Survival In Non-metastatic Patients Research Articles

Appendicular dedifferentiated chondrosarcoma: A management and survival study from the SEER database

IntroductionDedifferentiated chondrosarcoma (DDC) is an aggressive osseous neoplasm with a dismal prognosis. Treatment commonly involves limb-salvage surgery or amputation. In patients with appendicular DDC, we sought to describe demographic, clinical and treatment characteristics (1), analyze risk factors for metastasis (2) and overall death (3), and assess survival rates by treatment (4). Materials and methodsTwo-hundred-and-five patients from the SEER Database were included in our analysis. Demographic, clinical and treatment variables were analyzed. Multivariate regression was performed to identify risk factors. Survival analysis was performed using the Kaplan-Meier method. ResultsFifty-one (24.9 %) of the patients included presented metastasis at diagnosis. The most common locations were the lungs, other sites, and bone. Surgery to the primary site was more common in patients without metastasis (94.2 %) than those with (78.2 %); limb-salvage procedures were more common than amputations. Tumors >8 cm (T2) and those discontinuous (T3) were more likely to present metastasis at diagnosis (OR = 2.54, p = 0.043 and OR = 7.4, p = 0.008, respectively). Female gender was found to be a protective factor for overall death on crude analysis (OR = 0.33, p = 0.019). Metastases to sites other than the lungs (M1b) had the highest risk of overall death (OR = 49, p = 0.01). Combination of surgery and chemotherapy showed a trend towards higher overall survival in non-metastatic patients (p = 0.1069 and p = 0.1703). ConclusionsAppendicular DDC displays a high metastatic rate and low survival rates. The most common procedure is a limb-salvage surgery. Tumor size increases the risk of presenting metastases at diagnosis and female gender is a protective factor against death.

Osteosarcoma/Ewing Sarcoma

Osteosarcoma/Ewing Sarcoma

Primary urethral cancer: A GETUG French nationwide cohort study.

430 Background: Primary urethral cancer (PUC) is a rare and heterogeneous malignancy. Due to its scarcity, little data are available on the optimal treatment sequence and survival, especially in metastatic patients. Methods: Data from patients diagnosed with a PUC between 01/01/2000 and 12/31/2018 were retrospectively collected from nine French referral centers. Survival rate were estimated with the Kaplan-Meier method and prognostic factors were analyzed using the Cox proportional hazards model and the log-rank test. In order to increase the statistical power of survival analysis in the metastatic stage, patients with synchronous and metachronous metastatic disease were pooled. Results: We identified 44 (62%) males and 27 (38%) females with a PUC. The most frequent histological types were urothelial carcinomas (40.0%), squamous cell carcinomas (34.3%) and adenocarcinomas (14.3%). Twenty-five (35.2%) patients were diagnosed at a localized stage (≤ T2, N0, M0); 35 (49.3%) at a locally advanced stage (≥ T3 or ≥ N1, M0) and 11 (15.5%) at a distant stage (M1). Twenty-seven patients had a metachronous metastatic cancer. Multimodality therapy was used in 24.0% and 57.1% of the patients with a localized and locally advanced disease, respectively. In the entire cohort, median overall survival (OS) was 52.5 months (IC95% 32.2 – 64.1) and stage at diagnosis was a predictor of OS (p < 0.0001). For the 60 patients with a non-metastatic disease, 39 (65%) had a recurrence or were dead and the median disease-free survival (DFS) was 21.2 months (IC95% 16.8 – 34.5). Nodal involvement was the only factor associated with DFS (HR: 2.03, p = 0.0390). Multimodal treatment compared with unimodal treatment was not significantly associated with DFS (HR: 1.22, p = 0.5419). Regarding survival of the 38 metastatic patients, the median OS was 15.2 months (IC95% 8.2 – 23.5) and the median progression-free survival was 6.4 months (IC95% 4.4 – 9.8). Conclusions: This retrospective study showed an important heterogeneity in terms of histology, stage at diagnosis, and treatment of PUC. In this cohort, the multimodal approach did not show any improvement in survival of non-metastatic patients. This study is one of the few to describe the survival in metastatic patients.

Abstract 2448: Modeling the mechanisms behind the biphasic expression of the PTK7 tyrosine kinase receptor in colorectal cancer

Abstract Colorectal cancer (CRC) is the second deadliest cancer worldwide. Discovery of new biomarkers and therapeutic targets is thus essential (PMID: 27922044). CRC cells frequently reactivate developmental pathways such as WNT, Hedgehog and Hippo pathways, which participate to tumorigenesis and metastatic dissemination. The tyrosine kinase receptor PTK7 is a cell surface component from the WNT pathway involved in embryonic development in many species (PMID: 15229603). In retrospective studies, PTK7 was previously found overexpressed in CRC, an event associated with metastatic development, reduced metastases-free survival of non-metastatic patients, and resistance to chemotherapy (PMID: 25962058 and 21103379). PTK7 has pro-migratory and pro-metastatic functions in vitro and in vitro, but the mechanisms behind are not well understood yet. We recently conducted a prospective study collecting primary tumors, circulating tumor cells (CTCs) and metastases from CRC patients and evaluated expression of PTK7 in all types of samples at the mRNA and protein levels. PTK7 was confirmed as an independent poor prognosis marker in CRC with strong expression in primary tumors and metastases. Surprisingly, a large majority of CTCs were tested negative for the presence of PTK7 at their cell surface. We recapitulated this observation in a xenografted mouse model, as well as in an in vitro microfluidic setup preventing cell-matrix and cell-cell interactions of circulating CRC cells. Both results demonstrated the cell autonomous origin of PTK7 disappearance from CRC cells once in circulation. Interestingly, knockdown of PTK7 with small interfering RNA impaired the adhesion pattern of now PTK7-negative CRC cells on several matrix and promoted resistance to anoikis. A screen combining proximity labeling and mass spectrometry from CRC cells identified partners of PTK7 involved in cell adhesion, including integrins. In the absence of PTK7, two of them (ITGβ1 and ITGαV) had disabled function and expression, and their deregulation was associated with an increased phosphorylation of Focal Adhesion Kinase (FAK), a major actor of cancer cell survival and resistance to anoikis. We are currently investigating the mechanism of disappearance of PTK7 from the cell surface of CTCs and its consequence on drug resistance and metastatic dissemination of CRC cells. Citation Format: Laetitia Ganier, Anais Aulas, Olivier Cabaud, Alexia Lopresti, Kostyantyn Semenchenko, Pascal Finetti, Marine Gilabert, Anthony Goncalves, Claire Acquaviva, Daniel Birnbaum, Emilie Mamessier, Jean-Paul Borg. Modeling the mechanisms behind the biphasic expression of the PTK7 tyrosine kinase receptor in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2448.

The Advantages of Clinical Nutrition Use in Oncologic Patients in Italy: Real World Insights.

This retrospective observational study aimed to provide insights on the use of clinical nutrition (CN) (enteral and parenteral feeding) and outcomes in an Italian real-world setting. The data source comes from administrative databases of 10 Italian Local Health Units. Patients diagnosed with malignant neoplasms from 1 January 2010 to 31 December 2015 were included. Metastasis presence was ascertained by discharge diagnosis in the hospitalization database. CN was identified by specific codes from pharmaceutical and hospitalization databases. Two cohorts were created—one for metastatic patients (N = 53,042), and one for non-metastatic patients (N = 4379) receiving CN. Two survival analyses were set for the cohort of metastatic patients—one included patients receiving CN and the second included malnourished patients. Our findings show that (1) administration of CN is associated with positive survival outcomes in metastatic patients with gastrointestinal, respiratory, and genitourinary cancer; (2) CN in malnourished metastatic patients with gastrointestinal and genitourinary cancer was associated with significant improvement in survival; (3) early administration of CN was associated with improvement in survival in non-metastatic patients with gastrointestinal cancer (HR 95%CI: 0.5 (0.4–0.6), p-value < 0.05). This study highlights the need to improve the assessment of nutritional status in oncologic patients and suggests a potential survival benefit of CN treatment in metastatic disease.

A nomogram based on a gene signature for predicting the prognosis of patients with head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors. The purpose of this study was to establish and validate a gene-expression-based prognostic signature in non-metastatic patients with HNSCC. All the patients were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We randomly divided the GSE65858 samples into 70% (training cohort, n = 190) and 30% (internal validation cohort, n = 72). A total of 36 samples collected from the TCGA HNSCC databases were selected as an independent external validation cohort. The oligo package in R was used to normalize the raw data before analysis. Data characteristics were extracted, and a gene signature was built via the least absolute shrinkage and selection operator regression model. The predictive model was developed by multivariable Cox regression analysis. T stage, N stage, human papilloma virus status, and the gene signature were incorporated in this predictive model, which was shown as a nomogram. Calibration and discrimination were performed to assess the performance of the nomogram. The clinical utility of this nomogram was assessed by the decision curve analysis. Overall, 2001 significant messenger RNAs in HNSCC samples were identified compared with normal samples. The gene signature contained seven genes and significantly correlated with overall survival. The gene signature was also significant in subgroup analysis of the primary cohort. The calibration was plotted in the external cohort (C-index 0.90, 95% CI 0.85, 0.95) compared with the training (C-index 0.76, 95% CI 0.73, 0.79) and internal (C-index 0.71, 95% CI 0.66, 0.77) cohorts. In clinic, a decision curve analysis demonstrated that the model including the prognostic gene signature score status was better than that without it. This study developed and validated a predictive model, which can promote the individualized prediction of overall survival in non-metastatic patients with HNSCC.

TERT promoter mutations identify a high-risk group in metastasis-free advanced thyroid carcinoma

BackgroundTERT promoter mutations are associated with adverse clinicopathological characteristics in thyroid carcinomas and considered as a major indicator of poor outcomes. Nevertheless, most studies have pooled heterogeneous types of thyroid carcinomas and have been conducted retrospectively. We investigated the association between TERT promoter mutations and recurrence in a prospective series of 173 intermediate- to high-risk patients with thyroid cancer. PatientsPatients referred for radioiodine treatment after thyroidectomy for intermediate- to high-risk differentiated thyroid carcinoma were included in a prospective observational study and tested for TERT promoter, BRAF, and RAS mutations of their primary tumours. We analysed the relationship between TERT promoter mutations and outcomes. ResultsThe prevalence of TERT promoter mutations was 20.2% (35/173) in the total population. It was significantly higher in tumours harbouring aggressive histological features (poorly differentiated carcinoma, tall cell variant of papillary cancer or widely invasive follicular cancer) than in non-aggressive tumours: 32.7% (16/49) versus 15.3% (19/124; p = 0.020). TERT promoter mutations were also strongly associated with age ≥45 years (p = 0.005), pT4 stage (p = 0.015), metastatic disease (p = 0.014), and extrathyroidal extension (p = 0.002). TERT promoter mutations were associated with poor outcomes in the total population (p < 0.001) but not in the subgroup of non-metastatic patients (p = 0.051). However, they were associated with a worse outcome in patients both free of metastases and devoid of aggressive histological features. Neither BRAF nor RAS mutations were associated with event-free survival in non-metastatic patients. ConclusionAlthough their prognostic value does not seem to overcome that of histology, TERT promoter mutations may help to better define the prognosis of localized thyroid cancer patients without aggressive histology.

Overexpression of the Promigratory and Prometastatic PTK7 Receptor Is Associated with an Adverse Clinical Outcome in Colorectal Cancer.

Biomarkers and novel therapeutic targets are urgently needed in colorectal cancer (CRC). The pseudo tyrosine kinase receptor 7 (PTK7) is involved in planar cell polarity and it is deregulated in various malignancies, including CRC. Yet, little is known about its protein expression in human CRC, or about a possible correlation of its expression with clinical endpoints. Using a clinically annotated Tissue MicroArray (TMA) produced from from 192 consecutive CRC patients treated by initial surgery, we examined PTK7 expression by immunohistochemistry in tumoral tissue and matched normal mucosae, and correlated its expression with clinico-pathological features and patient outcome. PTK7 depletion by specific shRNA in HCT116 and HCT15 CRC cell lines was found to affect cell proliferation, resistance to drugs and cell migration. Tumor growth and metastatic phenotype were investigated in vivo using a xenograft mouse model of CRC cells with modulated expression of PTK7 levels. PTK7 was significantly up-regulated in CRC tissue as compared to matched healthy mucosae, and significant overexpression was found in 34% of patients. PTK7 overexpression was significantly associated with a reduced metastasis-free survival in non-metastatic patients. In HCT116 and HCT15 cells, shRNA PTK7 reduced migration but did not affect cell proliferation and resistance to drugs. In a xenograft mouse of HCT15 cells, downregulation of PTK7 led to reduced tumor growth, whereas its overexpression in PTK7-negative cancer cells led to increased metastatic events. PTK7 expression thus represents a potential prognostic biomarker and a novel therapeutic target in CRC.

Results with the intensive chemotherapy Mexican regimen in the treatment of pediatric high-grade osteosarcoma: Experience at the Instituto Nacional de Pediatria.

10058 Background: In Mexico, pediatric high-grade osteosarcoma (HGO) occupies the fifth place of all pediatrics cancers, representing the 4.4%. It presents with a high incidence of metastatic pulmonary disease and large primary tumor volume at diagnosis, resulting in poor survival. The results of the named 2005 Chemotherapy Regimen are very promising. Methods: A retrospective, longitudinal, clinical study was performed from January 2005 to January 2012, including 55 patients (&lt;18 years old) with extremity HGO and no prior chemotherapy treatment. All patients received a 10-week neoadjuvant-chemotherapy regimen (6 curses), with cisplatino 120mg/m2 plus doxorrubicina 75mg/m2 and a 15-week adjuvant-treatment (5 curses) with ciclofosfamide 1800 mg/m2 plus etoposide 900 mg/m2. Results: Median age was 12 years, 51% boys and 49% girls. There were 51% distal femur, 11% proximal humerus, 18.2% proximal tibia, 7.3% distal tibia, 5.4% fibula and 5.5% proximal femur. Thirty-two patients (58.2%) had pulmonary metastases at diagnosis. There were 76.4% osteoblastic tumors, 16% chondroblastic and 7.3% telangiectatic. Twenty patients (36.4%) had an amputation procedure and 15 (27%) a limb desarticulation, 18 by a great tumor volume at diagnosis and two by eventual local relapse. Twelve patients (22%) had limb-sparing surgery. There were 10 (18.2%) good-responder patients and 38 (69%) bad-responders to neoadjuvant-chemotherapy. The overall survival (OS) for non-metastatic patients was 70% and 35% for metastatic patients (p 0.016). The event-free survival for non-metastatic patients was 65% and 30% for metastatic patients (p 0.032). OS for good-responders was 80% and 50% for bad-responders (p 0.009). No important toxicity and no second malignancies were reported. Conclusions: In spite of the presence of significant unfavorable prognostic factors in our patients, this intensive chemotherapy regimen showed improved results in overall survival as compared to other standard regimens, being short, inexpensive and with relatively few adverse events. This regimen can be useful in other developing countries.

What determines testosterone levels?

This study is interesting as a negative study. It shows that the type of luteinizing hormone releasing-hormone (LHRH) agonists and primary therapy is not significant when it comes to testosterone levels.1 This commentary focuses on the actual testosterone levels, which are clinically relevant as many patients were experiencing breakthrough levels on LHRH agonists. Chemically castrate status in terms of testosterone has been argued to be 20 ng/dL or 50 ng/dL, which converts to 0.69 nmol/L or 1.7 nmol/L.2 Current consensus is 20 ng/dL, which bilateral surgical castration typically achieves.3 The median values reported in this study for LHRH alone, radiation and surgery were 40, 37 and 36 ng/dL, or 1.4, 1.3 and 1.25 nmol/L, respectively. The interquartile ranges also suggest that most patients (75%) did not have castrate levels of testosterone. Admittedly, this study does mention testosterone was only obtained once and circumstances surrounding it were uncertain. Anti-androgen status is also not mentioned. Bicalutamide and other anti-androgens are known to elevate testosterone levels as monotherapy and may have a confounding effect on the testosterone levels reported. Most likely testosterone was measured when prostate-specific antigen (PSA) was rising on LHRH agonist and one can surmise that the ordering physician was looking for and found “testosterone escape” (a single value above 50 ng/dL or 1.7 nmol/L) in many of the patients in this study.4 Although as stated previously, perhaps 20 ng/dL should be the current definition. The importance of testosterone escape is backed by several studies. It is known anti-androgens do not help orchiectomy patients in overall survival, but do for patients on LHRH agonists.5 Breakthrough testosterone levels on medication that did not occur for surgically castrate patients would be a likely explanation. Progression-free survival in non-metastatic patients in another study was longer, the lower the testosterone level.6 In this clinical scenario of testosterone escape, standard treatment was switching LHRH agonists, adding an anti-androgen and bilateral orchiectomy. Now, a new option with LHRH antagonists arises. It has been reported to have modest results with respect to decreasing PSA, but can possibly alleviate voiding symptoms more than LHRH agonist therapy.7 Regardless, the actual testosterone level is important for patients on LHRH agonists with rising PSA. Venkateswaran and colleagues make the case that it should be checked no matter what the primary therapy.1

Baseline Nutritional Status Is Predictive of Response to Treatment and Survival in Patients Treated by Definitive Chemoradiotherapy for a Locally Advanced Esophageal Cancer

To assess the impact of baseline nutritional status on treatment response and survival in nonmetastatic patients with a locally advanced esophageal cancer (LAEC) treated with definitive chemoradiotherapy (CRT). One hundred five patients with LAEC treated by definitive CRT were retrospectively included. The CRT regimen was based on an external radiotherapy (RT) delivered concomitantly to a cisplatin-based chemotherapy (CT). Patients were considered to have a complete response (CR) to CRT when no residual tumor was detected on CT scan and esophagoscopy performed 2 months after the end of CRT. Multivariate analysis of predictive factors of response to CRT and survival were performed using a logistic regression and a Cox model, respectively. Mean value of baseline nutritional parameters was significantly different between nonresponder (N = 42) and responder (N = 63) patients to CRT (weight loss 10%vs 5.8%, P= 0.0047; serum albumin level 35 g/L vs 38.7 g/L, P= 0.0004; BMI 22.8 kg/m2vs 25.2 kg/m2, P= 0.01). In multivariate analysis, serum albumin level > 35 g/L was the only independent predictive factor of CR to CRT (P= 0.009). Independent prognostic factors of survival were BMI > 18 kg/m2 (P= 0.003), dysphagia Atkinson score <2 (P= 0.008), dose of RT > 50 Grays (Gy) (P < 0.0001) and CR to CRT (P < 0.0001). Survival was influenced by baseline nutritional status as well as dysphagia, dose of RT, and CR to CRT. Despite the retrospective design of the study, our results may provide the concept basis for performing a prospective nutritional intervention study in patients treated by definitive CRT for an esophageal cancer.

Clinical features in osteosarcoma and prognostic implications

To identify the clinical features in osteosarcoma and to investigate their influence on the prognosis of children and adolescents presenting this disease. The records of children and adolescents with osteosarcoma treated by the Bone Tumors Group of the state of Rio Grande do Sul, Brazil, between January 1992 and December 2001 were reviewed. Fifty consecutive patients were included in this study. Mean age at diagnosis was 13 years (3-22); 68% of the patients were males. The primary site of disease was the femur in 50% of the patients, tibia in 30%, pelvis in 4%, humerus in 10%, fibula in 2% and other sites in 4%. Nineteen patients presented metastases at diagnosis (38%). All patients received chemotherapy and were treated with three different schemes. As for surgical treatment, 26 patients (52%) had an amputation and 17 (34%) received conservative surgery. Serum lactic dehydrogenase > 1,000 UI/ml (p = 0.0159, log rank), tumor necrosis < 90% and presence of metastases had a negative influence on prognosis. The overall 5-year survival was of 33.2+/-7.2% with mean follow-up of 36 months (6-126). Event-free survival was 29.7+/-7%. The 5-year event-free survival in non-metastatic patients was 45+/-10.7%, and zero in metastatic patients (follow-up of 78.4 and 18.7 months, respectively). Only two out of 19 metastatic patients are alive and free of disease at 18 and 30 months respectively. Metastatic disease at diagnosis, serum levels of serum lactic dehydrogenase > 1,000 UI/ml and tumor necrosis < 90% are predictors of unfavorable prognosis. The excessively high incidence of metastatic patients may suggest the presence of an aggressive pattern of disease in our population, or may indicate late diagnosis.