scholarly journals Epstein-Barr Virus associated gastric carcinoma in a patient with germline STAT3 gain-of-function mutation

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S65-S65
Author(s):  
J Mahadik ◽  
K Patel ◽  
N Cortes-Santiago
Keyword(s):  
Poor Response ◽  
Posterior Wall ◽  
Immune Dysregulation ◽  
The Body ◽  
Low Grade ◽  
Solid Organ ◽  
Muscularis Mucosa ◽  
Gain Of Function ◽  
First Case ◽  
Increased Risk

Abstract Introduction/Objective Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in inflammation, proliferation, differentiation and survival. STAT3 gain-of-function (GoF) disorders are characterized by immune dysregulation and present with polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)- or autoimmune lymphoproliferative syndrome (ALPS)-like features. While patients with STAT-3 GoF are known to have an increased risk for hematologic malignancies, neither solid tumors nor an increased risk for EBV-associated disorders have been described. We report the first case of an EBV-associated solid organ tumor in a patient with STAT-3 GoF. Methods/Case Report A 21-year-old male with germline mutation in STAT3 (variant p. M329K) presented with early satiety, abdominal pain and worsening of chronic anemia. Serology showed high EBV DNA PCR levels. Endoscopy showed multiple nodular lesions in the stomach, which were biopsied to reveal EBV-associated high-grade dysplasia and intramucosal adenocarcinoma. Initiation of chemotherapy with a poor response led to a total gastrectomy. Gross examination of the specimen showed a 7.9 x 6.5 x 1.8 cm tan-brown, exophytic mass in the posterior wall of the body and antrum, involving the greater curvature. Histology revealed an adenocarcinoma with tubulovillous morphology extending into the lamina propria, without invasion into the muscularis mucosa or submucosa. EBER in-situ hybridization was diffusely positive in the tumor cells. The background mucosa showed severe chronic active and atrophic gastritis with intestinal metaplasia and low-grade dysplasia. All the seventy examined lymph nodes were negative for metastasis. Helicobacter-like organisms were not seen. Results (if a Case Study enter NA) NA Conclusion This is the first report of a solid tumor in a patient with STAT3 GoF mutation. The role of the patient’s underlying immune dysregulation disorder in the development of EBV-associated gastric adenocarcinoma is unclear and warrants further investigation. The case also highlights the importance of a close clinical follow-up in this patient population, as unexpected malignancies can develop at younger ages.

scholarly journals O03 Continuation of golimumab (anti-TNF) in a patient with SpA and low-risk prostate cancer, what is the right decision?

2021 ◽  
Vol 5 (Supplement_1) ◽  
Author(s):  
Amelia Holloway ◽  
Catherine Mathews
Keyword(s):  
Prostate Cancer ◽  
Case Report ◽  
Low Risk ◽  
British Society ◽  
Tnf Alpha ◽  
Risk Category ◽  
Low Grade ◽  
Solid Organ ◽  
Ongoing Treatment ◽  
Increased Risk

Abstract Case report - Introduction Golimumab is an anti-TNF alpha drug used in the treatment of inflammatory arthritis including spondyloarthritis (SpA). The introduction of this drug class has revolutionised the treatment of SpA over the last 20 years with significantly improved patient outcomes. Despite their treatment benefits multiple adverse effects of TNF-alpha inhibition have been reported through clinical trials including a possible increased risk of malignancy. We describe a case of a patient with known ankylosing spondylitis (AS) on golimumab who was diagnosed with low-grade prostate carcinoma and discuss the factors taken into consideration in guiding our decision-making process regarding ongoing treatment. Case report - Case description A 57-year-old gentleman with known AS presented to the rheumatology clinic for routine review. His AS was well controlled, and he had been taking golimumab for the past 3 years. Upon review he was in clinical remission with a CRP <1 and ESR 5. Prior to the initiation of anti-TNF therapy his disease had been poorly controlled. However, following commencement his symptoms had significantly improved and he was able to work as a professional sports coach whilst bringing up a young family. On review he had recently been diagnosed with low-risk cancer of the prostate by his urologist. A prostate biopsy found Gleason 3 + 3 adenocarcinoma involving 2 out of 22 cores on each side, with a prostate specific antigen (PSA) of 3.95ng/ml. An MRI had shown chronic prostatitis. He was in the lowest risk category of grade group 1 prostate cancer and no treatment for his prostate cancer was indicated. The plan from his urology team was active surveillance with PSA monitoring. Whilst being investigated for possible malignancy his golimumab had been held for six months and during this period he had a significant flare in symptoms. He experienced severe back pain that forced him to stop working. Following his prostate cancer diagnosis, golimumab was restarted by his urologist with a subsequent improvement in his AS symptoms. To guide ongoing treatment his case was reviewed in the local biologics multi-disciplinary team meeting, alongside close communication with his urologist.  The patient was informed of the risks of continuing golimumab in relation to his malignancy. Despite this he was reluctant to stop anti-TNF therapy or switch to another treatment, citing concerns about the impact it might have on his symptoms and ability to work. Case report - Discussion  This case highlights the complexities involved in the management of a patient on anti-TNF therapy, who receives a diagnosis of malignancy, particularly when the diagnosis is classed as low risk. Traditionally anti-TNF therapy was contraindicated for patients with a history of a solid organ tumour within the previous five years. The British Society of Rheumatology (BSR) guidelines recommends that patients should be advised that there is no conclusive evidence for an increased risk of solid organ tumours but that on-going vigilance is required. A holistic patient-centred approach needs to be taken in these contexts, and consideration of cases on an individual basis is needed. Inter-disciplinary and multi-speciality team input, with the effective use of a biologics MDT, is crucial. The patient was understandably reluctant to stop his treatment due to the significant impact this may have on his quality of life. On liaison with his urologist his prostate cancer was in the lowest risk category with 99% 5-year survival rates with low risk of disease progression or spread. Evidence in this field to date has been conflicting and studies have predominantly focused on the safety of anti-TNFs in rheumatoid arthritis patients. Recent large national registry data has been reassuring. Few studies have looked at the AS and psoriatic arthritis anti-TNF treated population; however, a meta-analysis of RCTs found no evidence of increased incidence of malignancy. Taking into account his low-risk cancer, the patient’s wishes and clinical evidence in this field we have made to decision to continue anti-TNF treatment for now but with ongoing surveillance for any tumour progression. The patient will undergo urology follow up alongside regular PSA monitoring, and there will be a low threshold to stop or switch treatment in the future Case report - Key learning points

scholarly journals Gastric Mucormycosis: An Infection of Fungal Invasion into the Gastric Mucosa in Immunocompromised Patients

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Haider A. Naqvi ◽  
Muhammad Nadeem Yousaf ◽  
Fizah S. Chaudhary ◽  
Lawrence Mills
Keyword(s):  
Abdominal Pain ◽  
Gastric Mucosa ◽  
Chronic Renal Disease ◽  
Hematologic Malignancy ◽  
Acute Onset ◽  
The Body ◽  
Solid Organ ◽  
Immunocompromised Patients ◽  
Presenting Symptoms ◽  
Increased Risk

Primary gastric mucormycosis is a rare but potentially lethal fungal infection due to the invasion of Mucorales into the gastric mucosa. It may result in high mortality due to increased risk of complications in immunocompromised patients. Common predisposing risk factors to develop gastric mucormycosis are prolonged uncontrolled diabetes mellitus with or without diabetic ketoacidosis (DKA), solid organ or stem cell transplantation, underlying hematologic malignancy, and major trauma. Abdominal pain, hematemesis, and melena are common presenting symptoms. The diagnosis of gastric mucormycosis can be overlooked due to the rarity of the disease. A high index of suspicion is required for early diagnosis and management of the disease, particularly in immunocompromised patients. Radiological imaging findings are nonspecific to establish the diagnosis, and gastric biopsy is essential for histological confirmation of mucormycosis. Prompt treatment with antifungal therapy is the mainstay of treatment with surgical resection reserved in cases of extensive disease burden or clinical deterioration. We presented a case of acute gastric mucormycosis involving the body of stomach in a patient with poorly controlled diabetes and chronic renal disease, admitted with acute onset of abdominal pain. Complete resolution of lesion was noted with 16 weeks of medical treatment with intravenous amphotericin B and posaconazole.

scholarly journals Body Composition Findings by Computed Tomography in SARS-CoV-2 Patients: Increased Risk of Muscle Wasting in Obesity

2020 ◽  
Vol 21 (13) ◽  
pp. 4670 ◽  
Author(s):  
Paola Gualtieri ◽  
Carmela Falcone ◽  
Lorenzo Romano ◽  
Sebastiano Macheda ◽  
Pierpaolo Correale ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Body Composition ◽  
Nutritional Status ◽  
Bed Rest ◽  
Nutritional Therapy ◽  
The Body ◽  
Low Grade ◽  
Anthropometric Parameters ◽  
Imaging Diagnostics ◽  
Increased Risk

Obesity is a characteristic of COVID-19 patients and the risk of malnutrition can be underestimated due to excess of fat: a paradoxical danger. Long ICU hospitalization exposes patients to a high risk of wasting and loss of lean body mass. The complex management precludes the detection of anthropometric parameters for the definition and monitoring of the nutritional status. The use of imaging diagnostics for body composition could help to recognize and treat patients at increased risk of wasting with targeted pathways. COVID-19 patients admitted to the ICU underwent computed tomography within 24 h and about 20 days later, to evaluate the parameters of the body and liver composition. The main results were the loss of the lean mass index and a greater increase in liver attenuation in obese subjects. These could be co-caused by COVID-19, prolonged bed rest, the complex medical nutritional therapy, and the starting condition of low-grade inflammation of the obese. The assessment of nutritional status, with body composition applied to imaging diagnostics and metabolic profiles in COVID-19, will assist in prescribing appropriate medical nutritional therapy. This will reduce recovery times and complications caused by frailty.

scholarly journals Linking obesogenic dysregulation to prostate cancer progression

2015 ◽  
Vol 4 (4) ◽  
pp. R68-R80 ◽  
Author(s):  
Renea A Taylor ◽  
Jennifer Lo ◽  
Natasha Ascui ◽  
Matthew J Watt
Keyword(s):  
Prostate Cancer ◽  
Adipose Tissue ◽  
Cancer Progression ◽  
Prostate Gland ◽  
The Body ◽  
Endocrine Function ◽  
Low Grade ◽  
Prostate Cancer Progression ◽  
Cancer Aggressiveness ◽  
Increased Risk

The global epidemic of obesity is closely linked to the development of serious co-morbidities, including many forms of cancer. Epidemiological evidence consistently shows that obesity is associated with a similar or mildly increased incidence of prostate cancer but, more prominently, an increased risk for aggressive prostate cancer and prostate cancer-specific mortality. Studies in mice demonstrate that obesity induced by high-fat feeding increases prostate cancer progression; however, the mechanisms underpinning this relationship remain incompletely understood. Adipose tissue expansion in obesity leads to local tissue dysfunction and is associated with low-grade inflammation, alterations in endocrine function and changes in lipolysis that result in increased delivery of fatty acids to tissues of the body. The human prostate gland is covered anteriorly by the prominent peri-prostatic adipose tissue and laterally by smaller adipose tissue depots that lie directly adjacent to the prostatic surface. We discuss how the close association between dysfunctional adipose tissue and prostate epithelial cells might result in bi-directional communication to cause increased prostate cancer aggressiveness and progression. However, the literature indicates that several ‘mainstream’ hypotheses regarding obesity-related drivers of prostate cancer progression are not yet supported by a solid evidence base and, in particular, are not supported by experiments using human tissue. Understanding the links between obesity and prostate cancer will have major implications for the health policy for men with prostate cancer and the development of new therapeutic or preventative strategies.

Obesity and low-grade inflammation

2021 ◽  
Author(s):  
Javier Ávila Román
Keyword(s):  
Intestinal Microbiota ◽  
Inflammatory Process ◽  
Saturated Fat ◽  
Lipid Mediators ◽  
The Body ◽  
Oral Glucose ◽  
Low Grade ◽  
Increased Risk ◽  
Inflammatory State ◽  
Anti Inflammatory

Obesity is a non-communicable and multifactorial disease that may have a genetic component. However, the main causes of obesity are related to poor eating habits including consumption of high amounts of saturated fat and sugar and a sedentary lifestyle. These habits can lead to pathologies associated to obesity such as overweight, hypertension and type 2 diabetes, increased cholesterol, heart and liver diseases and an increased risk of suffering some types of cancer. Furthermore, changes in the composition of the intestinal microbiota, largely defined by diet, can cause differences in nutrients bioavailability and even in their metabolization, affecting the metabolic state of the individual. Obesity leads to an increase in the basal inflammatory state due to the consumption of saturated fat. This brings the breaking of the “tight junctions” that maintain the integrity of the intestinal barrier, allowing components of the diet or the lipopolysaccharide (LPS) of the bacterial wall to reach the bloodstream, causing the activation of the immune system. In this sense, inflammation is a protective mechanism of the body that involves lipid mediators synthesis, generically called oxylipins (OXLs). OXLs can be pro-inflammatory, anti-inflammatory or pro-resolving in nature. When an inflammatory process begins, the predominant OXLs are those derived from arachidonic acid (ARA) giving rise to leukotrienes (LTs), thromboxanes (TXs) and prostaglandins (PGs). However, once an inflammation threshold is reached, lipoxins (LXs) are synthesized from LTs, which have a pro-resolutive role. Furthermore, the human body can synthesize anti-inflammatory OXLs (resolvins, maresins, protectins and lipoxins) from dietary omega-3 acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). For this reason, in an obesogenic context, there is a higher basal inflammatory state than in a non-obese individual. In this context, we have carried out a study in 8-week-old male Wistar rats, fed a standard diet or cafeteria diet (CAF), which better simulates the high-fat and high-sugar diet in humans in comparison with a commercial pellet for 5 weeks. Four experimental groups were established, two groups were fed the standard diets and another two groups fed the CAF. Besides, one of each group mentioned received a cocktail of antibiotics (ABX) during the last two weeks to generate a dysbiosis of the microbiota. After this time, saphenous vein blood samples were taken for the metabolomic study of circulating lipid mediators and stool samples for intestinal microbiota determination. The model was validated by evaluating body weight gain and an oral glucose tolerance test, observing significant differences between both diets. The diversity of the microbiota was lower in those groups treated with ABX, regardless to diet. It was observed that both treatments with ABX and diet caused changes in the composition of microbiota, where ABX was the most relevant parameter. The Principal Component Analysis (PCA) study evaluates the OXLs profile that each animal shows with respect to 64 OXLs studied by metabolomics. This parameter showed a clear difference in the OXLs profile according to the diet. Correlations were made to know if there was a relationship between the composition of the microbiota and the presence of certain OXLs in blood, and it was concluded that there is a clear relationship between the changes in the microbiota and the profile of these OXLs in blood, which may explain the remarkable role of the microbiota in the inflammatory process. Furthermore, these findings may lead to the development of new obesity markers based on the OXLs profile associated with a microbiota profile. However, more studies are necessary to establish the specific action mechanisms responsible of this association.

scholarly journals Recessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locus

2021 ◽  
Author(s):  
Annemarie Steiner ◽  
Thomas Reygaerts ◽  
Alessandra Pontillo ◽  
Isabella Ceccherini ◽  
Jonas Moecking ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Autoinflammatory Disease ◽  
Clinical Manifestations ◽  
Immune Dysregulation ◽  
Inflammasome Activation ◽  
Low Grade ◽  
Homozygous Mutation ◽  
Increased Risk ◽  
Using Data

Abstract Purpose NLRC4-associated autoinflammatory disease (NLRC4-AID) is an autosomal dominant condition presenting with a range of clinical manifestations which can include macrophage activation syndrome (MAS) and severe enterocolitis. We now report the first homozygous mutation in NLRC4 (c.478G > A, p.A160T) causing autoinflammatory disease with immune dysregulation and find that heterozygous carriers in the general population are at increased risk of developing ulcerative colitis. Methods Circulating immune cells and inflammatory markers were profiled and historical clinical data interrogated. DNA was extracted and sequenced using standard procedures. Inflammasome activation assays for ASC speck formation, pyroptosis, and IL-1β/IL-18 secretion confirmed pathogenicity of the mutation in vitro. Genome-wide association of NLRC4 (A160T) with ulcerative colitis was examined using data from the IBD exomes portal. Results A 60-year-old Brazilian female patient was evaluated for recurrent episodes of systemic inflammation from six months of age. Episodes were characterized by recurrent low-grade fever, chills, oral ulceration, uveitis, arthralgia, and abdominal pain, followed by diarrhea with mucus and variable skin rash. High doses of corticosteroids were somewhat effective in controlling disease and anti-IL-1β therapy partially controlled symptoms. While on treatment, serum IL-1β and IL-18 levels remained elevated. Genetic investigations identified a homozygous mutation in NLRC4 (A160T), inherited in a recessive fashion. Increased ASC speck formation and IL-1β/IL-18 secretion confirmed pathogenicity when NLRC4 (A160T) was analyzed in human cell lines. This allele is significantly enriched in patients with ulcerative colitis: OR 2.546 (95% 1.778–3.644), P = 0.01305. Conclusion NLRC4 (A160T) can either cause recessively inherited autoinflammation and immune dysregulation, or function as a heterozygous risk factor for the development of ulcerative colitis.

scholarly journals Effect of oral antihyperglycemic drugs on purine metabolism

2021 ◽  
Vol 24 (4) ◽  
pp. 342-349
Author(s):  
T. S. Panevin
Keyword(s):  
Diabetes Mellitus ◽  
Cardiovascular Events ◽  
Metabolic Diseases ◽  
Purine Metabolism ◽  
The Body ◽  
Domestic Literature ◽  
First Case ◽  
Increased Risk ◽  
Oral Antihyperglycemic Drugs

Gout and diabetes mellitus are metabolic diseases, the pathogenesis of which is based on an excess of organic molecules in the body, in the first case — uric acid (UA), in the second — glucose. It is assumed that UA can also be involved in the pathogenesis of type 2 diabetes mellitus (T2DM), while insulin resistance and hyperglycemia affect purine metabolism. Both diseases are associated with an increased risk of cardiovascular events. In addition, chronic microcrystalline inflammation, which is absent in asymptomatic hyperuricemia, but is an obligatory component of gout, is probably an independent factor in T2DM, arterial hypertension, and cardiovascular events. The treatment of both diseases is strategically similar: in gout, the goal is to achieve a normal blood MC level, in T2DM — to normalize glycemia, and the frequent combination of these metabolic diseases requires taking into account the effect of drug therapy on concomitant diseases. Most modern antihyperglycemic drugs can affect purine metabolism, which is confirmed by the results of a number of foreign works. At the same time, the effect of T2DM therapy on purine metabolism and gout has not been adequately covered in the domestic literature, which was the purpose of this review.

Системная эндотоксинемия и показатели жирового обмена у новорожденных детей: одномоментное исследование

2017 ◽  
pp. 91-96
Author(s):  
М.М. Маркелова ◽  
И.И. Рюмина ◽  
И.М. Салахов ◽  
М.Ю. Яковлев
Keyword(s):  
Plasma Level ◽  
General Circulation ◽  
The Body ◽  
Atherogenic Index ◽  
Control Group ◽  
Low Grade ◽  
Fat Percentage ◽  
Cross Sectional ◽  
Increased Risk ◽  
Systemic Endotoxemia

Введение. Установлено, что ожирение сопровождается высоким провоспалительным фоном и повышенным содержанием эндотоксина (ЭТ) у взрослых. Одним из факторов риска развития ожирения у взрослых является низкий вес при рождении и чрезмерная прибавка массы тела в раннем возрасте. Цель. Определение взаимосвязи между показателями системной эндотоксинемии (СЭЕ) и жирового обмена у новорожденных детей. Методика. Обследовано 44 ребенка, находившихся в отделении патологии новорожденных и недоношенных детей Научного Центра Акушерства, Гинекологии и Перинатологии им. Кулакова в июле 2016 года. Определяли концентрацию ЭТ в плазме крови; антител к ЭТ; липидный профиль; состав тела методом воздухо-заместительной плетизмографии. Результаты. У детей с патологией, по сравнению с контрольной группой, концентрация ЭТ и липопротеинов высокой плотности (ЛПВП) были выше (2,31 ± 0,15 против 1,2 ± 0,13EU/ml и 1,15 ± 0,05 против 0,69 ± 0,1 ммоль/л соответственно), а содержание антител к ЭТ и холестерина были ниже 122 ± 9 против 202 ± 36 у.е.о.п.. и (1,97 ± 0,34 против 2,91 ± 0,09 мг/дл). Обратная корреляция обнаружена между уровнем ЭТ в крови и процентным содержанием жира в организме и между уровнем ЭТ и индексом атерогенности. Прямая корреляция была между уровнем ЭТ и ЛПВП. Заключение. Феномен системной эндотоксинемии сопровождает период новорожденности, что свидетельствует об участии кишечного ЛПС в адаптации к постнатальному периоду жизни, а избыточный уровень ЭТ в общем кровотоке сопутствует или предшествует развитию неонатальной патологии. Недостаточное содержанием жира в организме новорожденного может являться причиной ограниченного депонирования ЛПС и повышенного содержания его в крови. Background. It is established that obesity is accompanied by a low-grade inflammation and increased Endotoxin (ET) content in adults. Low birth weight and excessive weight gain in early infancy are associated with an increased risk of obesity, metabolic syndrome, cardiovascular disease in adults. Objective. To determine the relationship between systemic endotoxemia and fat metabolism in newborn infants. Materials and methods. Cross-sectional study included 44 infants who were at the department of newborn pathology of Research Center for Obstetrics, Gynecology and Perinatology in July 2016. The concentration of ET in the blood plasma, ET antibodies, lipid profile, body composition using air-displacement plethysmography were assessed. Results. In children with pathology in comparison with the control group the concentration of ET and high density lipids (HDL) were higher (2,31 ± 0,15 vs. 1,2 ± 0,13 EU/ml and 1,15 ± 0,05 vs. 0,69 ± 0,1 mmol/l respectively), while ET antibodies level was lower (122 ± 9 vs. 202 ± 36 O.D.) The inverse correlation observed between the ET plasma level and body fat percentage and between the ET plasma level and atherogenic index. Direct correlation between the ET and HDL levels was found. Conclusion. The phenomenon of systemic endotoxemia accompanies the neonatal period, which indicates the involvement of ET to postnatal adaptation, and excess levels of ET in the general circulation is accompanied or proceed to development of neonatal pathology. Lack of fat in the body of the newborn may be a reason for the limited deposit of ET and its high content in the blood.

Primary Peritoneal Serous Psammocarcinoma: a Case Report

2015 ◽  
Vol 24 (2) ◽  
pp. 253-256 ◽  
Author(s):  
Răzvan Dan Togănel ◽  
Ioan Şimon ◽  
Adriana Zolog ◽  
Răzvan Simescu ◽  
Angela Cozma ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Posterior Wall ◽  
Ca 125 ◽  
Low Grade ◽  
Abdominal Girth ◽  
Treatment Protocols ◽  
Standardized Treatment ◽  
Pelvic Peritonectomy ◽  
Optimal Debulking ◽  
Douglas Pouch

Background: Psammocarcinomas (PCas) are rare epithelial tumors, usually originating in the ovaries or the peritoneum. These tumors are morphologically characterized by extensive psammomatous calcifications, invasiveness and low-grade cytological features.Case report: We present the case of a 54-year-old woman who was referred to our department with an umbilical tumor and increasing abdominal girth. The patient had had an umbilical hernia for more than 20 years. The CA 125 level was normal. The CT scan showed small peritoneal nodules at the level of the Douglas pouch, including the posterior wall of the uterus, and the entire colon, as well as large nodules located on the caecum and the sigmoid colon. We performed partial enterectomy, total colectomy with ileo-rectal anastomosis, omentectomy, total histerectomy and bilateral adnexectomy, pelvic peritonectomy of the Douglas pouch. Pathology findings were consistent with F.I.G.O. stage IIIC peritoneal PCa. The patient received adjuvant chemotherapy with Taxol and Carboplatin. To date, twelve months after surgery, the follow-up shows no evidence of disease.Conclusion: Standardized treatment protocols are hindered by the rarity of the PCas. However, literature concludes that optimal debulking is mandatory, whereas the efficacy of adjuvant chemotherapy remains to be elucidated.

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