CA : A Cancer Journal for Clinicians

2458 Despite dramatic improvements in treatment over the past 40 years, acute lymphoblastic leukemia (ALL) remains one of the most common causes of death from disease in childhood. Glucocorticoids are among the most effective agents used in the treatment of lymphoid malignancies, and patient response to treatment is an important determinant of long-term outcome in childhood ALL. In spite of its clinical significance, the molecular basis of glucocorticoid resistance is still poorly understood. The aim of this study was to develop an experimental model system to define clinically relevant mechanisms of glucocorticoid resistance in childhood ALL. An in vivo model of childhood ALL has been developed in our laboratory, using patient biopsies established as xenografts in immune-deficient nonobese diabetic severe-combined immunodeficient (NOD/SCID) mice. This model is highly representative of the human disease (Lock et al., Blood, 99: 4100-4108, 2002). The in vivo responses of these xenografts to the glucocorticoid dexamethasone (DEX) correlated significantly with patient outcome (p 1 μM) in xenografts from six patients, five of whom died of their disease. In contrast, four DEX-sensitive xenografts (IC50 values 2-fold in sensitive xenografts within 8 hours of treatment. In contrast, Bim induction was dramatically attenuated in DEX-resistant xenografts. These results have identified a clinically significant and novel mechanism of glucocorticoid resistance in childhood ALL, which occurs downstream of receptor-ligand interactions, but upstream of the signalling pathway resulting in Bim induction and apoptosis.

Novel mechanisms of glucocorticoid resistance in childhood acute lymphoblastic leukemia.

Statistical Methods in Medical Research.

Worldwide, more than 20 million patients undergo groin hernia repair annually. The many different approaches, treatment indications and a significant array of techniques for groin hernia repair warrant guidelines to standardize care, minimize complications, and improve results. The main goal of these guidelines is to improve patient outcomes, specifically to decrease recurrence rates and reduce chronic pain, the most frequent problems following groin hernia repair. They have been endorsed by all five continental hernia societies, the International Endo Hernia Society and the European Association for Endoscopic Surgery. 
An expert group of international surgeons (the HerniaSurge Group) and one anesthesiologist pain expert was formed. The group consisted of members from all continents with specific experience in hernia-related research. Care was taken to include surgeons who perform different types of repair and had preferably performed research on groin hernia surgery. During the Group's first meeting, evidence-based medicine (EBM) training occurred and 166 key questions (KQ) were formulated. EBM rules were followed in complete literature searches (including a complete search by The Dutch Cochrane database) to January 1, 2015 and to July 1, 2015 for level 1 publications. The articles were scored by teams of two or three according to Oxford, SIGN and Grade methodologies. During five 2-day meetings, results were discussed with the working group members leading to 136 statements and 88 recommendations. Recommendations were graded as "strong" (recommendations) or "weak" (suggestions) and by consensus in some cases upgraded. In the Results and summary section below, the term "should" refers to a recommendation. The AGREE II instrument was used to validate the guidelines. An external review was performed by three international experts. They recommended the guidelines with high scores. 
The risk factors for inguinal hernia (IH) include: family history, previous contra-lateral hernia, male gender, age, abnormal collagen metabolism, prostatectomy, and low body mass index. Peri-operative risk factors for recurrence include poor surgical techniques, low surgical volumes, surgical inexperience and local anesthesia. These should be considered when treating IH patients. IH diagnosis can be confirmed by physical examination alone in the vast majority of patients with appropriate signs and symptoms. Rarely, ultrasound is necessary. Less commonly still, a dynamic MRI or CT scan or herniography may be needed. The EHS classification system is suggested to stratify IH patients for tailored treatment, research and audit. Symptomatic groin hernias should be treated surgically. Asymptomatic or minimally symptomatic male IH patients may be managed with "watchful waiting" since their risk of hernia-related emergencies is low. The majority of these individuals will eventually require surgery; therefore, surgical risks and the watchful waiting strategy should be discussed with patients. Surgical treatment should be tailored to the surgeon's expertise, patient- and hernia-related characteristics and local/national resources. Furthermore, patient health-related, life style and social factors should all influence the shared decision-making process leading up to hernia management. Mesh repair is recommended as first choice, either by an open procedure or a laparo-endoscopic repair technique. One standard repair technique for all groin hernias does not exist. It is recommended that surgeons/surgical services provide both anterior and posterior approach options. Lichtenstein and laparo-endoscopic repair are best evaluated. Many other techniques need further evaluation. Provided that resources and expertise are available, laparo-endoscopic techniques have faster recovery times, lower chronic pain risk and are cost effective. There is discussion concerning laparo-endoscopic management of potential bilateral hernias (occult hernia issue). After patient consent, during TAPP, the contra-lateral side should be inspected. This is not suggested during unilateral TEP repair. After appropriate discussions with patients concerning results tissue repair (first choice is the Shouldice technique) can be offered. Day surgery is recommended for the majority of groin hernia repair provided aftercare is organized. Surgeons should be aware of the intrinsic characteristics of the meshes they use. Use of so-called low-weight mesh may have slight short-term benefits like reduced postoperative pain and shorter convalescence, but are not associated with better longer-term outcomes like recurrence and chronic pain. Mesh selection on weight alone is not recommended. The incidence of erosion seems higher with plug versus flat mesh. It is suggested not to use plug repair techniques. The use of other implants to replace the standard flat mesh in the Lichtenstein technique is currently not recommended. In almost all cases, mesh fixation in TEP is unnecessary. In both TEP and TAPP it is recommended to fix mesh in M3 hernias (large medial) to reduce recurrence risk. Antibiotic prophylaxis in average-risk patients in low-risk environments is not recommended in open surgery. In laparo-endoscopic repair it is never recommended. Local anesthesia in open repair has many advantages, and its use is recommended provided the surgeon is experienced in this technique. 
General anesthesia is suggested over regional in patients aged 65 and older as it might be associated with fewer complications like myocardial infarction, pneumonia and thromboembolism. Perioperative field blocks and/or subfascial/subcutaneous infiltrations are recommended in all cases of open repair. Patients are recommended to resume normal activities without restrictions as soon as they feel comfortable. Provided expertise is available, it is suggested that women with groin hernias undergo laparo-endoscopic repair in order to decrease the risk of chronic pain and avoid missing a femoral hernia. Watchful waiting is suggested in pregnant women as groin swelling most often consists of self-limited round ligament varicosities. Timely mesh repair by a laparo-endoscopic approach is suggested for femoral hernias provided expertise is available. All complications of groin hernia management are discussed in an extensive chapter on the topic. Overall, the incidence of clinically significant chronic pain is in the 10-12% range, decreasing over time. Debilitating chronic pain affecting normal daily activities or work ranges from 0.5 to 6%. Chronic postoperative inguinal pain (CPIP) is defined as bothersome moderate pain impacting daily activities lasting at least 3 months postoperatively and decreasing over time. CPIP risk factors include: young age, female gender, high preoperative pain, early high postoperative pain, recurrent hernia and open repair. For CPIP the focus should be on nerve recognition in open surgery and, in selected cases, prophylactic pragmatic nerve resection (planned resection is not suggested). It is suggested that CPIP management be performed by multi-disciplinary teams. It is also suggested that CPIP be managed by a combination of pharmacological and interventional measures and, if this is unsuccessful, followed by, in selected cases (triple) neurectomy and (in selected cases) mesh removal. For recurrent hernia after anterior repair, posterior repair is recommended. If recurrence occurs after a posterior repair, an anterior repair is recommended. After a failed anterior and posterior approach, management by a specialist hernia surgeon is recommended. Risk factors for hernia incarceration/strangulation include: female gender, femoral hernia and a history of hospitalization related to groin hernia. It is suggested that treatment of emergencies be tailored according to patient- and hernia-related factors, local expertise and resources. Learning curves vary between different techniques. Probably about 100 supervised laparo-endoscopic repairs are needed to achieve the same results as open mesh surgery like Lichtenstein. It is suggested that case load per surgeon is more important than center volume. It is recommended that minimum requirements be developed to certify individuals as expert hernia surgeon. The same is true for the designation "Hernia Center". From a cost-effectiveness perspective, day-case laparoscopic IH repair with minimal use of disposables is recommended. The development and implementation of national groin hernia registries in every country (or region, in the case of small country populations) is suggested. They should include patient follow-up data and account for local healthcare structures. A dissemination and implementation plan of the guidelines will be developed by global (HerniaSurge), regional (international societies) and local (national chapters) initiatives through internet websites, social media and smartphone apps. 
An overarching plan to improve access to safe IH surgery in low-resource settings (LRSs) is needed. It is suggested that this plan contains simple guidelines and a sustainability strategy, independent of international aid. It is suggested that in LRSs the focus be on performing high-volume Lichtenstein repair under local anesthesia using low-cost mesh. Three chapters discuss future research, guidelines for general practitioners and guidelines for patients. 
The HerniaSurge Group has developed these extensive and inclusive guidelines for the management of adult groin hernia patients. It is hoped that they will lead to better outcomes for groin hernia patients wherever they live. More knowledge, better training, national audit and specialization in groin hernia management will standardize care for these patients, lead to more effective and efficient healthcare and provide direction for future research.

/pdf/international-guidelines-for-groin-hernia-management-3otlldvdxc.pdf

International guidelines for groin hernia management

Population-based study からみた神経予後不良因子の検討

Superficial venous aneurysms are a very uncommon disease probably associated with thrombosis and recurrent pulmonary thromboembolisms. Surgical treatment is safe and is performed in symptomatic cases. Surgical repair of superficial venous aneurysms is a recommended treatment, and no postoperative complications usually occur. The aim of this study is to report our experience treating superficial venous aneurysms, because they can cause devastating consequences. Obviously, they should be surgically treated if they are symptomatic, but there exists the possibility of complications such as thromboembolic events; however, they are unpredictable. Thus, the only solution to remove the potential risk of developing pulmonary or other embolic events is prophylactic surgery and anticoagulant therapy, also in low-risk patients.

To treat or not to treat basilic vein aneurysms? A clinical dilemma

The authors report their experience on surgical treatment of peptic bleeding lesions. From January 1994 till April 1999 they observed and surgically treated 35 patients (mean age 65) suffering from bleeding gastroduodenal ulcer. Complications linked to surgical treatment had an incidence of 17.5%, while those ones linked to the patient's general conditions of 21%; mortality was 20%. Surgery has been gradually substituted by endoscopy which represent the principal examination for diagnosis of bleeding gastroduodenal ulcer with the aid of different hemostatic techniques, so that surgery has been relegated to the last place in uncontrollable bleeding treatment. Observed results, following those ones of other authors, show the unfavourable prognosis linked to patient's different conditions when surgeon operates.

[Surgical treatment of bleeding peptic lesions: our experience].

L'impiego di protesi nel trattamento chirurgico dei laparoceli

Chronic postoperative pain is a common complication of inguinal hernia repair. An important Danish study revealed that 28.7% of patients undergoing hernioplasty suffered a varying degree of chronic pain, severe enough to interfere with normal daily activities in 11% of cases. The difficulty in treating this complication has led numerous surgeons to complete the surgical procedure ilioinguinal or iliohypogastric neurectomy. This method is proving effective in preventing the onset of chronic postoperative pain. We report the results obtained in patients undergoing neurectomy of the iliohypogastric nerve during anterior inguinal hernioplasty.

Iliohypogastric neurectomy in the prevention of postoperative pain following inguinal hernioplasty

Introduction Abdominal pain (AP) is one of the most frequent clinical condition observed in elderly patients The differential diagnosis is wide and definitive diagnosis is often difficult due to delayed symptoms, altered laboratory parameters, pre-existing medical disorders, abuse of drugs and in absence of an accurate medical history Evidence acquisition A systematic literature review was carried out through PubMed database for studies published in the last ten years The following search string was used: {("geriatric"[Title] OR "older"[Title] OR "aged"[Title] OR "elderly"[Title]) AND ((("abdomen"[Title] AND "acute"[Title]) OR "acute abdomen"[Title] OR ("acute"[Title] AND "abdomen"[Title])) OR ("abdominal"[Title] AND "pain"[title]) OR "abdominal pain"[Title])} Full articles and abstracts were included Case reports, commentaries, editorials and letters were excluded from the analysis Evidence synthesis As the age of people presenting AP advances, both rates of surgical procedures and mortality rate increase Conclusions A systematic approach based on the organization of differential diagnoses into categories, may provide a helpful framework by the combined use of history-taking, physical examination, and results of diagnostic studies In elderly patients admitted to the emergency department, a crucial role is played by a prompt use of radiological investigations in order to discriminate between older subjects admitted to the emergency department with abdominal pain and pathological cases requiring immediate surgical treatment

Francesco Basile

Papers

To treat or not to treat basilic vein aneurysms? A clinical dilemma

[Surgical treatment of bleeding peptic lesions: our experience].

L'impiego di protesi nel trattamento chirurgico dei laparoceli

Iliohypogastric neurectomy in the prevention of postoperative pain following inguinal hernioplasty

Acute abdominal pain in older adults: a clinical and diagnostic challenge.