The FAPα-activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway

Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties,a high incidence of pulmonary metastasis and a poor prognosis.Chemotherapy is the mainstay of treatment for osteosarcoma.Currently,there are no molecular targeted drugs approved for osteosarcoma treatment,particularly effective drugs for osteosarcoma with pulmonary metastases.It has been reported that fibroblast activation protein alpha(FAPa)is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis,demonstrating that FAPa-targeted agents might be a promising therapeutic strategy for osteosarcoma.In the present study,we reported that the FAPa-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPa-positive osteosarcoma cells in vitro and in vivo.Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells.Importantly,it also decreased the migration and invasion capacities and reversed epithelial-mesenchymal transition(EMT)of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo.Mechanistically,Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway,leading to inhibition of the growth and metastatic spread of osteosarcoma cells.These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPa-positive osteosarcoma,particularly osteosarcoma with pulmonary metastases.

Effect of perioperative chemotherapy on resection of isolated pulmonary metastases from colorectal cancer:A single center experience

BACKGROUND Numerous studies have assessed surgical resection as a standard treatment option for patients with colorectal cancer(CRC)and resectable pulmonary metastases(PM).However,the role of perioperative chemotherapy after complete resection of isolated PM from patients with CRC patients remains controversial.We hypothesize that perioperative chemotherapy does not provide significant survival benefits for patients undergoing resection of PM from CRC.AIM To determine whether perioperative chemotherapy affects survival after radical resection of isolated PM from CRC.METHODS We retrospectively collected demographic,clinical,and pathologic data on patients who underwent radical surgery for isolated PM from CRC.Cancerspecific survival(CSS)and disease-free survival were calculated using Kaplan-Meier analysis.Inter-group differences were compared using the log-rank test.For multivariate analysis,Cox regression was utilized when indicated.RESULTS This study included 120 patients with a median age of 61.6 years.The 5-year CSS rate was 78.2%,with 36.7% experiencing recurrence.Surgical resection for isolated PM resulted in a 5-year CSS rate of 50.0% for second metastases.Perioperative chemotherapy(P=0.079)did not enhance survival post-resection.Factors associated with improved survival included fewer metastatic lesions[hazard ratio(HR):2.51,P=0.045],longer disease-free intervals(HR:0.35,P=0.016),and wedge lung resections(HR:0.42,P=0.035).Multiple PM predicted higher recurrence risk(HR:2.22,P=0.022).The log-rank test showed no significant difference in CSS between single and repeated metastasectomy(P=0.92).CONCLUSION Perioperative chemotherapy shows no survival benefit post-PM resection in CRC.Disease-free intervals and fewer metastatic lesions predict better survival.Repeated metastasectomy is warranted for eligible patients.

Adjuvant chemotherapy for isolated resectable colorectal lung metastasis: A retrospective study using inverse probability treatment weighting propensity analysis

BACKGROUND The benefit of adjuvant chemotherapy(ACT)for patients with no evidence of disease after pulmonary metastasis resection(PM)from colorectal cancer(CRC)remains controversial.AIM To assess the efficacy of ACT in patients after PM resection for CRC.METHODS This study included 96 patients who underwent pulmonary metastasectomy for CRC at a single institution between April 2008 and July 2023.The primary end-point was overall survival(OS);secondary endpoints included cancer-specific survival(CSS)and disease-free survival(DFS).An inverse probability of treat-ment-weighting(IPTW)analysis was conducted to address indication bias.Sur-vival outcomes compared using Kaplan-Meier curves,log-rank test,Cox regre-ssion and confirmed by propensity score-matching(PSM).RESULTS With a median follow-up of 27.5 months(range,18.3-50.4 months),the 5-year OS,CSS and DFS were 72.0%,74.4%and 51.3%,respectively.ACT had no significant effect on OS after PM resection from CRC[original cohort:P=0.08;IPTW:P=0.15].No differences were observed for CSS(P=0.12)and DFS(P=0.68)between the ACT and non-ACT groups.Multivariate analysis showed no association of ACT with better survival,while sublobar resection(HR=0.45;95%CI:0.20-1.00,P=0.049)and longer disease-free interval(HR=0.45;95%CI:0.20-0.98,P=0.044)were associated with improved survival.CONCLUSION ACT does not improve survival after PM resection for CRC.Further well-designed randomized controlled trials are needed to determine the optimal ACT regimen and duration.

DIAGNOSIS AND TREATMENT OF THE MALIGNANT GESTATIONAL TROPHOBLASTIC TUMOR WITH PULMONARY METASTASIS COMPLICATED WITH PULMONARY TUBERCULOSIS

Objective. To evaluate the diagnosis and treatment for malignant gestational trophoblastic tumor(MGTT) with pulmonary metastasis complicated with pulmonary tuberculosis. Methods. To analyze ten cases of MGTT with pulmonary metastasis complicated with pulmonary tuberculosis in our hospital from 1980 to 1997 retrospectively. Results.From the x ray film, there are great resemblances between MGTT with pulmonary metastasis and pulmonary tuberculosis. Of 10 patients, 7 of them were examined out pulmonary tuberculosis during the chemotherapy of MGTT. Pulmonary tuberculosis appeared six months before chemotherapy in three cases. All of the patients were treated with multiagent chemotherapy. Seven patients achiceved a complete remission, 2 patients developed drug resistance and died of cerebral haemorrhage and cerebral herniation, 1 woman who had achieved a complete remission from MGTT for 14 months died of miliary tuberculosis. Conclusion. It is very important to make differential diagnosis of the MGTT with pulmonary metastasis complicated with pulmonary tuberculosis. Trying to avoid excessive anti tumor treatment owing to mistake pulmonary tuberculosis for pulmonary metastasis, and avoiding missing an opportunity of anti tuberculosis treatment because of missed diagnosis should be emphasized.

Clinical outcome after pulmonary metastasectomy from primary hepatocellular carcinoma:Analysis of prognostic factors

AIM： To review the surgical outcomes in terms of the surgical indications and relevant prognostic factors. METHODS： Sixteen patients underwent therapeutic lung surgery between March 1999 and May 2006. The observation period was terminated on May 31, 2007. The surgical outcomes and the clinicopathological factors were compared. RESULTS： There was no mortality or major morbidity encountered in this study. The mean follow-up period after metastasectomy was 26.7 ＋ 28.2 （range： 1-99 mo）, and the median survival time was 20 mo. The 1- and 5-year survival rates were 56% and 26%, respectively. At the end of the follow-up, 1 patient died from hepatic failure without recurrence, 6 died from hepatic failure with a recurrent hepatocellular carcinoma （HCC）, and 4 died from recurrent HCC with cachexia. Among several clinical factors, Kaplan Meier analysis revealed as a treatment for the that liver transplantation primary lesion, grade of cell differentiation, and negative evidence HBV infection were independent predictive factors. On Cox＇s proportional hazard model, there were no significant factors affecting survival after pulmonary metastasectomy in patients with HCC. CONCLUSION： A metastasectomy should be performed before other treatments in selected patients, Although not significant, patients with liver transplantation of a primary HCC survived longer, Liver transplantation might be the most beneficial modality that can offer patients better survival, A multi- institutional and collaborative study would be needed for identifying clinical prognostic factors predicting survival in patients with HCC and lung metastasis.

Surgery for oligometastasis of pancreatic cancer

The incidence of pancreatic adenocarcinoma（PDAC） has steadily increased over the past several decades. The majority of PDAC patients will present with distant metastases, limiting surgical management in this population. Hepatectomy and pulmonary metastasectomy（PM） has been well established for colorectal cancer patients with isolated, resectable hepatic or pulmonary metastatic disease. Recent advancements in effective systemic therapy for PDAC have led to the selection of certain patients where metastectomy may be potentially indicated. However, the indication for resection of oligometastases in PDAC is not well defined. This review will discuss the current literature on the surgical management of metastatic disease for PDAC with a specific focus on surgical resection for isolated hepatic and pulmonary metastases.

Treatment of respiratory failure in metastatic pulmonary choriocarcinoma： an experience at Peking Union Medical College Hospital, China

Background Respiratory failure caused by metastatic pulmonary choriocarcinoma usually develops rapidly and is associated with a high mortality. The clinical management strategy is important in choriocarcinoma patients with acute respiratory failure. The objective of this study was to evaluate the clinical characteristics, treatment outcome and potential risk factors in patients with acute respiratory failure from metastatic pulmonary choriocarcinoma. Methods Sixteen patients with acute respiratory failure from pulmonary metastases choriocarcinoma were enrolled and treated at Peking Union Medical College Hospital from 1995 to 2010. Clinical characteristics, causes of pulmonary failure, treatment profiles and outcomes were analyzed retrospectively. Results The presence of respiratory infection or hemorrhage was associated with acute respiratory failure in patients with metastatic choriocarcinoma. Fifteen （93.8%） patients presented with pulmonary infection, 8 （50.0%） patients with pulmonary hemorrhage. All patients were treated with face mask or mechanical ventilation. Fourteen （87.5%） patients received initial chemotherapy at a low dosage or with modified regimens, with a median of 2 cycles （range 1 to 4）. Seven patients achieved a complete remission （CR）, two had a partial remission. Six CR patients remained alive with a median follow-up of 59 months （range 16 to 120）. Seven patients developed progressive diseases and subsequently died. Conclusions Respiratory infection and hemorrhage were associated with acute respiratory failure in metastatic pulmonary choriocarcinoma. The initial administration of gentle chemotherapy regimens, accompanied with mechanical ventilation, is feasible and effective in attenuatina resDiratorv failure in patients with metastatic oulmonarv choriocarcinoma.

Surgical resection for pulmonary recurrence of esophageal cancer after curative esophagectomy

Aim:To clarify the significance of surgical resection for pulmonary recurrence after curative esophagectomy for esophageal cancer.Methods:Clinical details,such as the recurrence site,timing,and contents of therapies for recurrence,and the prognosis,were examined in 14 patients who underwent surgical resection for pulmonary recurrence that developed after curative esophagectomy.Results:The median disease-free interval after esophagectomy was 17.2 months.Two patients underwent pulmonary resection two times,and in one patient,three times.All pulmonary resections were performed when other extra-pulmonary recurrences had been controlled,and R0 resection was achieved.Chemotherapy and/or radiotherapy were additionally performed for pulmonary metastasis in 13 patients.The median survival time after initial pulmonary resection was 45.5 months,and the 1-,3-,and 5-year overall survival rates were 93%,68%,and 43%,respectively.The 5-year overall survival rate after initial pulmonary resection was 13%in patients with Stage III or IV esophageal cancer and 100%in those with Stage I or II disease(P=0.010).The rate was 56%in patients with tumors<20 mm in size,while all 5 patients with lesions≥20 mm in size died within 3 years(P=0.005).Conclusion:Surgical resection along with systemic therapy is a promising treatment strategy for pulmonary recurrence after curative esophagectomy when it is solitary and localized.Clinical factors,such as the esophageal cancer stage and the size of the pulmonary metastasis,are useful for deciding on the surgical indication.