A French multifactorial prospective study of tumor protein and genetic markers in stage I-III colorectal cancer (CRC): Highlight on molecular characteristics related to mismatch repair (MMR) status.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3596-3596
Author(s):  
Gerard Milano ◽  
Maurice Chazal ◽  
Pierre Laurent-Puig ◽  
Sylviane Olschwang ◽  
Marie-Pierre Gaub ◽  
...  
Keyword(s):  
Adjuvant Treatment ◽  
Tumor Staging ◽  
Dihydropyrimidine Dehydrogenase ◽  
Disease Free Survival ◽  
Stage I ◽  
Braf V600e ◽  
Molecular Characteristics ◽  
Rt Pcr ◽  
Primary Tumors ◽  
Multicentric Study

3596 Background: There is still a need to identify prognostic markers in stage II CRC for setting up adjuvant treatment. The prognostic value of tumor genetic and protein markers was analyzed in CRC patients, as well as relationships between markers. Given the strong prognostic and predictive value of deficient MMR (dMMR), we examined whether dMMR tumors had a distinct protein profile as compared to proficient (pMMR) tumors. Methods: This prospective multicentric study involved 251 stage I-II-III CRC patients with complete surgical resection. Primary end-point was disease free survival (DFS, 60 events, median follow-up 88 months). Biomarkers analyzed on frozen primary tumors were: MMR status (bat 25, bat 26), mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CIMP status, ploidy, S-phase fraction, LOH (8p, 17p, 18q), EGFR (ligand-binding assay), VEGFA expression (Elisa), thymidylate synthase (TS) enzyme activity and expression (RT-PCR), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions (RT-PCR). Results: 30 stages I, 116 stages II and 105 stages III were included (FUFOL adjuvant treatment in 30 stages II and 61 stages III). 14% were dMMR. Multivariate Cox analyses showed that tumor staging was the only significant predictor of DFS. Log Rank analyses restricted to stage III showed tendencies for a shorter DFS in KRAS-mutated (p=0.005), BRAF wt (p=0.009) and pMMR tumors (p=0.036). dMMR tumors significantly expressed elevated TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (p<0.001) and tended to express higher DPD expression (median 14.9 vs 7.9, p=0.027) and EGFR content (median 69 vs 38, p=0.037) relative to pMMR. Conclusions: The present data, suggesting for the first time that both TS (5FU target) and DPD (FU catabolism enzyme) are overexpressed in dMMR tumors, bring strong arguments to explain the resistance of dMMR CRC tumors to FU-based therapy. The fact that dMMR tumors tend to express elevated EGFR levels and are prone to be KRAS wt suggests that anti-EGFR may be a relevant therapy in these patients. Clinical trial information: 1997.CHUNice-948.

Results of Postoperative Radiotherapy in the Treatment of 29 Uterine Sarcoma Patients

2003 ◽  
Vol 89 (2) ◽  
pp. 183-188 ◽  
Author(s):  
Durmuş Etiz ◽  
Melahat Garipağaoğrlu ◽  
Emine Elmas Etiz ◽  
Faruk M Köse ◽  
Fulya Kayikçioğrlu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Postoperative Radiotherapy ◽  
Menopausal Status ◽  
Disease Free Survival ◽  
Uterine Sarcoma ◽  
Stage I ◽  
Primary Tumors ◽  
Local Recurrences ◽  
Number Of Patients ◽  
Disease Free

Aims and background The objective of this study was to evaluate the results of surgery combined with postoperative radiotherapy (RT) in patients with uterine sarcoma in order to describe the patterns of relapse and to define prognostic factors. Methods We report on 29 patients with uterine sarcoma (US) treated from 1980 to 1995; 18 patients with primary tumors were treated with surgery and adjuvant irradiation, while 11 patients with local recurrences (LR) after previous surgical resection received only radiotherapy. We evaluated the influence of stage, histology, grade, menopausal status, total radiation dose and brachytherapy on survival. Histological diagnosis was leiomyosarcoma in 13 patients (44.8%), endometrial stromal sarcoma in 10 patients (34.5%), and mixed mesodermal tumors in six patients (20.7%). Fifteen patients presented with stage I-II disease, three with stage III, and 11 with local recurrences. External pelvic RT was administered to all patients, in five patients combined with brachytherapy. The mean total dose was 54 Gy (SE 1.78). Univariate and multivariate analyses were carried out. Results Overall survival (OS) for the stage I-III group was 61.1% at two years and 33.3% at five years (median 29 months, SE 13.79). Disease-free survival (DFS) was 55.6% at two years and 33.3% at five years. Median DFS was 26 months (SE 14.85). In LR cases, median OS was only 10 months (SE 4.5). Multivariate analysis demonstrated that stage was the only prognostic factor after RT for US. Conclusions These data suggest that postoperative and/or salvage RT has a questionable impact on disease-free and overall survival because of the lack of homogeneity of stages in the series reported in the literature; it has, however, acceptable late side effects. Prospective multicenter trials including a statistically evaluable number of patients are necessary to further clarify the role of RT treatment programs for US.

Retrospective analysis of adjuvant treatment for localized, operable uterine leiomyosarcoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11072-11072
Author(s):  
Jomjit Chantharasamee ◽  
Karlton Wong ◽  
Pasathorn Potivongsajarn ◽  
Amir Aqorbani ◽  
Bartosz Chmielowski ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Adjuvant Chemotherapy ◽  
Adjuvant Treatment ◽  
Tumor Size ◽  
Disease Free Survival ◽  
Mitotic Rate ◽  
Stage I ◽  
Uterine Leiomyosarcoma ◽  
Recurrence Rates ◽  
The Impact

11072 Background: Surgery is the standard of care for uterine leiomyosarcoma, but recurrence rates are high and outcomes are poor. Standard adjuvant treatment of localized uterine leiomyosarcoma(uLMS) has not yet been established as clinical trials to address this question have been small or hindered by slow accrual. Methods: We reviewed the medical records of patients with uLMS who underwent upfront surgery between 2000-2018. We evaluated the clinical characteristics and adjuvant therapy on outcomes. Patient characteristics and treatment outcomes were described using descriptive statistics. Kaplan-Meier survival analysis was used for DFS. Cox proportional hazard regression was used to compare difference between groups. Results: 59 patients with a median age of 52 years were analyzed and the median time from surgery to adjuvant treatment was 47 days. 48/59 (81.4%) underwent TAH-BSO. 64.4% were FIGO stage I, 16.9% were stage II and 6.7% were stage III. The median tumor size was 11 cm (range: 3-21cm) and the median mitotic rate was 13 mitoses/ 10 high-power fields (HPF), (range: 1-63). 34/59 (57.6%) of patients received adjuvant chemotherapy +/- radiation therapy and 25 patients (42.3%) did not receive adjuvant treatment. With a median follow-up time of 42.8 months, 42 patients (71.2%) had disease relapse and 15 (35.7%) had pulmonary metastases. The median disease-free survival (mDFS) for all patients was 23.1 months. Any adjuvant treatment (chemotherapy or radiation) had a trend toward longer mDFS than no adjuvant treatment (36.6 vs 13.6 months, p = 0.14). Patients who had adjuvant chemotherapy had a non-significant longer mDFS compared to who did not receive any adjuvant treatment (33.8 vs 13.6 months, p = 0.18). Patients with stage I disease had trend towards higher mDFS in the chemotherapy group, it was not statistically significant (29.7 vs 16.6 months, p = 0.59). Multivariate analysis found that the independent prognostic factors for worse DFS included tumor size larger than 10 cm, and mitotic rate over 10/ 10HPF. More morcellated specimens were found in non-adjuvant treatment arm (36%) compare to 8% in adjuvant arm. In the non-treatment arm, 14 patients had recurrences within 6 months. Conclusions: In a retrospective uLMS population, the mDFS was 23.1 months. Tumor size > 10cm and mitotic rate > 10/10 HPF were independent prognostic factors for lower DFS. The non-treatment group had a significantly higher number of patient with morcellization and relapsed within 6 months, confounding analyses of the impact of adjuvant chemotherapy.

scholarly journals Ten-Year Results of Postoperative Adjuvant Treatment In Women With Stage I Endometrial Cancer

2021 ◽  
Author(s):  
Peiying Fu ◽  
Ting Zhou ◽  
Pengfei Cui ◽  
Shixuan Wang ◽  
Ronghua Liu
Keyword(s):  
Endometrial Cancer ◽  
Adjuvant Treatment ◽  
Early Stage ◽  
Disease Free Survival ◽  
Figo Stage ◽  
Stage I ◽  
Rank Test ◽  
Adjuvant Therapies ◽  
Early Stage Endometrial Cancer ◽  
Postoperative Adjuvant Treatment

Abstract Background: It remains controversial whether postoperative adjuvant treatment is beneficial for the survival of patients after surgery for early-stage endometrial cancer. To evaluate whether postoperative adjuvant treatment is beneficial for the survival of patients after surgery for early-stage endometrial cancer. We analyzed the outcomes of patients treated with radiotherapy, chemotherapy, or progestagen combined with other adjuvant treatments. Methods: We retrospectively examined disease-free survival (DFS), overall survival (OS) and high risk factors that affected the survival status of all patients who received different postoperative adjuvant therapies. Results: The total relapse and mortality rates were 5.57% and 1.68%, respectively. During follow-up period, fourteen patients (7.29%) developed isolated local recurrence, and 2 patients died (1.04%) of recurrence. The 5-year DFS and OS rates in all patients were 95.83% and 93.75%, respectively. No significant differences were observed in the 5-year DFS, 5-year OS, OS, or DFS among the four groups of patients with FIGO stage I endometrial cancer. The differences in the log-rank test results of the estimates of the 5-year DFS, 5-year OS, DFS and OS of patients with different disease stages and different ages were all significant, but no differences were observed in these parameters between patients with varying degrees of differentiation. Histologic grade, CA125 level, ER and PR status and whether adjuvant therapies had no significant effect on the DFS and OS of all patients according to univariate and multivariate regression analyses, but age stratification did reveal significant differences in DFS and OS in the univariate and multivariate analyses. Conclusion: This retrospective study showed that adjuvant treatments after surgery were not significantly associated with improved DFS or OS in patients with early-stage endometrial cancer. However, FIGO stage and age affected the survival of patients with stage I endometrial cancer.

scholarly journals A metagene of NRF2 expression is a prognostic biomarker in all stage colorectal cancer

2019 ◽  
Author(s):  
Séan M. O’Cathail ◽  
Chieh-Hsi Wu ◽  
Annabelle Lewis ◽  
Chris Holmes ◽  
Maria A Hawkins ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Poor Prognosis ◽  
Prognostic Biomarker ◽  
Molecular Taxonomy ◽  
Disease Free Survival ◽  
Stage Iv ◽  
Stage I ◽  
Braf V600e ◽  
Stage Iv Disease ◽  
Nrf2 Expression

ABSTRACTObjectiveNrf2 overexpression confers poor prognosis in some cancers but its role in colorectal cancer (CRC) is unknown. Due to its role as a transcription factor we hypothesise a metagene of NRF2 regulated genes could act as a prognostic biomarker in CRC.DesignUsing known NRF2 regulated genes, we defined an NRF2 metagene to represent the pathway expression using principal component analysis and Cox proportional hazard models. The NRF2 metagene was validated in four independent datasets, including the recently profiled MRC FOCUS randomised controlled trial.Results36 genes comprised the final prognostic metagene in the training set. 1,360 patients were included in the validation analyses. High NRF2 metagene expression is associated with worse disease free survival (DFS) and overall survival (OS) outcomes in stage I/II/III disease and worse OS in stage IV disease. In multivariate analyses, NRF2 expression remained significant when adjusted for known prognostic factors of adjuvant chemotherapy and stage in stage I/II/III disease, as well as BRAF V600E mutation and sidedness in stage IV disease. NRF2 metagene expression exhibits variation within each of the Consensus Molecular Subtypes (CMS) but high expression is particularly enriched in CMS 4.ConclusionWe demonstrate in a large scale analysis that NRF2 expression is a novel biomarker of poor prognosis across all stages of colorectal cancer. Higher expression observed in CMS 4 further refines the molecular taxonomy of colorectal cancer.

Prevalence of BRAF gene mutation in Thai sporadic colorectal cancer patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14051-e14051
Author(s):  
Krittiya Korphaisarn ◽  
Ekkapong Roothumnong ◽  
Akarin Nimmannit ◽  
Chanin Limwongse ◽  
Ananya Manuyakorn ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gene Mutation ◽  
Braf Mutation ◽  
Prognostic Value ◽  
Braf V600e Mutation ◽  
Stage I ◽  
Braf V600e ◽  
Braf Gene ◽  
Primary Tumors ◽  
Caucasian Patients

e14051 Background: The role of BRAF gene mutation has been studied for its association with prognosis of colorectal cancer (CRC). The prevalence was reported 10-15% in Caucasian patients. However, there is no existing data in Thai patients. This study aimed to determine the prevalence of BRAF V600E mutation, association with various clinicopathological features and outcome in Thai sporadic CRC patients. Methods: DNA was extracted from randomly selected formalin-fixed paraffin-embedded tumor blocks of CRC patients with stage I-IV receiving surgery of the primary tumors at Siriraj Hospital between 2006 and 2007. BRAF V600E mutation was performed by two-round allele-specific PCR and analysis using high sensitivity DHPLC. The association between patient characteristics and BRAF status with overall survival (OS) and disease free survival (DFS) were explored by Kaplan-Meier estimation and log-rank test together with Cox’s proportional hazard regression. Results: BRAF V600E mutation was identified in 7 out of 188 patients (3.7%). Four patients were female. There were more likely to found in tumors on the left side (n=4) compared with right side (n=2) and rectum (n=1). All patients with mutation had stage I-III diseases; one with stage I and 3 with stage II and III each. Four had moderately differentiated tumors. Six patients had neither lymphovascular nor perineural invasion. Patients with mutation seemed to have better survival. In multivariate analysis, BRAF mutation did not have major prognostic value regarding DFS or OS. Conclusions: The prevalence of BRAF V600E mutation in Thai sporadic CRC was 3.7% which was lower than what reported in Caucasian patients. Further study with larger number of patients is warranted to determine whether BRAF mutation has significant prognostic value.

Pilocytic Astrocytoma: A Review of General, Clinical, and Molecular Characteristics

2020 ◽  
Vol 35 (12) ◽  
pp. 852-858
Author(s):  
Débora Salles ◽  
Gabriela Laviola ◽  
Andréa Cristina de Moraes Malinverni ◽  
João Norberto Stávale
Keyword(s):  
Tumor Development ◽  
Diagnostic Methods ◽  
Braf V600e ◽  
Molecular Diagnostic ◽  
Molecular Characteristics ◽  
Primary Tumors ◽  
Molecular Alterations ◽  
Pilocytic Astrocytomas ◽  
Polymerase Chain

Pilocytic astrocytomas are the primary tumors most frequently found in children and adolescents, accounting for approximately 15.6% of all brain tumors and 5.4% of all gliomas. They are mostly found in infratentorial structures such as the cerebellum and in midline cerebral structures such as the optic nerve, hypothalamus, and brain stem. The present study aimed to list the main characteristics about this tumor, to better understand the diagnosis and treatment of these patients, and was conducted on search of the published studies available in NCBI, PubMed, MEDLINE, Scielo, and Google Scholar. It was possible to define the main histologic findings observed in these cases, such as mitoses, necrosis, and Rosenthal fibers. We described the locations usually most affected by tumor development, and this was associated with the most frequent clinical features. The comparison between the molecular diagnostic methods showed great use of fluorescent in situ hybridization, polymerase chain reaction (PCR), and reverse transcriptase–PCR, important techniques for the detection of BRAF V600E mutation and BRAF-KIAA1549 fusion, characteristic molecular alterations in pilocytic astrocytomas.

scholarly journals Disease Free Survival of Stage I Endometrial Cancer after Surgery with or without Adjuvant Treatment

2021 ◽  
Vol 55 (1) ◽  
pp. 37
Author(s):  
Woraluk Moradokkasem ◽  
Nungrutai Saeaib ◽  
Tippawan Liabsuetrakul
Keyword(s):  
Endometrial Cancer ◽  
Adjuvant Treatment ◽  
Disease Free Survival ◽  
Myometrial Invasion ◽  
Stage I ◽  
Rank Test ◽  
Free Survival ◽  
Factors Associated ◽  
Disease Free ◽  
Better Than

This study aimed to define the disease free survival (DFS) and factors associated with recurrence in stage I endometrial cancer after surgery with and without adjuvant treatment. The demographic data, pathological results, adjuvant treatment (AT) and the outcome of patients with endometrial cancer stage I after surgery in Songklanagarind Hospital between January 2002 and July 2014 were collected. The DFS was analyzed by survival analysis and represented by Kaplan–Meier curves. The difference of DFS between AT and non-adjuvant treatment (NAT) groups was tested by the log-rank test. Distributions of risk factors by AT and recurrent status were analyzed using chi-square or Fisher exact tests for discrete factors, and unpaired t or Wilcoxon rank-sum tests for continuous factors. The 5-year DFS was; 91.6%, from a total of 268 patients. DFS in the NAT group was significantly better than that in the AT group (95.2 versus 86.5%, p-value = 0.01). Factors associated with recurrence in the NAT group were age, tumor grading, tumor size, and presence of lymphovascular involvement. Among the AT group, age and ratio of myometrial invasion were associated with recurrence. DFS in NAT was better than in AT and the potential factors associated with recurrence, after surgery with or without AT, were not the same.

scholarly journals Disease Free Survival of Stage I Endometrial Cancer after Surgery with or without Adjuvant Treatment

2019 ◽  
Vol 55 (1) ◽  
pp. 37
Author(s):  
Woraluk Moradokkasem ◽  
Nungrutai Saeaib ◽  
Tippawan Liabsuetrakul
Keyword(s):  
Endometrial Cancer ◽  
Adjuvant Treatment ◽  
Disease Free Survival ◽  
Myometrial Invasion ◽  
Stage I ◽  
Rank Test ◽  
Free Survival ◽  
Factors Associated ◽  
Disease Free ◽  
Better Than

This study aimed to define the disease free survival (DFS) and factors associated with recurrence in stage I endometrial cancer after surgery with and without adjuvant treatment. The demographic data, pathological results, adjuvant treatment (AT) and the outcome of patients with endometrial cancer stage I after surgery in Songklanagarind Hospital between January 2002 and July 2014 were collected. The DFS was analyzed by survival analysis and represented by Kaplan–Meier curves. The difference of DFS between AT and non-adjuvant treatment (NAT) groups was tested by the log-rank test. Distributions of risk factors by AT and recurrent status were analyzed using chi-square or Fisher exact tests for discrete factors, and unpaired t or Wilcoxon rank-sum tests for continuous factors. The 5-year DFS was; 91.6%, from a total of 268 patients. DFS in the NAT group was significantly better than that in the AT group (95.2 versus 86.5%, p-value = 0.01). Factors associated with recurrence in the NAT group were age, tumor grading, tumor size, and presence of lymphovascular involvement. Among the AT group, age and ratio of myometrial invasion were associated with recurrence. DFS in NAT was better than in AT and the potential factors associated with recurrence, after surgery with or without AT, were not the same.

Multifactorial prospective study of tumoral factors related to disease-free survival (DFS) in colorectal cancer patients

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3604-3604
Author(s):  
G. Milano ◽  
M. Francoual ◽  
A. Bourgeon ◽  
D. Benchimol ◽  
M. Chazal ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Methylenetetrahydrofolate Reductase ◽  
Tumor Staging ◽  
Dihydropyrimidine Dehydrogenase ◽  
Tumor Resection ◽  
Disease Free Survival ◽  
Normal Mucosa ◽  
Proximal Colon ◽  
Intron 1 ◽  
Cox Analysis

3604 Background: There is still a need to identify faithful biological prognostic factors in colorectal cancer, particularly in stage 2, so as to decide upon adjuvant treatment. We thus conducted a prospective multicentric multifactorial study to this end. Methods: Primary colorectal tumors (30 stage 1, 119 stage 2, 107 stage 3) were prospectively collected in 256 patients undergoing total tumor resection (152 men, 104 women ; mean age 69, extremes 29–90). Adjuvant 5FU-based chemotherapy was administered in 92 patients. Median follow-up was 54 months (53 patients developed metastasis or recurrence). Tumors were analyzed for thymidylate synthase (TS), thymidine phosphorylase and dihydropyrimidine dehydrogenase expression (RT-PCR), TS activity (radioenzymatic assay), EGFR level (ligand-binding assay), VEGF (Elisa), DNA content and cell cycle (flow cytometry), p53 mutations (exon 4 to 8), microsatellite instability (bat 25, bat 26), EGFR genotype (CA repeats in intron 1 and -216G>T), TS genotype in 3’ (6 bp deletion) and 5’ (28 bp repeats including the G>C mutation), and methylenetetrahydrofolate reductase genotype (677C>T and 1298A>C). Results: With the exception of tumor TS expression (p = 0.034, the higher the expression, the better the DFS), none of the analyzed parameters were linked to DFS. In multivariate Cox analysis, tumor staging (p = 0.001) and TS expression (p = 0.062) were the sole factors associated to DFS. Focus on tumoral EGFR revealed large inter-patient variability (from 1 to 510 fmol/mg prot) with a significant influence of tumor localisation (p = 0.009, higher in proximal colon) and differentiation status (p = 0.01, higher in poorly differentiated tumors). EGFR within the tumors was 30 % lower than in adjacent normal mucosa (p<0.001). The longer the intron 1 CA repeats, the higher the tumor EGFR (p = 0.044). EGFR -216G>T polymorphism was linked to intron 1 polymorphism, although -216G>T did not influence EGFR levels. Conclusions: The present results underline the major impact of TS expression as a prognostic factor and provide new insights in the knowledge of EGFR in colorectal cancer. No significant financial relationships to disclose.

Role of Radical Surgery in Early Stages of Vaginal Cancer—Our Experience

2016 ◽  
Vol 26 (6) ◽  
pp. 1176-1181 ◽  
Author(s):  
Vandana Jain ◽  
Rupinder Sekhon ◽  
Shveta Giri ◽  
Rashmi Rekha Bora ◽  
Kanika Batra ◽  
...  
Keyword(s):  
Adjuvant Treatment ◽  
Radical Surgery ◽  
Disease Free Survival ◽  
International Federation ◽  
Stage I ◽  
Vaginal Cancer ◽  
Free Survival ◽  
Gynecology And Obstetrics ◽  
Disease Free

ObjectivesThe objective of our present study was to evaluate the efficacy of radical vaginectomy with or without radical hysterectomy in patients with International Federation of Gynecology and Obstetrics stage I and II vaginal cancers.Materials and MethodsA retrospective study was carried out on 11 patients aged 35 to 78 years. All the patients underwent radical surgery for vaginal cancer from April 2010 till June 2015. Kaplan-Meier analyses were used to calculate the disease-free survival and overall survival at 12 months.ResultsThe mean age of patients was 53.2 years. Ten patients were with International Federation of Gynecology and Obstetrics stage I, whereas one had stage II vaginal cancer. The histology was squamous cell cancer in 9 patients and small cell neuroendocrine cancer in 2 patients. The lesion was confined to the upper two third of the vagina in 8 cases, and the lower one third was involved in 3 cases. All the patients underwent radical surgery. Lymph node dissection was done in 9 patients out of whom lymph nodes were positive in 3 patients. Two patients had positive margins. Adjuvant treatment was given to patients with positive margins or positive nodes. Five patients did not require any adjuvant treatment, and 1 patient defaulted adjuvant treatment. One patient developed vesicovaginal fistula. Over a follow-up period ranging from 5 to 67 months, local recurrence developed in 1 patient, whereas no patient died of disease. One patient was lost to follow-up at 15 months. The 12-month disease-free survival was 88.9%, and 12-month overall survival was 100%.ConclusionsStage I and selected stage II vaginal cancer patients have good outcomes in terms of survival and local tumor control if managed judiciously by initial surgery followed by selective adjuvant therapy.

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