Efficacy of concurrent chemoradiotherapy in subgroups of stage III nasopharyngeal carcinoma: an analysis based on 10-year follow-up

Abstract Purpose To evaluate the efficacy of concurrent chemoradiotherapy (CCRT) in subgroups of stage III nasopharyngeal carcinoma (NPC) in the context of intensity-modulated radiotherapy (IMRT). Methods A total of 272 patients with stage III NPC who underwent IMRT with or without concurrent chemotherapy were retrospectively reviewed. Clinicopathological features were evaluated by a Cox regression model to identify independent prognostic factors. Survival outcomes were assessed using the Kaplan–Meier method and log-rank test. Results The median follow-up time was 108 months. The 10-year locoregional-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates were 87.8%, 80.7%, 68.8%, and 74.9%, respectively. Multivariate analysis showed that the N classification was significantly associated with DMFS (hazard ratio [HR] 3.616, 95% confidence interval [CI] 1.387–9.428, P = 0.009), DFS (HR 2.417, 95% CI 1.291–4.423, P = 0.006), and OS (HR 3.024, 95% CI 1.385–6.602, P = 0.005). In patients with T1-3N2 disease, CCRT was associated with improved 10-year LRFS (89.6% vs. 65.4%, P = 0.005), DFS (71.9% vs. 39.4% P = 0.001) and OS (80.0% vs. 50.5%, P = 0.004) compared with IMRT alone. However, in patients with T3N0-1 disease, no significant survival differences were observed between patients treated with IMRT alone and CCRT (P > 0.05). Conclusions CCRT is an effective therapy in stage III NPC, especially for patients with N2 disease, but IMRT alone may be adequate for N0-1 disease. Individualized treatment strategies are essential for patients with varying disease risks.

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Efficacy of Concurrent Chemoradiotherapy In Subgroups of Stage III Nasopharyngeal Carcinoma: An Analysis Based On 10-Year Follow-Up

10.21203/rs.3.rs-682419/v1 ◽

2021 ◽

Author(s):

Lei Wang ◽

Wu Zheng ◽

Wanqin Cheng ◽

Dehuan Xie ◽

Feifei Lin ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Concurrent Chemoradiotherapy ◽

Cox Regression ◽

Disease Free Survival ◽

Concurrent Chemotherapy ◽

Stage Iii ◽

Rank Test ◽

Free Survival ◽

N2 Disease

Abstract PurposeTo evaluate the efficacy of concurrent chemoradiotherapy (CCRT) in subgroups of stage III nasopharyngeal carcinoma (NPC) in the context of intensity-modulated radiotherapy (IMRT).Methods272 patients with stage III NPC who underwent IMRT with or without concurrent chemotherapy (CCT) were retrospectively reviewed. Clinicopathological features were evaluated by a Cox regression model to identify independent prognostic factors. Survival outcomes were assessed using Kaplan-Meier method and log-rank test.ResultsThe median follow-up time was 108 months. The 10-year locoregional-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates were 87.8%, 80.7%, 68.8%, and 74.9%, respectively. Multivariate analysis showed that the N classification was significantly associated with DMFS (hazard ratio [HR] 3.616, 95% confidence interval [CI] 1.387-9.428, P=0.009), DFS (HR 2.417, 95% CI 1.291-4.423, P=0.006), and OS (HR 3.024, 95% CI 1.385-6.602, P=0.005). In patients with T1-3N2 disease, CCRT was associated with improved 10-year LRFS (89.6% vs. 65.4%, P=0.005), DFS (71.9% vs. 39.4%, P=0.001) and OS (80.0% vs. 50.5%, P=0.004) compared with IMRT alone. However, in patients with T3N0-1 disease, no significant survival differences were observed between patients treated with IMRT alone and CCRT (P>0.05). ConclusionCCRT is an effective therapy in stage III NPC, especially for patients with N2 disease but N0-1 disease. Individualized treatment strategies are essential for patients with varying disease risks.

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An open-labeled, multicentric clinical study of cetuximab combined with intensity-modulated radiotherapy (IMRT) plus concurrent chemotherapy in locoregionally advanced (LA) nasopharyngeal carcinoma (NPC): A 2-year follow-up report.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.5535 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 5535-5535 ◽

Cited By ~ 3

Author(s):

Chun-yan Chen ◽

Chong Zhao ◽

Li Gao ◽

Jin-yi Lang ◽

Jian-ji Pan ◽

...

Keyword(s):

Overall Survival ◽

Disease Free Survival ◽

Concurrent Chemotherapy ◽

Stage Iii ◽

Chinese Patients ◽

Recurrence Free Survival ◽

Spontaneous Bleeding ◽

Cervical Lymph Nodes ◽

Free Survival

5535 Background: To evaluate the safety and efficacy outcomes of concurrent cetuximab plus IMRT and cisplatin in Chinese patients with LA NPC. Methods: Patients with primary stage III-IVb (UICC/AJCC 2002 staging system) and non-keratinizing NPC were enrolled in this prospective, multicentric, phase II study. Cisplatin (80mg/m2,q3week) and cetuximab (400mg/m2 one w before radiation, and then 250mg/m2/w) were given concurrently. The prescription dose of IMRT to GTVnx (primary tumor in nasopharynx) was 66 Gy - 75.9 Gy, GTVnd (positive cervical lymph nodes) was 60 Gy - 70Gy, The response rate was evaluated according to RECIST 1.0 criteria, and adverse events (AEs) were graded according to NCI CTCAE V3.0 criteria. Results: From July 2008 to April 2009, 100 patients were enrolled (74 male), with median age of 43 years. The proportion of stage III, IVa and IVb patients were 71%, 22% and 7% respectively. 99% of enrolled patients completed the planned treatment. AEs were within the expected range and manageable. No toxic death occurred during the treatment. Acneiform skin eruptions, mucositis, in-field dermatitis, xerostomia and neucopenia were the most common seen AEs, with 64% grade 2/3 acneiform eruptions, 26% grade 2/3 in-field dermatitis, 90% ≥ grade 2 mucositis (2 cases of grade 4 mucositis with spontaneous bleeding), 40% ≥ grade 2 xerostomia and 8% grade 2/3 neucopenia. With a median follow-up time of 23.5 months, the 2 year overall survival (OS), disease-free survival (DFS), local recurrence-free survival, regional (cervical lymph node) recurrence free survival and distant metastasis-free survival rates for the ITT population were 91%, 89%, 90%, 90% and 89%, respectively Multivariate analysis showed that N stage was the only prognostic factor for OS (p=0.0392, HR=2.946) and DFS (p=0.0062, HR=4.246) in these patients. Conclusions: Cetuximab combined with IMRT plus concurrent cisplatin in patients with LA NPC shows satisfactory 2-year locoregional control rate and 2-year overall survival. The combination seems to be well tolerated with a manageable side-effect profile.

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Phase III Study of Concurrent Chemoradiotherapy Versus Radiotherapy Alone for Advanced Nasopharyngeal Carcinoma: Positive Effect on Overall and Progression-Free Survival

Journal of Clinical Oncology ◽

10.1200/jco.2003.06.158 ◽

2003 ◽

Vol 21 (4) ◽

pp. 631-637 ◽

Cited By ~ 501

Author(s):

Jin-Ching Lin ◽

Jian-Sheng Jan ◽

Chen-Yi Hsu ◽

Wen-Miin Liang ◽

Rong-San Jiang ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Concurrent Chemoradiotherapy ◽

Combined Treatment ◽

Survival Rates ◽

Progression Free Survival ◽

Patient Characteristics ◽

Concurrent Chemotherapy ◽

Phase Iii ◽

Rank Test ◽

Free Survival

Purpose: Nasopharyngeal carcinoma (NPC) is a radiosensitive and chemosensitive tumor. This randomized phase III trial compared concurrent chemoradiotherapy (CCRT) versus radiotherapy (RT) alone in patients with advanced NPC. Patients and Methods: From December 1993 to April 1999, 284 patients with 1992 American Joint Committee on Cancer stage III to IV (M0) NPC were randomly allocated into two arms. Similar dosage and fractionation of RT was administered in both arms. The investigational arm received two cycles of concurrent chemotherapy with cisplatin 20 mg/m2/d plus fluorouracil 400 mg/m2/d by 96-hour continuous infusion during the weeks 1 and 5 of RT. Survival analysis was estimated by the Kaplan-Meier method and compared by the log-rank test. Results: Baseline patient characteristics were comparable in both arms. After a median follow-up of 65 months, 26.2% (37 of 141) and 46.2% (66 of 143) of patients developed tumor relapse in the CCRT and RT-alone groups, respectively. The 5-year overall survival rates were 72.3% for the CCRT arm and 54.2% for the RT-only arm (P = .0022). The 5-year progression-free survival rates were 71.6% for the CCRT group compared with 53.0% for the RT-only group (P = .0012). Although significantly more toxicity was noted in the CCRT arm, including leukopenia and emesis, compliance with the combined treatment was good. The second cycle of concurrent chemotherapy was refused by nine patients and was delayed for ≥ 1 week for another nine patients. There were no treatment-related deaths in either arm. Conclusion: We conclude that CCRT is superior to RT alone for patients with advanced NPC in endemic areas.

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NCIC CTG MA.17: Intent to treat analysis (ITT) of randomized patients after a median follow-up of 54 months

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.549 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 549-549 ◽

Cited By ~ 6

Author(s):

J. Ingle ◽

D. Tu ◽

L. Shepherd ◽

M. Palmer ◽

J. Pater ◽

...

Keyword(s):

Cox Regression ◽

Menopausal Status ◽

Disease Free Survival ◽

Rank Test ◽

Free Survival ◽

Before And After ◽

Intent To Treat ◽

Treat Analysis ◽

Better Than

549 Background: MA.17 evaluated letrozole (LET) or placebo (PLAC) after 5 years of tamoxifen (Tam) and showed [median follow-up 30 months (mos)] significant improvement in disease-free survival (DFS) for LET [hazard ratio (HR) 0.57, p = 0.00008]. The trial was unblinded and PLAC patients (pts) were offered LET. An ITT analysis of all outcomes, before and after unblinding, based on the original randomization was performed. Methods: A stratified log-rank test was used to compare DFS, distant (D)DFS, overall survival (OS) and incidence of contra-lateral breast cancer (CBC). The Cox regression model used baseline stratification variables and two prespecified factors, menopausal status at the start of Tam and time on Tam. Subgroup analyses for DFS and OS were performed for the two prespecified subsets. All p-values were two-sided Results: 5187 pts were randomized at baseline and, at unblinding, 1655 of 2268 PLAC pts accepted LET. At median follow-up of 54 mos (range,16–86) 363 recurrences or CBC’s (144 LET and 219 PLAC) occurred; 118 LET and 176 PLAC pts had recurrent disease and 26 LET and 43 PLAC pts had CBC. 4 year DFS was 94.3% (LET) and 91.4% (PLAC) (HR 0.64; 95% CI, 0.52 - 0.79; p = 0.00002). Corresponding 4 year DDFS was 96.2% and 94.9% (HR 0.76; 0.58–0.99; p = 0.041). 4 year OS was 95.0% (LET) and 95.1% (PLAC) (HR 1.00; 0.78–1.28; p = 0.99). LET was equally effective in node +ve and -ve pts (i.e., similar HRs) in DFS. OS was not significantly different for LET and PLAC in any subgroup. The annual rate of CBC was 0.29% LET (0.18–0.40) and 0.47% PLAC (0.34–0.61); HR 0.61 (0.38–0.98) p = 0.037. 255 pts had died as of the data cut-off (128 LET and 127 PLAC). Conclusions: In this ITT analysis, pts originally randomized to LET within 3 months of stopping Tam did better than PLAC pts in DFS, DDFS and CBC, despite 73% of PLAC pts crossing to LET after unblinding. This highlights the strong beneficial effect of extended adjuvant therapy with LET. [Table: see text]

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Adjuvant Chemotherapy Following Combined Induction Chemotherapy and Concurrent Chemoradiotherapy Improves Survival in N2-3-positive Nasopharyngeal Carcinoma Patients

10.21203/rs.3.rs-848732/v1 ◽

2021 ◽

Author(s):

Hao-Yun Tao ◽

Hui Liu ◽

Cai-Xian He ◽

Ran Li ◽

Kun-Peng Du ◽

...

Keyword(s):

Adjuvant Chemotherapy ◽

Nasopharyngeal Carcinoma ◽

Induction Chemotherapy ◽

Distant Metastasis ◽

Concurrent Chemoradiotherapy ◽

Cox Regression ◽

Disease Free Survival ◽

Clinical Value ◽

Free Survival ◽

Kaplan Meier

Abstract Objective: This study aimed to explore the clinical value of adjuvant chemotherapy (ACT) in locoregionally advanced nasopharyngeal carcinoma (LANC) following concurrent chemoradiotherapy (CCRT) and induction chemotherapy (ICT).Methods: We included 839 newly diagnosed LANC patients in the study. ICT plus CCRT (ICT+CCRT group) was administered to 443 patients and 396 patients who received ACT after receiving ICT plus CCRT (ICT+CCRT+ACT group). Univariate and multivariate Cox regression analyses were carried out in this study. Furthermore, to balance the study and control groups, propensity score matching (PSM) was applied.Results: 373 pairs of LANC patients were obtained after the PSM analysis. We found that ACT following ICT+CCRT had no significant effect on improving the survival of LANC patients. By further exploring the ICT+CCRT+ACT regimen, we excluded N0-1-positive patients and performed PSM in the ICT+CCRT and ICT+CCRT+ACT groups again. Each group consisted of 237 patients. Kaplan-Meier analysis revealed that there was a difference between the ICT+CCRT and ICT+CCRT+ACT groups in terms of the 5-year overall survival (OS) (78.9% vs. 85.0%, P = 0.034), disease-free survival (DFS) (73.4% vs. 81.7%, P = 0.029), and distant metastasis-free survival (DMFS) (84.9% vs. 76.0%, P = 0.019). In addition, the ICT+CCRT+ACT group had a higher incidence of grade 3-4 acute leukocytopenia/neutropenia.Conclusion: Compared with ICT+CCRT, ACT following ICT plus CCRT can reduce distant metastasis of N2-3-positive LANC and improve the OS and DFS of these patients, thus demonstrating higher clinical feasibility.

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The Clinical Outcomes and Toxicities of Induction Chemotherapy Followed by Concurrent Chemoradiotherapy Plus Adjuvant Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2020.619625 ◽

2021 ◽

Vol 10 ◽

Author(s):

Rui Zou ◽

Jing-Jing Yuan ◽

Qiang Li ◽

Jian-Wu Ding ◽

Bing Liao ◽

...

Keyword(s):

Adjuvant Chemotherapy ◽

Nasopharyngeal Carcinoma ◽

Adverse Events ◽

Induction Chemotherapy ◽

Concurrent Chemoradiotherapy ◽

Disease Free Survival ◽

Free Survival ◽

Grade 3 ◽

Disease Free

PurposeTo analyze the outcomes and toxicities of induction chemotherapy (ICT) followed by concurrent chemoradiotherapy (CCRT) plus adjuvant chemotherapy (ACT) in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC).MethodsRetrospective analysis of 163 patients with LA-NPC referred from August 2015 to December 2018 was carried out. All patients underwent platinum-based ICT followed by CCRT plus ACT.ResultsThe median follow-up time was 40 months, ranging from 5 to 69 months. The 3-year disease-free survival (DFS), overall survival (OS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) rates were 80.8, 90.0, 91.6, and 87.4%, respectively. The most frequent acute grade 3/4 adverse events were leukopenia (66.8%), neutropenia (55.8%), mucositis (41.1%), thrombocytopenia (27.0%), and anemia (14.7%).ConclusionICT followed by CCRT plus ACT did not seemingly enhance DFS and OS in LA-NPC patients compared to the addition of ICT to CCRT (historical controls). In contrast, ICT followed by CCRT plus ACT had more acute adverse events than ICT followed by CCRT. Longer-term clinical studies are required to examine the treatment outcomes and late toxicities.

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Association of immune markers and Immunoscore with survival of stage III colon carcinoma (CC) patients (pts) treated with adjuvant FOLFOX: NCCTG N0147 (Alliance).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3579 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3579-3579 ◽

Cited By ~ 8

Author(s):

Frank A. Sinicrope ◽

Qian Shi ◽

Fabienne Hermitte ◽

Erica N Heying ◽

Al Bowen Benson ◽

...

Keyword(s):

B Lymphocyte ◽

Cox Regression ◽

Disease Free Survival ◽

Tumor Infiltrating Lymphocytes ◽

Stage Iii ◽

Immune Markers ◽

Free Survival ◽

Resected Stage ◽

Infiltrating Lymphocytes

3579 Background: Tumor infiltrating lymphocytes (TIL) indicate a host immune response that may influence survival. Immunoscore was developed using CD3+ and CD8+density and location in primary CC pts with pooled stages, varying treatment and follow-up. We determined if individual immune markers and/or Immunoscore are prognostic in resected stage III CC pts (N=600). Methods: CD3+ and CD8+ T-cell or CD20+ B lymphocyte density in central tumor (CT) and invasive margin (IM) was evaluated by immunostaining and quantified by image analysis. Immunoscore was calculated on a scale of I0 to I4 with high densities of CD3+ and CD8+in both CT and IM scored as I4; low densities scored as I0. Associations with disease-free survival (DFS) were evaluated by multivariable Cox regression adjusting for covariates. Results: Data for CD3+, CD8+ and CD20+ were generated (N=595). Higher density of CD3+ CT, CD3+ IM and CD8+ IM were associated with longer DFS adjusting for covariates (Table). CD3+ IM had the strongest association with DFS, and was stronger in left-sided (HRadj.=0.81, 95% CI, 0.70-0.94, padj.= 0.0049) vs right-sided (HRadj.=0.93, 95% CI, 0.85-1.0 padj.=0.52) tumors (pinteraction=0.039). Higher density of CD3+ IM was associated with older age (p=0.034), T1/2 (p<.0001), N1 (p=0.017), right-sided (p=0.013), high TILs (p=0.0008), and deficient MMR (p=0.0003). Using a prior Immunoscore risk stratification, higher scores were associated with better DFS (HR.=0.62, CI, 0.44-0.87, p=0.006) (Table). Conclusions: Densities of CD3+ and CD8+, especially at IM, are individually prognostic in FOLFOX-treated pts. Association of CD3+IM with prognosis differed by primary CC site. Immunoscore was strongly prognostic, and this result provides validation in a clinical trial cohort. [Table: see text]

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A Nomogram Based on Serum Biomarkers and Clinical Characteristics to Predict Survival in Patients With Non-Metastatic Nasopharyngeal Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2020.594363 ◽

2020 ◽

Vol 10 ◽

Author(s):

Qing-Jie Li ◽

Yan-Ping Mao ◽

Rui Guo ◽

Cheng-Long Huang ◽

Xue-Liang Fang ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Cox Regression ◽

Disease Free Survival ◽

Staging System ◽

Tnm Staging ◽

Concurrent Chemotherapy ◽

Free Survival ◽

Cox Regression Analysis ◽

Tnm System ◽

Hemoglobin C

ObjectiveThis study focused on developing an effective nomogram for improving prognostication for patients with primary nasopharyngeal carcinoma (NPC) restaged according to the eighth edition of the AJCC/UICC TNM staging system.MethodsBased on data of 5,903 patients with non-metastatic NPC (primary cohort), we used Cox regression analysis to identify survival risk factors and created a nomogram. We used the nomogram to predict overall survival (OS), distant metastasis-free survival (DMFS) and disease-free survival (DFS) in the primary and independent validation (3,437 patients) cohorts. Moreover, we compared the prognostic accuracy between the 8th TNM system and the nomogram.ResultsThe nomogram included gender, age, T stage, N stage, Epstein–Barr virus DNA, hemoglobin, C-reactive protein, lactate dehydrogenase, and radiotherapy with/without induction or concurrent chemotherapy. In the prediction of OS, DMFS and DFS, the nomogram had significantly higher concordance index (C-index) and area under ROC curve (AUC) than the TNM system alone. Calibration curves demonstrated satisfactory agreements between nomogram-predicted and observed survival. The stratification in different groups permitted remarkable differentiation among Kaplan–Meier curves for OS, DMFS, and DFS.ConclusionThe nomogram led to a more precise prognostic prediction for NPC patients in comparison with the 8th TNM system. Therefore, it could facilitate individualized and personalized patients’ counseling and care.

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Pituitary surgery as alternative to dopamine agonists treatment for microprolactinomas, a cohort study

Acta Endocrinologica ◽

10.1530/eje-21-0293 ◽

2021 ◽

Author(s):

Bertrand Baussart ◽

Chiara Villa ◽

Anne Jouinot ◽

Marie-Laure Raffin-Sanson ◽

Luc Foubert ◽

...

Keyword(s):

Dopamine Agonists ◽

Cox Regression ◽

Disease Free Survival ◽

Pituitary Surgery ◽

Cerebrospinal Fluid Leakage ◽

Neurosurgical Department ◽

Free Survival ◽

Kaplan Meier ◽

Disease Free

Objective: Microprolactinomas are currently treated with dopamine agonists. Outcome information on microprolactinoma patients treated by surgery is limited. This study reports the first large series of consecutive non-invasive microprolactinoma patients treated by pituitary surgery and evaluates the efficiency and safety of this treatment. Design: Follow-up of a cohort of consecutive patients treated by surgery. Methods: Between January 2008 and October 2020, 114 adult patients with pure microprolactinomas were operated on in a single tertiary expert neurosurgical department, using an endoscopic endonasal transsphenoidal approach. Eligible patients were presenting a microprolactinoma with no obvious cavernous invasion on MRI. Prolactin was assayed before and after surgery. Disease-free survival was modeled using Kaplan-Meier representation. A cox regression model was used to predict remission. Results: Median follow-up was 18.2 months (range: 2.8 to 155). In this cohort, 14/114 (12%) patients were not cured by surgery, including 10 early surgical failures, and 4 late relapses occurring 37.4 months (33 to 41.8) after surgery. From Kaplan Meier estimates, 1-year and 5-year disease free survival were 90.9% (95% CI, 85.6%-96.4%) and 81% (95% CI,71.2%-92.1%) respectively. The preoperative prolactinemia was the only significant preoperative predictive factor for remission (P<0.05). No severe complication was reported, with no anterior pituitary deficiency after surgery, one diabetes insipidus, and one postoperative cerebrospinal fluid leakage properly treated by muscle plasty. Conclusions: In well selected microprolactinoma patients, pituitary surgery performed by an expert neurosurgical team is a valid first-line alternative treatment to dopamine agonists.

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Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer

10.1093/med/9780199384075.003.0011 ◽

2017 ◽

Author(s):

Kelly McLeon

Keyword(s):

Colon Cancer ◽

Adjuvant Treatment ◽

Disease Free Survival ◽

Stage Iii ◽

Reference Standard ◽

Free Survival ◽

Stage Iii Colon Cancer ◽

Study Intervention ◽

Disease Free

The landmark MOSAIC trial examined whether the addition of oxaliplatin to a postoperative adjuvant treatment regimen of fluorouracil and leucovorin affected disease-free survival from colon cancer. The MOSAIC trial established the efficacy of FOLFOX over 5-FU/LV as adjuvant treatment for stage III colon cancer and established FOLFOX4 as the reference standard for adjuvant treatment for stage III disease. This chapter describes the basics of the study, including funding, year study began, year study was published, study location, who was studied, who was excluded, how many patients, study design, study intervention, follow-up, endpoints, results, and criticism and limitations. The chapter briefly reviews other relevant studies and information, gives a summary and discusses implications, and concludes with a relevant clinical case.

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