Density and maturity of peritumoral tertiary lymphoid structures in oesophageal squamous cell carcinoma predicts patient survival and response to immune checkpoint inhibitors.

BACKGROUND: Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates in non-lymphoid tissues, which are associated with improved prognosis in some cancer types. This study aimed to investigate the clinical significance of TLSs in oesophageal cancer (EC). METHODS: In a series of 316 EC surgical specimens from two different institutes, we evaluated the density and maturity of peritumoral TLSs using haematoxylin/eosin, immunohistochemistry, and multiplex immunofluorescence staining. We analysed the association between TLSs and clinicopathological parameters. The clinical significance of TLSs was further evaluated in a different cohort of 34 patients with recurrent EC treated with anti-PD-1 antibody. RESULTS: Tumours with high TLS density predominantly consisted of matured TLSs. High TLS density was significantly associated with less advanced tumour stage, absence of lymphatic/vascular invasion, better serum nutrition parameters (neutrophils count, albumin, neutrophil-to-lymphocyte ratio, and prognostic nutritional index), and prolonged survival. This survival trend was more remarkable in cases with matured TLSs, which represented an increased population of CD138+ plasma cells. In the second EC cohort, TLS density predicted the clinical response to anti-PD-1 antibody and patient survival. CONCLUSION: The density and maturity of peritumoral TLSs are useful parameters for predicting long-term survival and response to anti-PD-1 antibody treatment in EC patients.

Peritumoral Lymphatic Vessels Associated with Resistance to Neoadjuvant Chemotherapy and Unfavorable Survival in Esophageal Cancer.

BACKGROUND: Peri- or intra-tumor lymphangiogenesis is induced in several types of cancer. However, the significance of peritumoral lymphatic vessels (LVs) in esophageal cancer (EC) remains to be clarified. METHODS: This study included 162 eligible EC patients with or without neoadjuvant chemotherapy (NAC). The numbers of non-tumoral and peritumoral LVs were counted in resected specimens based on podoplanin immunostaining. The association between peritumoral LV number and clinicopathologic parameters, including tumor heterogeneity as measured by positron emission tomography, NAC response, and patient survival were analyzed. RESULTS: In non-NAC patients, the number of peritumoral LVs was highest in the lamina propria mucosa (LPM), followed by non-tumoral LVs in the LPM, peritumoral LVs in the submucosa (SM), and non-tumoral LVs in the SM. The patients with a low number of peritumoral LVs in the LPM versus those with a high number constituted a larger fraction of the NAC patients (67.8% vs. 50.0%; P = 0.022) and had a poorer pathologic response to NAC (grades 0-1a: 68.8% vs. 47.2%; P = 0.035), as well as greater tumor heterogeneity and worse survival (5-year overall survival: 50.6% vs. 72.8%; P = 0.0097). The number of peritumoral LVs in the LPM was identified as an independent prognostic factor with the highest hazard ratio (HR) of overall survival (HR 2.06; P = 0.0049) in the multivariate analysis. CONCLUSION: For EC patients, peritumoral LVs in the LPM layer are associated with tumor heterogeneity, response to NAC, and unfavorable survival.

[Long-Term Survival with Multidisciplinary Treatment and Nutritional Therapy for Thoracic Esophageal Cancer with Multiple Liver Metastases-A Case Report].

The patient was a 63-year-old man with a chief complaint. Upper endoscopic examination revealed a semicircular type 2 lesion, sized 24-28 cm, on the incisor teeth and a 3 cm sized elevated lesion directly above the EGJ. When biopsy was performed, squamous cell carcinoma(SCC)was detected. In this case, lymph node metastasis and multiple liver metastases were observed, and diagnosis at the first examination was cT3N2M1(HEP), Stage Ⅳ. After 7 months of chemotherapy, he underwent right thoracic esophageal subtotal resection, 3-field lymph node dissection, posterior mediastinal gastric tube reconstruction, and partial hepatectomy. Despite receiving postoperative chemotherapy, he showed recurrence in the liver(S8). Four additional courses of chemotherapy were administered and partial hepatectomy(S8)was performed, without the appearance of new lesions. He was considered to be cured 1 year and 6months after starting the treatment and was followed- up without chemotherapy. However, 4 months later, chemotherapy was resumed when right adrenal and abdominal wall metastases and liver recurrence(S3)were found. After that, the regimen was modified, and he continued treatment. More than 4 years have passed since the start of treatment, but the treatment has been continued without a decline in ADL.

[A Case of Recurrent Colorectal Cancer with Bilateral Ovarian Metastases That Were Reduced with Regorafenib Therapy].

A 63-year-old woman had recurrences of metastatic rectal cancer in the lung, peritoneum, and ovary. Regorafenib was administered at 160mg/day as third-line chemotherapy. The patient developed Grade(Gr)3 hand-foot syndrome(HFS) and Gr 2 rash, but the abdominal distension and pain were relieved by the 1st course. Analgesics could be reduced and regorafenib was administrated at reduced dosage. The patient received keishi-bukuryo-gan(EK-25)and sai-rei-tou(TJ-114) for HFS. At the beginning of therapy, ovarian metastases were not reduced and showed poor contrast enhancement on CT. Serum levels of lactate dehydrogenase(LDH)and tumor markers were increased. During the 4th course of therapy, ovarian metastases tended to shrink and serum levels of LDH and tumor markers were decreased. Ovarian metastases showed a partial response(PR)after the 6th course. Lung metastases showed a progressive disease during the 2nd course, but a PR after the 3rd course, and were not apparent after the 6th course. Reduction of metastases was maintained at 16 months after the start of therapy, and HFS was assessed at Gr 2 or lower. Physical, laboratory, and imaging findings should be carefully evaluated prior to long-term administration of regorafenib.

[Surgical Dissection for an Abdominal Para-Aortic Lymph Node Recurrence after Curative Resection for Early Gastric Cancer - Report of a Case].

A 72-year-old man underwent endoscopic submucosal dissection for early gastric cancer at antrum in July 2015. The histopathological examination revealed an adenocarcinoma invading the deep submucosal layer(SM2)with lymphatic invasion, consistent with the diagnosis of non-curative resection. Additional surgery was recommended, and he underwent laparoscopic distal gastrectomy in August 2015. The histopathological examination of resected specimen revealed there were no lymph node metastases, and postoperative diagnosis was Stage I A. However, 8 months after the surgery, abdominal enhanced computed tomography(CT)revealed an enlargement of para-aortic lymph node. Positron emission tomography-CT showed high accumulation at the enlarged lymph node. A para-aortic lymph node metastasis was suspected, and laparoscopic lymph node dissection was performed in July 2016. The histopathological examination revealed lymph node metastasis of gastric cancer. He was given systematic chemotherapy using S-1 plus cisplatin after the surgery, and has been followed-up without recurrences for 21 months after the first operation. Although recurrence of the para-aortic lymph nodes was assumed as part of a systemic metastasis, some population certainly benefit from multidisciplinary treatment including surgical approach.