Renal cell carcinoma (RCC) features altered lipid metabolism and accumulated polyunsaturated fatty acids (PUFAs). Elongation of very long–chain fatty acid (ELOVL) family enzymes catalyze fatty acid ...elongation, and ELOVL5 is indispensable for PUFAs elongation, but its role in RCC progression remains unclear. Here, we show that higher levels of ELOVL5 correlate with poor RCC clinical prognosis. Liquid chromatography/electrospray ionization‐tandem mass spectrometry analysis showed decreases in ELOVL5 end products (arachidonic acid and eicosapentaenoic acid) under CRISPR/Cas9‐mediated knockout of ELOVL5 while supplementation with these fatty acids partially reversed the cellular proliferation and invasion effects of ELOVL5 knockout. Regarding cellular proliferation and invasion, CRISPR/Cas9‐mediated knockout of ELOVL5 suppressed the formation of lipid droplets and induced apoptosis via endoplasmic reticulum stress while suppressing renal cancer cell proliferation and in vivo tumor growth. Furthermore, CRISPR/Cas9‐mediated knockout of ELOVL5 inhibited AKT Ser473 phosphorylation and suppressed renal cancer cell invasion through chemokine (C‐C motif) ligand‐2 downregulation by AKT‐mTOR‐STAT3 signaling. Collectively, these results suggest that ELOVL5‐mediated fatty acid elongation promotes not only cellular proliferation but also invasion in RCC.
Elevated ELOVL5 expression is associated with poor renal cancer clinical prognosis. ELOVL5 promotes cellular proliferation by inhibiting apoptosis. ELOVL5 promotes cellular invasion via the AKT‐mTOR‐STAT3‐CCL2 signaling pathway.
Background
To elucidate the clinicopathological features, hospital-based care volume and prognoses associated with primary retroperitoneal sarcoma (PRS).
Methods
Clinical data on PRS cases, diagnosed ...from 2008 to 2009 (cohort A) and from 2012 to 2015 (cohort B), were obtained from the national hospital-based cancer registry in Japan. Since data on survival, 5 years after PRS diagnosis, were available only for cohort A, patient prognoses were analyzed in this group alone.
Results
The numbers of participating hospitals were 154 in cohort A and 537 in cohort B. In total, 380 and 2011 patients with PRS were identified in cohorts A and B, respectively. The incidence of PRS among all the registered urogenital malignancies was 0.52% (2391/462,866). Liposarcoma was the most commonly observed PRS subtype (55.8%), followed by leiomyosarcoma (19.0%). In cohort A, the 5-year overall survival (OS) was 40.4%. The 5-year OS associated with stage I (
n
= 107), stages II and III (
n
= 61), and stage IV (
n
= 59) disease were 59%, 39%, and 6%, respectively. Only two institutions treated over ten patients per year in each cohort. When institutions were divided by hospital care volume (8 hospitals with ≥ = 3 cases and 149 with < 3 cases/year), there were any statistic differences in the OS.
Conclusions
We presented the distribution and prognoses associated with PRS using a real-world large cohort database. Centralization for PRS management was not established in Japan, while the prognosis did not significantly depend on the treatment volume of hospitals.
The International Germ Cell Cancer Collaborative Group Update Consortium showed the improved survival of patients with a non-seminomatous germ cell tumor. We updated the survival data of the ...non-seminomatous germ cell tumor patients treated at our hospital.
We analyzed the outcomes of 138 patients treated in 1981-2018. We compared the survival of the patients treated in the early (1981-99) and later (2000-18) periods and determined the groups' progression-free survival and overall survival using the Kaplan-Meier method. We used a web-based application of the International Germ Cell Cancer Collaborative Group Update model to calculate each patient's predicted 3-year progression-free survival.
The 5-year progression-free survival rates of the good, intermediate and poor prognosis groups were 91, 83 and 64%, and their 5-year overall survival rates were 97, 89 and 82%, respectively. There were no significant differences in the progression-free survival or overall survival of the good and intermediate prognosis groups by treatment year. The 5-year progression-free survival of the poor prognosis group was almost identical in both treatment year (60 and 65%, respectively). By contrast, the 5-year overall survival in the later period (85%) was higher than that in the early period (70%). The median-predicted 3-year progression-free survival rates of the good, intermediate and poor prognosis groups were 92, 83 and 51% (P < 0.01), respectively. The concordance index for the good, intermediate and poor prognosis groups were 0.56, 0.79 and 0.67, respectively.
The survival of our poor prognosis non-seminomatous germ cell tumor patients improved over time. The 5-year overall survival of patients treated in 2000-18 reached 85%.
Abstract
Objective
We retrospectively analyzed the incidence and localization of venous thromboembolism in patients undergoing chemotherapy for advanced germ cell tumor and separately evaluated the ...risk factors for venous thromboembolism development before and during chemotherapy.
Methods
We included 121 patients treated with cisplatin-based chemotherapy between 2005 and 2018. Venous thromboembolism was defined as venous thrombosis diagnosed using radiological imaging with or without thromboembolic symptoms. We analyzed the clinical parameters for identifying the possible venous thromboembolism risk factors. Khorana score was used to calculate the venous thromboembolism risk.
Results
Thirteen patients showed prechemotherapy venous thromboembolism and 13 developed venous thromboembolism during chemotherapy. The most common venous thromboembolism was deep vein thrombosis (10 patients), followed by inferior vena cava thrombus (eight patients) and pulmonary thrombus (six patients). Compared to the group without venous thromboembolism, the group with prechemotherapy venous thromboembolism showed higher proportion of patients with tumors originating in the right testis (10 out of 13), significantly higher lactate dehydrogenase levels (828 IU/L versus 436 IU/L, P = 0.013), significantly higher proportion of patients with retroperitoneal lymph node (RPLN) metastases >5 cm in diameter (76.9% versus 33.7%, P = 0.003) and slightly higher proportion of patients with high-risk Khorana score (≥ 3; 30.8% versus 11.6%). No significant differences were observed between the clinical characteristics of patients with venous thromboembolism developed during chemotherapy and patients without venous thromboembolism.
Conclusions
We show that both RPLN mass > 5 cm and high lactate dehydrogenase levels are significant risk factors for prechemotherapy venous thromboembolism but not for venous thromboembolism development during chemotherapy.
Retroperitoneal lymph node metastases >5 cm and high lactate dehydrogenase levels are significant risk factors for prechemotherapy venous thromboembolism but not for venous thromboembolism development during chemotherapy.
Objectives
To evaluate the histologic findings and clinical outcomes of post‐chemotherapy retroperitoneal lymph node dissection for advanced germ cell tumor.
Methods
We analyzed the medical records ...of 66 patients who underwent post‐chemotherapy retroperitoneal lymph node dissection between 2005 and 2019 at Tsukuba University Hospital.
Results
The proportions of necrosis, teratoma, and viable germ cell tumor in the specimens were 62.1%, 36.4%, and 1.5%, respectively. The 5‐year progression‐free and overall survival rates were 82.3% and 91.3%, respectively. The 5‐year overall survival rate of patients with residual teratoma was significantly worse than that of patients with necrosis only (74.1% vs 100%). Overall, three patients died: one from cancer and two from teratoma with somatic‐type malignancy. Of these, two patients relapsed after incomplete resection of residual teratoma. When limited to patients with completely resected teratoma, the 5‐year overall survival rate was 91.7%, which did not differ from that for patients with necrosis only. Multivariate analysis showed that presence of teratoma in the primary site and decrease in retroperitoneal lymph node mass to less than 50% of the initial tumor size were independent factors for residual teratoma. However, the absence of these factors could not reliably predict necrosis only in retroperitoneal lymph node dissection specimens.
Conclusions
In our series, 98% of post‐chemotherapy retroperitoneal lymph node dissection pathology was either necrosis or teratoma, with viable germ cell tumor only found in 2% of patients. Residual teratoma was associated with poorer prognosis, especially in cases of incomplete resection.
We aimed to compare the diffusion capacity of carbon monoxide (DLCO), which was adjusted using the two equations the Cotes method and the Dinakara method, to assess bleomycin-induced lung injury in ...testicular cancer patients preparing for post-chemotherapy surgery.
Between November 1990 and October 2018, 89 patients with advanced testicular cancer were recruited into the study. All patients received chemotherapy and underwent DLCO measurements using the single-breath technique prior to surgery for residual tumor removal.
The mean DLCO adjusted for hemoglobin using the Cotes and Dinakara methods was 69.5% and 86.0%, respectively (P < 0.001). According to the Cotes method, adjusted DLCO was severely diminished to below 65% in 40 patients (45%), whereas this proportion was only 16% according to the Dinakara method. We observed a significant correlation between hemoglobin levels and DLCO adjusted using the Cotes method (P < 0.001), but not using the Dinakara method. Four patients received a clinical diagnosis of bleomycin-induced pneumonitis (BIP), and all patients recovered after oral steroid therapy or observation. The DLCO adjusted by either methods was not well correlated with the development of BIP. No patients had major postoperative respiratory complications.
We found that Cotes-adjusted DLCO may be influenced by anemia. We recommend the addition of Dinakara-adjusted DLCO, along with chest computed tomography, for preoperative risk assessment.
Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the ...early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment responses in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues, before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME using bioinformatics from The Cancer Genome Atlas (TCGA) cohort. An adaptive immune response was activated in the TNFSF9-high-expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8+ T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. This suggests that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 high-expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection.
Objectives
To investigate the clinical characteristics of patients with penile cancer in Japan using the nationwide hospital‐based cancer registry database.
Methods
Using hospital‐based cancer ...registry data, we described the distribution of age, pathology, tumor–node–metastases classification, and first‐course treatment in patients treated between 2012 and 2015. We compared the patterns of first‐line treatment between elderly and non‐elderly patients.
Results
A total of 1012 patients were diagnosed with squamous cell carcinoma among 1773 patients with penile tumors who registered under topography code C60. The median age at diagnosis was 74 years, and 85.9% of patients were aged >60 years. The most common pathology was usual‐type squamous cell carcinoma (91.9%), followed by verrucous carcinoma (5.0%), sarcomatoid carcinoma (1.1%), papillary carcinoma (0.7%), basaloid carcinoma (0.6%), adenosquamous carcinoma (0.4%), warty carcinoma (0.2%) and mixed carcinoma (0.1%). A total of 61.3% of patients were diagnosed with localized disease. In contrast, the proportions of patients with lymph node and distant metastases were 27.5% and 2.1% at diagnosis, respectively. The proportion of patients who were treated with chemotherapy as the first‐course treatment was significantly lower among elderly patients (≥80 years) with clinical stage III (27.6% vs 7.1%, P = 0.0312) and clinical stage IV (53.2% vs 14.3%, P = 0.0086).
Conclusions
Most penile cancer patients in Japan are diagnosed with usual‐type squamous cell carcinoma, and those with human papilloma virus‐related squamous cell carcinomas are <1%. Chemotherapy for advanced penile cancer is administered less in Japanese elderly (≥80 years) patients.
Genitourinary sarcomas are rare in adults and few large-scale studies on adult genitourinary sarcoma are reported. We aimed to elucidate the clinical characteristics, survival outcomes, and ...prognostic factors for overall survival of adult genitourinary sarcoma in Japan.
A hospital-based cancer registry data in Japan was used to identify and enroll patients diagnosed with genitourinary sarcoma in 2013. The datasets were registered from 121 institutions.
A total of 116 men and 39 women were included, with a median age of 66 years. The most common primary site was the kidney in 47 patients, followed by the paratestis in 36 patients. The most common histological type was liposarcoma in 54 patients, followed by leiomyosarcoma in 25 patients. The 5-year overall survival rates were 57.6%. On univariate analysis, male gender, paratestis as primary organ, and histological subtype of liposarcoma were predictive of favorable survival while primary kidney, bladder, or prostate gland location were predictive of unfavorable survival. On multivariate analysis, primary paratestis was an independent predictor of favorable survival while primary kidney, bladder, or prostate gland were independent predictors of unfavorable survival.
This is the first report showing the clinical characteristics and survival outcomes of adult genitourinary sarcoma in Japan using a real-world large cohort database.
