EASL-EORTC clinical practice guidelines : management of hepatocellular carcinoma

https://www.emcdda.europa.eu/attachements.cfm/att_231442_EN_INT17_easl-recommendations-on-treatment-of-hepatitis-C.pdf

EASL Recommendations on Treatment of Hepatitis C

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Risk factors for HCC include chronic hepatitis B and hepatitis C, alcohol addiction, metabolic liver disease (particularly nonalcoholic fatty liver disease) and exposure to dietary toxins such as aflatoxins and aristolochic acid. All these risk factors are potentially preventable, highlighting the considerable potential of risk prevention for decreasing the global burden of HCC. HCC surveillance and early detection increase the chance of potentially curative treatment; however, HCC surveillance is substantially underutilized, even in countries with sufficient medical resources. Early-stage HCC can be treated curatively by local ablation, surgical resection or liver transplantation. Treatment selection depends on tumour characteristics, the severity of underlying liver dysfunction, age, other medical comorbidities, and available medical resources and local expertise. Catheter-based locoregional treatment is used in patients with intermediate-stage cancer. Kinase and immune checkpoint inhibitors have been shown to be effective treatment options in patients with advanced-stage HCC. Together, rational deployment of prevention, attainment of global goals for viral hepatitis eradication, and improvements in HCC surveillance and therapy hold promise for achieving a substantial reduction in the worldwide HCC burden within the next few decades.

/pdf/a-global-view-of-hepatocellular-carcinoma-trends-risk-26dq6hubb1.pdf

A global view of hepatocellular carcinoma: trends, risk, prevention and management.

In the adult male, a population of diploid stem-cell spermatogonia continuously undergoes self-renewal and produces progeny cells, which initiate the complex process of cellular differentiation that results in mature spermatozoa. We report here that stem cells isolated from testes of donor male mice will repopulate sterile testes when injected into seminiferous tubules. Donor cell spermatogenesis in recipient testes showed normal morpholigical characteristics and produced mature spermatozoa. This methodology, besides opening new avenues of basic research into spermatogenesis and stem-cell self-renewal, may prove useful as a tool for biomedical science and biotechnology.

https://www.pnas.org/content/pnas/91/24/11298.full.pdf

Spermatogenesis following male germ-cell transplantation

A basic doctrine of reproductive biology is that most mammalian females lose the capacity for germ-cell renewal during fetal life, such that a fixed reserve of germ cells (oocytes) enclosed within follicles is endowed at birth. Here we show that juvenile and adult mouse ovaries possess mitotically active germ cells that, based on rates of oocyte degeneration (atresia) and clearance, are needed to continuously replenish the follicle pool. Consistent with this, treatment of prepubertal female mice with the mitotic germ-cell toxicant busulphan eliminates the primordial follicle reserve by early adulthood without inducing atresia. Furthermore, we demonstrate cells expressing the meiotic entry marker synaptonemal complex protein 3 in juvenile and adult mouse ovaries. Wild-type ovaries grafted into transgenic female mice with ubiquitous expression of green fluorescent protein (GFP) become infiltrated with GFP-positive germ cells that form follicles. Collectively, these data establish the existence of proliferative germ cells that sustain oocyte and follicle production in the postnatal mammalian ovary.

Germline stem cells and follicular renewal in the postnatal mammalian ovary

The alkylating agent busulfan (Myleran) adversely affects spermatogenesis in mammals. We treated male mice with single doses of busulfan in order to quantitate its cytotoxic action on spermatogonial cells for comparison with effects of other chemotherapeutic agents, to determine its long-term effects on fertility, and to assess its possible mutagenic action. Both stem cell and differentiating spermatogonia were killed and, at doses above 13 mg/kg, stem cell killing was more complete than that of differentiating spermatogonia. Azoospermia at 56 days after treatment, which is a result of stem cell killing, was achieved at doses of over 30 mg/kg; this dose is below the LD50 for animal survival, which was over 40 mg/kg. Busulfan is the only antineoplastic agent studied thus far that produces such extensive damage to stem, as opposed to differentiating, spermatogonia. The duration of sterility following busulfan treatment depended on the level of stem cell killing and varied according to quantitative predictions based on stem cell killing by other cytotoxic agents. The return of fertility after a sterile period did not occur unless testicular sperm count reached 15% of control levels. Dominant lethal mutations, measured for assessment of possible genetic damage, were not increased, suggesting that stem cells surviving treatment did not propagate a significant number of chromosomal aberrations. Sperm head abnormalities remained significantly increased at 44 weeks after busulfan treatment, however, the genetic implications of this observation are not clear. Thus, we conclude that single doses of busulfan can permanently sterilize mice at nonlethal doses and cause long-term morphological damage to sperm produced by surviving stem spermatogonia.

Effects of busulfan on murine spermatogenesis: cytotoxicity, sterility, sperm abnormalities, and dominant lethal mutations

Although nowadays considered
 as feasible and effective surgery
 in terms of short- and long-term results and oncological radicality, laparoscopic right colectomy is performed by a small number of surgeons, and in the vast majority of cases, this technique was performed with an extracorporeal anastomosis. Current literature failed to solve the controversies between intracorporeal and extracorporeal anastomosis after laparoscopic right colectomy.
 A multicenter case-controlled study has been designed, including 286 patients who underwent laparoscopic right hemicolectomy with intracorporeal anastomosis (IA) compared with 226 matched patients who underwent laparoscopic right hemicolectomy with extracorporeal anastomosis (EA). There was no significant difference in terms of age, sex, BMI, and ASA score between the two groups. Surgical post history, tumor localization, and stage of disease according to AJCC/UICC TNM were similar too. Although similar oncologic radicality in term of number of lymph nodes harvested (25.7 ± 10.7 of IA group vs. 24.8 ± 8.7 of EA group; p = 0.3), as well as similar operative time (166 ± 43.7 min. in IA group vs. 157.5 ± 67.2 min in EA group) have been registered, time to flatus was statistically lower after intracorporeal anastomosis (40.8 ± 24.3 h in TLRC group vs. 55.2 ± 19.2 h in LARC group; p < 0.001) Laparoscopic colectomy with intracorporeal anastomosis was associated with a lower rate of post-operative complications (OR 0.65, 95 % CI 0.44, 0.95, p = 0.027). However, when stratifying according to clavien classification, the difference was consistently confirmed for less severe (class I and II) complications (OR 0.63, 95 % CI 0.42, 0.94, p = 0.025), but not for class III, IV, and V complications (OR 1.015, 95 % CI 0.64, 1.6, p = 0.95). Our results are encouraging to consider the intracorporeally approach the better way to fashion the anastomosis after laparoscopic right colectomy. This study clearly provides the rationale for a randomized clinical trial, which would be useful to give definitive conclusion.

Intracorporeal versus extracorporeal anastomosis. Results from a multicentre comparative study on 512 right-sided colorectal cancers

Fifty-eight patients, 30 males and 28 females, aged between 42 and 60 years (mean age 57 years) suffering from cirrhosis of the liver with signs and symptoms of portosystemic encephalopathy were studied. The double-blind study was performed according to a double-dummy experimental design, comparing the antibiotic rifaximin, administered at a dose of 1200 mg/day, with lactulose, administered at a dose of 30 g/day, both for 15 days. At the end of the treatment with the two drugs, there was a significant improvement in the main symptoms of portosystemic encephalopathy (mental state, asterixis, 'A' cancellation test, Reitan test). The improvement, which was also confirmed by a reduction in the overall score attributed to the degree of portosystemic encephalopathy was undoubtedly correlated with the reduction in the levels of serum ammonia concentrations, recorded after only 3 days of treatment. Tolerability of the treatment with rifaximin was decidedly higher with respect to lactulose. The greater rapidity of action and the lack of side-effects with rifaximin recommend the use of this intestinal antibiotic in patients with medium to severe portosystemic encephalopathy.

Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy.

Background: The diagnosis of small bowel Crohn’s disease (CD) is performed by ileocolonoscopy, whereas the assessment of its extension can be achieved by radiologic studies or, noninvasively, by magnetic resonance (MR) enterography and bowel sonography (BS). However, few comparative studies exist directly comparing the diagnostic accuracy of BS and MRI. The aim of this study was to evaluate the diagnostic accuracy of BS and MRI for the diagnosis of small bowel CD. Methods: We prospectively performed a noninferiority diagnostic study including 234 consecutive subjects with suspected small bowel CD. All patients underwent IC (used as gold standard for diagnosis), BS, and MR enterography performed in random order by physicians who were blinded about the results. Results: The diagnosis of small bowel CD was made in 120 of 249 subjects (48%). Sensitivity, specificity, positive predictive value, and negative predictive value for CD diagnosis were 94%, 97%, 97%, and 94% for BS and 96%, 94%, 94%, and 96% for MR enterography, respectively. BS was less accurate than MR enterography in defining CD extension (r ¼ 0.69), whereas the concordance in terms of CD location between the 2 procedures was high (k ¼ 0.81). Also, MRI showed a fair concordance with BS about strictures (k ¼ 0.82) and abscesses (k ¼ 0.88), with better detection of enteroenteric fistulas (k ¼ 0.67). Conclusions: BS and MR enterography are 2 accurate procedures for the diagnosis of small bowel CD, although MR seems to be more sensitive in defining its extension. BS could be used to select the patients for subsequent MRI examination. (Inflamm Bowel Dis 2013;0:1–8)

Noninvasive diagnosis of small bowel Crohn's disease: direct comparison of bowel sonography and magnetic resonance enterography.

An epidemiological survey of hereditary ataxias and paraplegias was conducted in Molise, a region of Italy (335, 211 inhabitants on 1 January 1989). Total prevalence was 7.5 x 10−5 inhabitants (95% confidence limits 4.8–11.1). There were 7 patients with Friedreich's disease, 5 with early onset cerebellar ataxia with retained tendon reflexes, 4 with ataxia-telangiectasia, 9 with hereditary spastic paraplegias (2 autosomal dominant and 7 autosomal recessive cases). There was no patient with autosomal dominant cerebellar ataxia.

Luigi Bucci

Papers

Effects of busulfan on murine spermatogenesis: cytotoxicity, sterility, sperm abnormalities, and dominant lethal mutations

Intracorporeal versus extracorporeal anastomosis. Results from a multicentre comparative study on 512 right-sided colorectal cancers

Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy.

Noninvasive diagnosis of small bowel Crohn's disease: direct comparison of bowel sonography and magnetic resonance enterography.

Prevalence of hereditary ataxias and spastic paraplegias in Molise, a region of Italy.