BackgroundThere was much hard work to study the trastuzumab resistance in HER2-positive gastric cancer (GC), but the information which would reveal this abstruse mechanism is little. In this study, we aimed to investigate the roles of tumor cell-derived CCL2 on trastuzumab resistance and overcome the resistance by treatment with the anti-CD40-scFv-linked anti-HER2 (CD40 ×HER2) bispecific antibody (bsAb).MethodsWe measured the levels of CCL2 expression in HER2-positive GC tissues, and revealed biological functions of tumor cell-derived CCL2 on tumor-associated macrophages (TAMs) and the trastuzumab resistance. Then, we developed CD40 ×HER2 bsAb, and examined the targeting roles on HER2 and CD40, to overcome the trastuzumab resistance without systemic toxicity.ResultsWe found the level of CCL2 expression in HER2-postive GC was correlated with infiltration of TAMs, polarization status of infiltrated TAMs, trastuzumab resistance and survival outcomes of GC patients. On exposure to CCL2, TAMs decreased the M1-like phenotype, thereby eliciting the trastuzumab resistance. CCL2 activated the transcription of ZC3H12A, which increased K63-linked deubiquitination and K48-linked auto-ubiquitination of TRAF6/3 to inactivate NF-κB signaling in TAMs. CD40 ×HER2 bsAb, which targeted the CD40 to restore the ubiquitination level of TRAF6/3, increased the M1-like phenotypic transformation of TAMs, and overcame trastuzumab resistance without immune-related adversary effects (irAEs).ConclusionsWe revealed a novel mechanism of trastuzumab resistance in HER2-positive GC via the CCL2-ZC3H12A-TRAF6/3 signaling axis, and presented a CD40 ×HER2 bsAb which showed great antitumor efficacy with few irAEs.

Background Extraskeletal osteosarcoma (ESOS) is a rare mesenchymal malignancy, which produces osteoid, bone, or chondroid material and is located in the soft tissue without attachment to skeletal bones and periosteum. One of the things that ESOS originated from mesentery is much rarer. Case presentation A 75-year female had a history of pain in the left lower abdomen for more than 4 months. Abdominal computerized tomography (CT) and magnetic resonance imaging revealed a large, irregular, and solid-cystic mass (largest diameter was 11.5 cm). The tumor was radically removed during an open operation. It was composed of abundant osteoid and polyhedral-shaped tumor cells with high atypia and high mitotic activity microscopically. The final pathological diagnosis was osteoblastic osteosarcoma, arising from the sigmoid mesocolon with negative margins. A 9-month follow-up by CT exhibited signs of peritoneal metastasis. Conclusions Given the rarity of cases of mesenteric ESOS, diagnosis mainly depended on pathology findings or should be taken into consideration when the mesenteric mass was found. Its most effective treatment had not been determined, with surgical excision being generally accepted. Ensuring negative surgical margins may be an important factor affecting prognosis.

Background Primary malignant tumors of the small bowel (PMTSB) are relatively uncommon in gastrointestinal tumors. It is difficult to make an early diagnosis due to the atypical primary symptoms, special anatomical position and lack of effective diagnostic methods. Objective To improve the level of early diagnosis of PMTSB so as to speculate the pathological types and get better prognoses for patients. Method Clinicopathologic and follow-up data about 104 surgically treated patients with PMTSB (65 males and 39 females) at the median age of 58.1 years (range 23–85 years) were analyzed. Result The most common clinical features of the patients were anemia (73.1%), abdominal pain (62.5%), and weight loss (51.9%). Abdominal enhanced Computed Tomography (CT) had the highest detection rate (95.4%) and diagnosis rate (80%). Gastrointestinal hemorrhage, soft tissue mass on CT, no regional lymph nodes enlargement, and no intestinal obstruction were the independent predictors of diagnosis in GIST. Anemia, intestinal obstruction, without soft tissue mass on CT were the independent predictors of diagnosis in adenocarcinoma. Independent predictors of diagnosis of lymphoma included fever, and regional lymph nodes enlargement on CT. Conclusion Anemia, abdominal pain and weight loss were the main clinical manifestations for PMTSB, as CT was the most effective imaging examination. Based on clinical and imaging features, we analyzed several factors which related to diagnose the pathological classification, and expected to give patients the earlier diagnosis and better prognoses.

Background: Extraskeletal osteosarcoma (ESOS) is a very rare mesenchymal malignancy, characterized by the production of osteoid, bone or chondroid material and typically located in the soft tissue without attachment to skeletal bones and periosteum. One of the things that ESOS originated from mesentery is much rarer. Case presentation: A 75-year female with a more than 4-months history of pain in the left lower abdomen. Abdominal computerized tomography and magnetic resonance imaging revealed a large, irregular and solid-cystic mass, which largest diameter was 11.5cm. The tumor was radically removed during open operation. The tumor was composed of abundant osteoid and polyhedral-shaped tumor cells with high atypia and high mitotic activity microscopically. The final pathological diagnosis was osteoblastic osteosarcoma, arising from the sigmoid mesocolon with negative margins. The patient was followed up 5 months after surgery and found no signs of systemic metastasis Conclusion: Given the rarity of cases of mesenteric ESOS, diagnosis mainly depended on pathology findings or should be taken into consideration when the mesenteric mass was found. Its most effective treatment had not been determined, with surgical excision was generally accepted. Negative surgical margin may be an important factor affecting the prognosis.