scholarly journals Long-term follow-up of children with neuroblastoma receiving radiotherapy to metastatic lesions within the German Neuroblastoma Trials NB97 and NB 2004

2020 ◽  
Author(s):  
Danny Jazmati ◽  
Sarina Butzer ◽  
Barbara Hero ◽  
Jerome Doyen ◽  
Dalia Ahmad Khalil ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Primary Tumor ◽  
Secondary Malignancy ◽  
Primary Tumor Site ◽  
Free Survival ◽  
Stage 4 ◽  
Metastatic Sites ◽  
The Impact

Abstract Purpose Neuroblastoma (NB) is the most common extracranial solid malignancy during childhood. Despite a multimodal treatment approach, the prognosis of patients with metastatic NB is not satisfactory. Although radiotherapy (RT) has become an integral part of treatment of the primary tumor, the role of RT in osteomedullary lesions is not well defined. A retrospective analysis was conducted to evaluate the impact of RT for metastatic sites in children with high-risk NB. Methods All patients with stage 4 NB from the prospective, multicenter NB trials NB97 and NB2004 who received RT to metastatic sites during frontline treatment were included in this retrospective analysis. Results A total of 18 children were irradiated with a median dose of 36 Gray (Gy; range 20–45 Gy) to one or more (range 1–3) osteomedullary metastases with or without concomitant RT to the primary tumor site. The median follow-up time was 149 months (range 55–220) in survivors. At 5 years, local relapse-free survival (LRFS) at irradiated metastatic sites and metastases-free survival (MFS) at distant, non-irradiated site rates were 51.4 and 39.9%, respectively. The estimated overall survival (OS) rate at 5 years was 49.4%. No high-grade acute or late toxicity and no secondary malignancy was reported. Conclusion RT to metastases is feasible for patients with stage 4 NB. However, an impact of RT to residual metastatic sites on outcome was not found. Studies with larger cohorts or prospective trials would be desirable in order to elucidate the role of RT for metastases.

Role of Surgery in the Treatment of Patients With Stage 4 Neuroblastoma Age 18 Months or Older at Diagnosis

2013 ◽  
Vol 31 (6) ◽  
pp. 752-758 ◽  
Author(s):  
Thorsten Simon ◽  
Beate Häberle ◽  
Barbara Hero ◽  
Dietrich von Schweinitz ◽  
Frank Berthold
Keyword(s):  
Local Control ◽  
Primary Tumor ◽  
Tumor Resection ◽  
Local Control Rate ◽  
Complete Resection ◽  
Incomplete Resection ◽  
Primary Tumor Site ◽  
Free Survival ◽  
Stage 4 ◽  
The Impact

Purpose Although intensive multimodal treatment has improved the prognosis of patients with metastatic neuroblastoma, the impact of primary tumor resection on outcome is a matter of medical debate. Patients and Methods Patients from the German prospective clinical trial NB97 with stage 4 neuroblastoma and age 18 months or older at diagnosis were included. Operation notes and imaging reports were reviewed by two independent experienced physicians. Finally, the extent of tumor resections was correlated with local control rate and outcome. Results A total of 278 patients were included in this study. Image-defined risk factors present at diagnosis were found to be predictive for the extent of tumor resection at first (P < .001) and best (P < .001) operation. No patient died from surgery. Before chemotherapy, complete resection, incomplete resection, and biopsy or no surgery were performed in 6.1%, 5.0%, and 88.5% of patients, respectively. The extent of first operation had no impact on event-free survival (EFS; P = .207), local progression–free survival (LPFS; P = .195), and overall survival (OS; P = .351). After induction chemotherapy, 54.7% of patients underwent complete resection of the primary tumor, 30.6% underwent incomplete resection, and 13.3% had only biopsy or no surgery of the primary tumor. The extent of best operation also had no impact on EFS (P = .877), LPFS (P = .299), and OS (P = .778). Moreover, multivariate analyses showed that surgery did not affect EFS, LPFS, and OS. Conclusion In intensively treated patients with stage 4 neuroblastoma age 18 months or older at diagnosis, surgery of the primary tumor site has no impact on local control rate and outcome.

Sarcoligo: Impact of local ablative treatment of oligometastatic sarcomas on overall survival.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10042-10042
Author(s):  
Juliette Thariat ◽  
Laurence Moureau-Zabotto ◽  
Nicolas Penel ◽  
Antoine Italiano ◽  
Jacques-Olivier Bay ◽  
...  
Keyword(s):  
Overall Survival ◽  
Lung Metastases ◽  
Univariate Analysis ◽  
Survival Rates ◽  
Locoregional Treatment ◽  
Metastatic Sites ◽  
The Impact

10042 Background: 40-50% of sarcomas become metastatic. Median survival of metastatic patients has improved over time. The probably multifactorial reasons for such improvement are not fully clear. Noteworthy, for patients with a controlled primary and a limited number of lung metastases, complete resection of their metastases yields survival rates of up to 40% at three years. Advances in surgery, radiotherapy and radiofrequency have fostered the use of local treatments for various metastatic sites (lung, liver, spine...). Methods: A multicentric retrospective study of the Groupe Sarcome Francais (GSF-GETO); approved by the nationally-review board and ethical committee, was conducted to assess the impact of local ablative treatment on overall survival. Patients who had had oligometastases (any site, 1-5 synchronous metastases) at diagnostic or during the course of disease between 2000 and 2010 were included. Results: Median age of the 243 oligometastatic sarcoma patients was 53 years-old (11-86). Patients had grade I, II and III in 7.5%, 29.6% and 63.3% of cases, respectively with various histologies. 69% of patients underwent local ablative treatment of metastases. Median follow-up was 59 months (4-212) for living patients. Median overall survival was 51 months (1-348). On univariate analysis, grade, histology, absence of chemotherapy, local ablative treatment (surgery, irradiation, radiofrequency or chemoembolisation) correlated with survival but not age or site of oligometastasis. On multivariate analyses, grade (hazard ratio HR 0.12 [CI95 0.3-0.6]) and local ablative treatment (HR 3.8 [CI95 2.1-7.1]) remained significant. Conclusions: Local ablative treatment of metastases is associated with better survival in sarcoma patients with oligometastatic disease. The role of the locoregional treatment of metastases and its impact on quality of life should be assessed prospectively.

scholarly journals The role of neutrophil to lymphocyte ratio in patients with pTa non-muscle invasive bladder cancer

2020 ◽  
Vol 28 (1) ◽  
pp. 29-38
Author(s):  
Orsolya Mártha ◽  
Daniel Balan ◽  
Daniel Porav-Hodade ◽  
Emőke Drágus ◽  
Mihai Dorin Vartolomei ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Primary Tumor ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Free Survival ◽  
Lymphocyte Ratio ◽  
Kaplan Meier ◽  
Muscle Invasive

AbstractIntroduction: The peritumoral inflammatory reaction has a substantial importance in the oncologic outcome of bladder cancer (BC). One biomarker proven to be practical and accessible is the NLR (neutrophil-to-lymphocyte ratio) for high risk non-muscle invasive bladder cancer (NMIBC). The aim of the study was to investigate the role of NLR as a prognostic biomarker for disease recurrence, progression and survival of p Ta (pathological assesment of the primary tumor) NMIBC.Material and Methods: In our retrospective study we included 54 patients with pTa NMIBC from a total of 235 patients who underwent transurethral resection of bladder tumor (TURBT) during two consecutive years: January 2007 - December 2008 [median follow-up 106 months (interquartile range-IQR 68-116)]. Criteria for inclusion were: primary tumor, low-grade, with NLR available at 2 weeks prior to TURBT. NLR was considered altered if higher than 3.Results: The median age of the patients included was 63 years (IQR 55 - 72). Most of the patients had NLR---lt---3 (37 patients). Median EORTC (European Organization of Research and Treatment of Cancer) Recurrence Score was 4 (IQR 1-6), while EORTC Progression Score was 3 (IQR 0-6), respectively. Recurrence occurred in 8 out of 54 (14.81 %) patients and progression was identified in 2 out of 54 (3.70 %) patients with muscle-invasive BC during follow-up. NLR---gt---3 was not associated with clinical and pathological factors. In multivariable Cox regression analyses NLR as a continuous variable was an independent predictive factor for recurrence. Recurrence-free survival (RFS) Kaplan-Meier analysis did not show a statistical significance between NLR groups: 82.67% vs. 64.12%, p=0.26. Kaplan-Meier analysis showed a lower Progression-free survival (PFS) in the NLR---gt---3 group: 94.12% vs. 100%, p=0.04. During follow-up (106 months) 18 patients deceased with no impact of NLR as a prognostic factor in multivariable analyses. Kaplan-Meier overall survival (OS) analysis showed a 10-year OS of 70.27% in the low NLR group compared with 58.82% in the high NLR group, p=0.45.Conclusion: In this cohort, high NLR was associated with high recurrence rate in patients with Ta NMIBC. In low-risk NMIBC NLR could represent a valid biomarker for clinical usage regarding the intensity of follow-up schedule.

Clinical characteristics and outcomes of metastatic or recurrent gastric cancer with high progranulin expression in patients who had received palliative chemotherapy.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 83-83
Author(s):  
Dong-Hoe Koo ◽  
Ingu Do ◽  
Tae-Kyung Yoo ◽  
Sukjoong Oh ◽  
Yun-Gyoo Lee ◽  
...  
Keyword(s):  
Palliative Chemotherapy ◽  
Progression Free Survival ◽  
Cell Types ◽  
Autocrine Growth ◽  
Free Survival ◽  
Growth And Survival ◽  
Response To Chemotherapy ◽  
Metastatic Sites

83 Background: Progranulin (PGRN), characterized as an autocrine growth and survival factor, is known to stimulate the tumorigenesis and proliferation of several cancer cell types. However, little is known about the prognostic role of PGRN in metastatic or recurrent gastric cancers (MRGCs). Methods: A retrospective analysis was performed on patients with MRGCs who had received palliative chemotherapy between January 2010 and March 2014. PGRN expression in tumor cells by immunohistochemical staining was calculated as the product of proportion (0 = none; 1 ≤ 25%; 26% ≤ 2 ≤ 50%; 3 > 50%) and intensity score (0, no staining; 1, weak; 2, moderate; 3, strong), and categorized as high expression (Score ≥ 4) or low expression ( < 4). Results: A total of 101 patients were analyzed with the median age of 57 years (range, 24–79) at first-line chemotherapy, and 66 patients (65%) were male. Twenty-three patients (23%) had high PGRN expression tumors, and they were almost younger patients (≤ 65 years, 96%). In terms of metastatic sites, the patients with high PGRN tumors had more liver metastasis (30% vs. 17%), and the patients with low PGRN had more bone metastasis (10% vs. 4%). There were no significant differences in the proportion of patients with a response to chemotherapy (32% vs 38%) between patients with high or low PGRN tumors. The median follow-up duration of surviving patients was 54.8 months (range 34.5-81.4 months). Overall, 90 patients (89%) died, and a median overall survival (OS) and progression free survival (PFS) were 13.1 months (95% CI, 9.5–16.8 months) and 5.6 months (95% CI, 4.7-6.5), respectively. The PFS and OS were not statistically different between patients with high PGRN tumors and those that were low PGRN (median PFS 5.2 vs 5.9 and OS 14.9 vs 13.0 months, P = 0.471 and 0.927, respectively). In addition, multivariate analysis showed that PGRN expression was not a prognostic factor in both PFS and OS after adjusting for possible confounding factors including sex, age, performance, histopathology and number of metastasis. Conclusions: There was no relationship between PGRN expression and response to chemotherapy or prognosis in patients with MRGCs.

Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients’ Survival

2021 ◽  
Author(s):  
Victor Srougi ◽  
Irina Bancos ◽  
Marilyne Daher ◽  
Jeffrey E Lee ◽  
Paul H Graham ◽  
...  
Keyword(s):  
Cytoreductive Surgery ◽  
Adrenocortical Carcinoma ◽  
Primary Tumor ◽  
Risk Of Death ◽  
The Mean ◽  
Metastasis Therapy ◽  
Local Metastasis ◽  
The Impact

Abstract Context The role of cytoreduction of adrenocortical carcinoma (ACC) remains poorly understood. Objective To analyze the impact of cytoreductive surgery of the primary tumor in patients with metastatic ACC. Design and Setting We performed a multicentric, retrospective paired cohort study comparing the overall survival (OS) in patients with metastatic ACC who were treated either with cytoreductive surgery (CR group) or without cytoreductive surgery (no-CR group) of the primary tumor. Data were retrieved from 9 referral centers in the American-Australian-Asian Adrenal Alliance (A5) collaborative research group. Patients Patients aged ≥18 years with metastatic ACC at initial presentation who were treated between January 1, 1995, and May 31, 2019. Intervention Performance (or not) of cytoreductive surgery of the primary tumor. Main outcome and measures A propensity score match was done using age and the number of organs with metastasis (≤2 or &gt;2). The main outcome was OS, determined from the date of diagnosis until death or until last follow-up for living patients. Results Of 339 patients pooled, 239 were paired and included: 128 in the CR group and 111 in the no-CR group. The mean follow-up was 67 months. Patients in the no-CR group had greater risk of death than did patients in the CR group (HR, 3.18; 95% CI, 2.34-4.32). Independent predictors of survival included age (HR, 1.02; 95% CI, 1.00-1.03), hormone excess (HR, 2.56; 95% CI, 1.66-3.92), and local metastasis therapy (HR, 0.41; 95% CI, 0.47-0.65). Conclusion Cytoreductive surgery of the primary tumor in patients with metastatic ACC is associated with prolonged survival.

Sound Production Treatment for Acquired Apraxia of Speech: An Examination of Dosage in Relation to Probe Performance

2020 ◽  
pp. 1-16
Author(s):  
Julie L. Wambaugh ◽  
Lydia Kallhoff ◽  
Christina Nessler
Keyword(s):  
Retrospective Analysis ◽  
Sound Production ◽  
Apraxia Of Speech ◽  
Practice Schedule ◽  
Practice Schedules ◽  
Baseline Performance ◽  
The Mean ◽  
Number Of Treatment ◽  
The Impact

Purpose This study was designed to examine the association of dosage and effects of Sound Production Treatment (SPT) for acquired apraxia of speech. Method Treatment logs and probe data from 20 speakers with apraxia of speech and aphasia were submitted to a retrospective analysis. The number of treatment sessions and teaching episodes was examined relative to (a) change in articulation accuracy above baseline performance, (b) mastery of production, and (c) maintenance. The impact of practice schedule (SPT-Blocked vs. SPT-Random) was also examined. Results The average number of treatment sessions conducted prior to change was 5.4 for SPT-Blocked and 3.9 for SPT-Random. The mean number of teaching episodes preceding change was 334 for SPT-Blocked and 179 for SPT-Random. Mastery occurred within an average of 13.7 sessions (1,252 teaching episodes) and 12.4 sessions (1,082 teaching episodes) for SPT-Blocked and SPT-Random, respectively. Comparisons of dosage metric values across practice schedules did not reveal substantial differences. Significant negative correlations were found between follow-up probe performance and the dosage metrics. Conclusions Only a few treatment sessions were needed to achieve initial positive changes in articulation, with mastery occurring within 12–14 sessions for the majority of participants. Earlier occurrence of change or mastery was associated with better follow-up performance. Supplemental Material https://doi.org/10.23641/asha.12592190

Bifurcated bypass in severe chronic limb threatening ischaemia

Vascular ◽  
2021 ◽  
pp. 170853812199985
Author(s):  
Daniele Adami ◽  
Michele Marconi ◽  
Alberto Piaggesi ◽  
Davide M Mocellin ◽  
Raffaella N Berchiolli ◽  
...  
Keyword(s):  
Survival Rates ◽  
Primary Patency ◽  
Free Survival ◽  
Mortality And Morbidity ◽  
Bypass Patency ◽  
Stage 4 ◽  
Endovascular Approach ◽  
The Mean ◽  
Clinical Records

Objectives Revascularization according to the angiosome concept is of proven importance for limb salvage in chronic limb threatening ischaemia but it is not always practicable. Bifurcated bypasses could be considered as an option when an endovascular approach is not feasible or has already failed and a single bypass would not allow direct revascularization of the ischaemic area. Bifurcated bypasses are characterized by landing on two different arteries, the main artery (in direct continuity with the foot vessels) and the secondary one (perfusing the angiosome district). The aim of this study is to evaluate the safety and effectiveness of bifurcated bypass in chronic limb threatening ischaemia. Methods Thirty-five patients were consecutively treated with a bifurcated bypass for chronic limb threatening ischaemia from January 2014 to December 2019 in a single vascular surgery centre. Data from clinical records and operative registers were collected prospectively in an electronic database and retrospectively analysed. Primary and primary assisted bypass patency, amputation-free survival, morbidity and mortality rates at 12 and 24 months were analysed. Results Mean follow-up period was 25.1 months (range 2–72 months). Thirty-six bifurcated bypasses were performed on 35 patients (age 75.3 ± 7.2 years; 69.4% were male). According to Wound, Ischemia, foot Infection classification 22.2% belonged to stage 3 and 77.8% to stage 4 and the mean Rutherford’s class was 5.1 ± 0.7. Immediate technical success was 100%. Early mortality and morbidity rates were respectively 5.5%, and 33.3%; foot surgery was performed in 50% of cases with wound healing in all patients. Primary patency and primary assisted bypass patency were 96.7% and 100% at 6 months; 85.2% and 92% at 12 months, 59.9% and 73.4% at 24 months, respectively. Amputation-free survival at 12 and 24 months was, respectively, 95.6% and 78.8%. Overall survival rates at 12 and 24 months were respectively 94.4% and 91.6%. Conclusions Bifurcates bypass can provide good results in patients with chronic limb threatening ischaemia without endovascular option, especially in diabetic ones. Bifurcated bypass is a complex surgical solution, both to be planned and performed, and it is quite invasive for frail patients that should be accurately selected.

scholarly journals CTNI-63. PROGNOSTIC FACTORS IN PATIENTS WITH BASAL GANGLIA GERM-CELL TUMORS: A RETROSPECTIVE ANALYSIS OF THE SINGLE CHINESE INSTITUTE EXPERIENCE FROM 2009 TO 2019

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii57-ii57
Author(s):  
Qingjun Hu ◽  
Juan Li ◽  
Mingyao Lai ◽  
Cheng Zhou ◽  
Zhaoming Zhou ◽  
...  
Keyword(s):  
Survival Rate ◽  
Basal Ganglia ◽  
Germ Cell ◽  
Retrospective Analysis ◽  
Surgical Resection ◽  
Germ Cell Tumors ◽  
Progression Free Survival ◽  
Course Of Disease ◽  
Free Survival

Abstract OBJECTIVE To evaluate the clinical factors related to the prognosis of basal ganglia germ cell tumors. METHODS A retrospective analysis of 52 cases of the basal ganglia germ cell tumors treated from January 2009 to January 2019 in the department of oncology of Guangdong Sanjiu Brain Hospital. The median age: 12 years (range: 5–32), The median course of disease: 11.7 months (range: 1–54). Thirteen cases were diagnosed by biopsy and 39 cases were diagnosed by elevated tumor markers. There were 31 patients (59.6%) diagnosed with germinomas and 21 patients (40.4%) with non-germ germ cell tumors. Univariate and multivariate survival analysis was performed. RESULTS To October 15, 2019, the median follow-up time was 30.4 months (range 2–124 months). The 5-year survival rate was 85%, and the 5-year progression-free survival rate was 84%. Multivariate analysis found whether serum AFP was greater than 100mIU / ml, (with HR: 11.441,95% CI: 2.09–47.66, P = 0.005),the degree of surgical resection(with HR 5.323 (1.19–23.812), P = 0.029), PD as the effect of radiotherapy (HR: 16.53, (1.19–23.81), P = 0.001) were independent prognostic factor affecting survival. CONCLUSION The pathological type, degree of surgical resection, and response to initial treatment can all affect survival.

scholarly journals Therapeutic Value of Single Nucleotide Polymorphisms on the Efficacy of New Therapies in Patients with Multiple Sclerosis

2021 ◽  
Vol 11 (5) ◽  
pp. 335
Author(s):  
María José Zarzuelo Romero ◽  
Cristina Pérez Ramírez ◽  
María Isabel Carrasco Campos ◽  
Almudena Sánchez Martín ◽  
Miguel Ángel Calleja Hernández ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mechanism Of Action ◽  
Dimethyl Fumarate ◽  
Response To Treatment ◽  
Nucleotide Polymorphisms ◽  
New Therapies ◽  
Therapeutic Value ◽  
The Impact

The introduction of new therapies for the treatment of multiple sclerosis (MS) is a very recent phenomenon and little is known of their mechanism of action. Moreover, the response is subject to interindividual variability and may be affected by genetic factors, such as polymorphisms in the genes implicated in the pathologic environment, pharmacodynamics, and metabolism of the disease or in the mechanism of action of the medications, influencing the effectiveness of these therapies. This review evaluates the impact of pharmacogenetics on the response to treatment with new therapies in patients diagnosed with MS. The results suggest that polymorphisms detected in the GSTP1, ITGA4, NQO1, AKT1, and GP6 genes, for treatment with natalizumab, ZMIZ1, for fingolimod and dimethyl fumarate, ADA, for cladribine, and NOX3, for dimethyl fumarate, may be used in the future as predictive markers of treatment response to new therapies in MS patients. However, there are few existing studies and their samples are small, making it difficult to generalize the role of these genes in treatment with new therapies. Studies with larger sample sizes and longer follow-up are therefore needed to confirm the results of these studies.

Expression of A9 Antigen and Loss of Blood Group Antigens as Determinants of Survival in Patients with Head and Neck Squamous Carcinoma

1987 ◽  
Vol 96 (3) ◽  
pp. 221-230 ◽  
Author(s):  
Thomas E. Carey ◽  
Gregory T. Wolf ◽  
S. Hsu ◽  
J. Poore ◽  
K. Peterson ◽  
...  
Keyword(s):  
Head And Neck ◽  
Blood Group ◽  
Squamous Cell ◽  
Primary Tumor ◽  
Primary Tumor Site ◽  
Disease Free Interval ◽  
Free Interval ◽  
Disease Free

The murine monoclonal antibody (A9), raised to the human squamous cell carcinoma (SCC) cell-line UM-SCC-1, defines a squamous cell antigen associated with aggressive biologic behavior of SCC cell lines in vivo and in vitro. In the present investigation, A9 antigen was detected in tissue sections from 37 consecutive, previously untreated patients with SCC of the head and nack. All tumors were positive for A9 binding, although three distinct patterns (reflecting different intensities of A9 expression) were identified. The intensity of A9 expression was independent of primary tumor site, tumor differentiation, keratinization, or growth pattern. The frequency of high expression (Pattern 1) grew with increasing T class, N class, and tumor stage, and was associated with loss of blood group expression in the tumor and with low levels of lymphocyte infiltration In the tumor. Strong A9 expression had a statistically signification association with low nuclear grade (i.e., tumors with more mature and fewer enlarged nuclei, P = 0.019), low vascular/stromal response (i.e., patchy response rather than continuous, P = 0.014), and impaired in vitro lymphokine production by peripheral blood leukocytes ( P = 0.0011). Of greatest interest, however, was the strong association of high A9 expression with shortened disease-free interval (DFI) ( P = 0.085) and survival ( P = 0.081) relative to patients with weak A9 tumor staining (Patterns 2 and 3). Similarly, the loss of blood group antigen expression was strongly associated with decreased DFI ( P = 0.038) and survival ( P = 0.062). While neither Pattern 1 A 9 expression nor loss of blood group reach statistical significance in prediction of survival, the combination of Pattern 1 A 9 expression and loss of blood group expression in primary tumors was significantly associated, both with decreased disease-free interval ( P = 0.017) and with decreased overall survival ( P = 0.011) (median length of follow-up = 22 months). The length of follow-up (LFU) ranged from 2 to 38 months, with a median LFU of 22 months. While the number of patients (37) is small, the significant association between the expression of these cell-surface markers with relapse and survival indicates that immunohistologic staining of the primary tumor will be an important prognostic indicator useful in identification of individual patients at greatest risk of recurrence or early death from head and neck cancer, independent of tumor size, site, or stage at presentation. These markers may thus provide means of selecting patients who should receive adjuvant therapy and more intensive monitoring for the early detection of recurrent disease.

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