Yu-Shang Yang

The role of mitochondrial folate enzyme MTHFD1L in esophageal squamous cell carcinoma

Abstract Objective: The lack of novel therapeutic targets poses the major challenge to prolong survival and improve the quality of life for esophageal squamous cell carcinoma (ESCC). Methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) plays critical roles in folate cycle maintenance. However, little information is available concerning the role of MTHFD1L in cancer cells, and no studies have addressed such issues in esophageal cancer. Materials and method: Surgical cancer and adjacent normal esophageal tissues were obtained from patients with esophagectomy and esophagogastrostomy for ESCC. Western blot, immunohistochemistry and Quantitative RT-PCR were performed to evaluate protein and RNA expression levels of MTHFD1L. Knockdown of MTHFD1L expression was achieved by using short hairpin RNA. The effects of MTHFD1L silencing on ESCC cell proliferation and apoptosis were assessed by the MTT assay, Celigo assays, Annexin V FACS assay and Caspase-3/7 array in vitro. Results: Twenty-three paired cancer and adjacent normal esophageal tissues from patients with ESCC were included in this study. MTHFD1L protein and RNA expression levels were significantly upregulated in ESCC tissue as compared with normal tissue. High expression of MTHFD1 was also detected in two esophageal cancer cell lines (TE-1 and EC109). Knockdown of MTHFD1L expression inhibited the proliferation of TE-1 cells, and the apoptosis was distinctly increased following shMTHFD1L infection. Conclusions: Our preliminary study highlighted for the first time that MTHFD1L might be involved in the development of ESCC, which may provide a new potential tumor-specific therapeutic targeting for anti-folate agents.

Prognostic Ability of Central Lymph Node Metastasis for Gastric Cancer Deserves Additional Investigation

To the Editors, We read with great interest the well-written article by Dr. Ikoma and colleagues on the investigation of the prognostic role of central lymph nodes (CnLNs) in gastric cancer. This study demonstrated that positive CnLNs in gastric cancer were a strong predictor of survival, especially in patients who have undergone preoperative therapy. We congratulate Dr. Ikoma and his colleagues for this innovative and excellent study. As the lymph node (LN) at a higher-order echelon, CnLNs are defined as common hepatic, celiac, and proximal splenic artery LNs (stations no. 8, 9, and 11p) in Ikoma’s study, which are also belonging to the extra-perigastric group. Intriguingly, we have recently investigated the prognostic ability of anatomical extent of lymph nodemetastasis (LNM) in esophageal cancer treated with surgery. Generally, the two studies shared the important findings: LNM at higher-order echelon had an additional adverse effect on overall survival as compared with those with LNM at lower echelon. However, we have stratified patients into groups based on metastatic pattern, and this subgroup analyses indicated that the LNM at higher-order echelon only confer additional adverse prognosis to the group with a sequential LNM pattern (involvement both in low and in high echelon node), while no additional adverse effect was observed in the group with a skip metastasis pattern. In theory, dissemination of tumor cells through the lymphatic system initially occurs in the lymph nodes close to primary tumor (first echelon node), then the tumor cells subsequently flows to the next higher group of nodes in a stepwise sequential fashion. However, sometimes metastatic LN can be detected far from the original tumor with the absence of metastatic infiltration in lymph node adjacent to primary tumor, which is called node skip metastasis (NSM). For gastric cancer, several studies have reported that the patients with NSM had a better OS as compared with that of patients without NSM, and a similar prognosis compared with that of patients with LNM at lower-order echelon. Although no data on NSM was provided in Ikoma’s study, the prognostic role of NSM may be inferred from the following result: CnLN metastasis negatively affected survival in pN2/3 patients, but not in pN1 patients. Since the NSM is the unusual pattern of LNM and current Nstaging system is numeric-based, it means that the NSM rate is higher in pN1 group than that in pN2/3 group. As the relatively favorable prognostic factor, NSM may partially explain the conflict result of this sensitivity analysis. In short, the prognostic effect of central lymph nodes metastasis may be different according to LNM patterns, which needs further investigation.

A Rare Cause of Upper Gastrointestinal Bleeding: Adult Pulmonary Sequestration

A 51-year-old male presented to emergency department with a massive hematemesis. One year ago, he had suffered from bronchoesophageal fistula (BEF), which was incidentally discovered during the management of left lower lung abscess and closed with the over-the-scope clip system through fibergastroscope (Fig. 1b, open arrow). However, the fistula happened again 4 months ago, presented with coughing up with food particles and purulent sputum production. Esophagography revealed a duct (Fig. 2, dashed circle) going from the lower esophagus to the sequestered lung tissue. Computed tomography angiography identified an anomalous artery extending from the left gastric artery to the left lower lobe (Figs. 1 and 3, white arrow). After the diagnosis of pulmonary sequestration and BEF was confirmed, successful right lower lobectomy and repair of the esophageal fistula were performed. The postoperative course was uneventful. No further hematemesis was reported at routine follow-up. Bronchoesophageal fistula in adulthoodmostly occurs following malignant diseases such as esophageal cancer and pulmonary cancer, and benign cases are rare condition. In addition, our report presents an extremely rare case of benign BEF. First, traumatic diseases are the common cause of benign BEF, and the case as the sequel of pulmonary sequestration is one of the rarest. Second, it is also extremely rare that the anomalous artery of pulmonary sequestration arises from left gastric artery.