0.001). Furthermore, sarcopenic patients experienced more severe complications than non-sarcopenic patients (OR =1.80; 95% CI: 1.10-2.95; P=0.019). Conclusions: This meta-analysis suggested that preoperative sarcopenia is useful as a prognostic factor of impaired OS in older patients after gastrectomy. Preoperative evaluation and intervention for skeletal muscle loss should be considered. Further studies of sarcopenic impact on disease-related survival are required.

Preserving inferior right hepatic vein enabled bisegmentectomy 7 and 8 without venous congestion: a case report.

BACKGROUND: In hepatectomy, the preservation of portal perfusion and venous drainage in the remnant liver is important for securing postoperative hepatic function. Right hepatectomy is generally indicated when a hepatic tumor involves the right hepatic vein (RHV). However, if a sizable inferior RHV (IRHV) exists, hepatectomy with preservation of the IRHV territory may be another option. In this case, we verified the clinical feasibility of anatomical bisegmentectomy 7 and 8 with RHV ligation, averting the right hepatic parenchyma from venous congestion, utilizing the presence of the IRHV. CASE PRESENTATION: A 70-year-old man was presented with a large hepatic tumor infiltrating the RHV on computed tomography during a medical checkup. The patient was diagnosed with hepatocellular carcinoma (HCC), T2N0M0, stage III. Right hepatectomy was first considered, but multi-detector computed tomography (MDCT) also revealed a large IRHV draining almost all of segments 5 and 6, suggesting that IRHV-preserving liver resection may be another option. The calculated future remnant liver volumes were 382 mL (26.1% of the total volume) after right hepatectomy and 755 mL (51.7% of the total volume) after anatomical bisegmentectomy 7 and 8; therefore, we scheduled IRHV-preserving anatomical bisegmentectomy 7 and 8 considering the prevention of postoperative liver failure and increased chance of performing repeat resections in cases of recurrence. Preoperative three-dimensional simulation using MDCT clearly revealed the portal perfusion area and venous drainage territories by the RHV and IRHV. There was an issue with invisibility of the anatomical resection line of segments 7 and 8, which was completely dissolved by intraoperative ultrasonography using Sonazoid and the portal dye injection technique with counter staining. The postoperative course in the patient was uneventful, without recurrence of HCC, for 30 months after hepatectomy. CONCLUSIONS: IRHV-preserving anatomical bisegmentectomy 7 and 8 is a safe and feasible procedure utilizing the three-dimensional simulation of the portal perfusion area and venous drainage territories and the portal dye injection technique.

Surgical strategies for treatment of clinical T4 esophageal cancer in Japan.

Definitive chemoradiation (dCRT) is the mainstay treatment for cStage IVa esophageal squamous cell carcinoma (ESCC) with good performance status (PS), according to standard practice guidelines. Salvage surgery may incur operation complications and risk of mortality. According to the esophageal cancer practice guidelines outlined by the Japan Esophageal Society, when a tumor is residual and recurrent, chemotherapy and palliative symptomatic treatment is continued. However, salvage operation has been selected as a therapeutic option for recurrent or residual tumors after dCRT. There is weak evidence for not recommending surgery for cStage IVa ESCC exhibiting residual disease following dCRT. It has been reported that during salvage surgery the only prognostic factor that is thought to be performed is complete resection (R0), but at the same time, salvage esophagectomy increases the incidence of postoperative complications and mortality. The phase II chemoselection study by Yokota T et al. in Japan showed that multidisciplinary treatment initiated by induction therapy, in which docetaxel is added to cisplatin and 5-fluorouracil, resulted in a good prognosis in the short term. In this review, we discuss the surgical strategy and future of unresectable clinical T4 (cT4) ESCC.

Current status of immune checkpoint inhibitor therapy for advanced esophageal squamous cell carcinoma.

Esophageal cancer is the seventh most common cancer, with an estimated 572,000 new cases, and the sixth most common cause of cancer-related deaths in 2018 with 509,000 annual worldwide deaths. Advanced esophageal squamous cell carcinoma (ESCC) is one of devastating tumors with a 5-year survival rate of less than 5% in patients with metastatic disease. Treatment options for patients with advanced ESCC are limited. Current guidelines recommend chemotherapy containing a platinum and a fluoropyrimidine agent as a first-line treatment. Recently, immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab, have demonstrated antitumor activity and clinical efficacy in patients with advanced ESCC that is refractory or intolerant to first-line chemotherapy. ICIs are game-changers that not only transformed oncological strategy but also have a wide range of clinical potential in combination with conventional cytotoxic chemotherapy and radiotherapy. There is still an urgent, unmet need for reliable treatment options to conquer this intractable disease.

Current status of doublet combinations of platinum and fluoropyrimidines using oxaliplatin for advanced gastric cancer.

The most common treatment for advanced gastric cancer (AGC) is systemic chemotherapy. The standard treatment for advanced gastric cancer differs worldwide. In Japan, two phase III clinical trials demonstrated the non-inferiority of S-1 compared with 5-fluorouracil (5-FU) and superiority of cisplatin plus S-1 (CS), compared with S-1, with respect to overall survival (SPIRITS trial). Oxaliplatin (L-OHP) has a favorable toxicity profile compared with cisplatin; hence, a phase III clinical trial (G-SOX trial) demonstrated the progression-free survival (PFS) and overall survival in CS was 5.4 and 13.1 months and those in SOX was 5.5 and 14.1 months, respectively. Serious adverse events were more frequently seen in CS than in SOX. So, SOX is as effective as CS for advanced gastric cancer with favorable safety profile. After the publication of this G-SOX trial, the combination of oral or intravenous 5-FU and various doses of L-OHP have been reported. And FOLFOX6 regimen (FOLFOX: a combination of 1-LV and FU with L-OHP) was approved for the treatment of AGC in Japan in 2017. FOLFOX was promising for patients with severe peritoneal metastasis from AGC, because the FOLFOX regimen does not require hydration and does not include oral agents. This review summarizes the efficacy and safety of doublet combinations of platinum and fluoropyrimidines using L-OHP for advanced gastric cancer.

Clinicopathological significance of cystatin A expression in progression of esophageal squamous cell carcinoma.

We previously conducted transcriptome analysis of a paired specimen of normal and esophageal squamous cell carcinoma (ESCC) tissues and found that mRNA expression of cystatin A (CSTA), a member of the cystatin superfamily, was perturbed in tumors compared with that in the background mucosa. However, little is known about the significance of CSTA expression in ESCC.The mRNA expression of CSTA was evaluated by qRT-PCR using 28 paired frozen samples of tumor and nontumor mucosae. The protein expression of CSTA was evaluated by the immunostaining of formalin-fixed, paraffin-embedded sections of ESCC samples from 59 patients who underwent surgery, and its relationship with clinical features was analyzed.The mRNA expression of CSTA was significantly decreased in ESCC compared with that in matched normal mucosa (P < .0001). The protein expression of CSTA was limited in stratum granulosum and stratum spinosum but not in stratum basal in normal esophageal mucosa. It was reduced in all ESCC tissue samples compared with normal tissues; however, CSTA expression levels in tumors showed considerable variation. Of the 59 samples, 20 did not express CSTA, whereas 39 clearly expressed it. The expression of CSTA in tumors was significantly associated with pT classification (deeper tumor invasions) (P = .0118) and advanced TNM stages (P = .0497). In CSTA-positive tumor samples, CSTA-expressing cancer cells often expressed Ki67, a proliferation marker, which was in sharp contrast to normal mucosa, where Ki67-expressing cells were limited to the basal layer and did not express CSTA. Furthermore, CSTA expression was observed in all 22 lymph node metastases analyzed.Relatively high levels of CSTA expression in tumors were correlated with tumor progression and advanced cancer stage, including lymph node metastasis.