Long-term results of transanal endoscopic microsurgery after endoscopic polypectomy of malignant rectal adenoma

Background

There is no consensus on the treatment and prognosis of malignant rectal polyps. The aim of the present study was to determine the role of transanal endoscopic microsurgery (TEM) after endoscopic complete polypectomy of malignant rectal adenomas with long-term follow-up.

Methods

Of 105 patients with pT1 rectal carcinoma in 32 patients TEM followed complete endoscopic polypectomy while 73 had primary TEM. Local recurrence (LR), distant metastasis, overall and cancer-specific survival were determined by the Kaplan–Meier method.

Results

Median follow-up was 9.1 years. In 32 patients with TEM following complete polypectomy no residual cancer was found. LR occurred in 3/28 (11%) patients with low-risk carcinoma (pT1 G1/2/X, L0/X, R0) and in 1/4 (25%) with high-risk carcinoma (pT1 G3/4 or L1). After primary TEM with complete resection (minimal distance >1 mm) LR occurred in 6/60 (10%) with low-risk carcinoma. After incomplete TEM resection (minimal distance ≤1 mm) LR occurred in 3/8 (38%) patients with low-risk and in 1/5 (20%) patients with high-risk carcinoma. Grading was the only significant risk factor for LR after endoscopic polypectomy followed by TEM (p = 0.002). At all outcomes did not differ between postpolypectomy TEM and primary TEM.

Conclusions

Patients with malignant rectal polyps removed by endoscopic polypectomy have a substantial risk of LR even if TEM of polyp site is cancer free. Risk of LR depends on tumor characteristics. In low-risk carcinoma long-term follow-up is necessary. The high LR rate in patients with high-risk rectal carcinoma restricts the use of TEM alone.

     

Community‐based real‐world treatment outcomes of sofosbuvir/ledipasvir in Asians with chronic hepatitis C virus genotype 6 in the United States

Sofosbuvir/ledipasvir (SOF/LDV) is the first all‐oral ribavirin‐free treatment approved for chronic hepatitis C virus (HCV) genotype 6, offering a safe and highly efficacious treatment option. Large studies evaluating real‐world outcomes of this regimen are lacking. We aim to evaluate real‐world treatment outcomes for HCV genotype 6. A retrospective cohort study evaluated 65 adults (age ≥18) with chronic HCV genotype 6 treated with SOF/LDV without ribavirin at a community gastroenterology clinic in the United States from November 2014 to May 2016. Rates of undetectable virus at week 4 on treatment, at end of treatment (EOT) and SVR12 were stratified by the presence of cirrhosis and prior treatment (treatment naïve vs treatment experienced). Among 65 patients with chronic HCV genotype 6 treated with SOF/LDV (52.3% male, mean age 66.3 years [SD 9.7], 41.5% cirrhosis and 15.4% treatment experienced), 97.3% had undetectable virus at week 4 on treatment, 96.9% had undetectable virus at EOT and 95.3% achieved SVR12. SVR12 was 100% in females vs 91.2% in males, P=.096, and 92.3% in patients with cirrhosis vs 97.4% in those without cirrhosis, P=.347. Resistance testing of treatment failures was attempted but unsuccessful due to lack of conforming primers to define the possible resistance mutations. Among the largest U.S. community‐based real‐world cohort of Asian chronic HCV genotype 6 patients treated with all‐oral SOF/LDV without ribavirin, SVR12 was similar to SVR12 reported in clinical trials, confirming the safety and effectiveness of this regimen and validating current HCV genotype 6 treatment guideline recommendations.     

Matching of sarcoplasmic reticulum and contractile properties in rat fast- and slow-twitch muscle fibres

1. The twitch characteristics (fast-twitch or slow-twitch) of skeletal muscle fibres are determined not only by the contractile apparatus properties of the fibre, but also by the time-course of Ca2+ release and re-uptake by the sarcoplasmic reticulum (SR). The present study examined, in individual fibres from non-transforming muscle of the rat, whether particular SR properties are matched to the contractile apparatus properties of the fibre, in particular in the case of fibres with fast-twitch contractile apparatus located in a slow-twitch muscle, namely the soleus. 2. Force was recorded in single, mechanically skinned fibres from extensor digitorum longus (EDL), gastrocnemius, peroneus longus and soleus muscles. Using repeated cycles in which the SR was emptied of all releasable Ca2+ and then reloaded, it was possible to determine the relative amount of Ca2+ present in the SR endogenously, the maximum SR capacity and the rate of Ca2+ loading. The sensitivity of the contractile apparatus to Ca2+ and Sr2+ was used to classify the fibres as fast-twitch (FT), slow-twitch (ST) or mixed (< 3% of the fibres examined) and thereby identify the likely troponin C and myosin heavy chain types present. 3. There was no significant difference in SR properties between the groups of FT fibres obtained from the four different muscles, including soleus. Despite some overlap in the SR properties of individual fibres between the FT and ST groups, the properties of the FT fibres in all four muscles studied were significantly different from those of the ST and mixed fibres. 4. In general, in FT fibres the SR had a larger capacity and the endogenous Ca2+ content was a relatively lower percentage of maximum compared with ST fibres. Importantly, in terms of their SR properties, FT fibres from soleus muscle more closely resembled FT fibres from other muscles than they did ST fibres from soleus muscle.     

Use of CroFab antivenin in the management of a very young pediatric copperhead envenomation

The use of crotalid Fab antivenin (CroFab) in the treatment of snake envenomations in the pediatric population is still an underexplored area. There are very limited data to confirm the efficacy and safety of dosing children the same as adults and even less information available to evaluate this antivenin use in copperhead snake bites in children. We report the first use of crotalid Fab antivenin in an adult dose for a copperhead snake envenomation in a 2-year-old child. She had rapid resolution of symptoms with no adverse effects. The report serves to increase the literature supporting the current dosing recommendations of crotalid Fab antivenin in very young pediatric patients evidenced by its effectiveness in this patient.     

Endothelial cell protection and complement inhibition in xenotransplantation: a novel in vitro model using whole blood

BACKGROUND: Studying the interactions between xenoreactive antibodies, complement and coagulation factors with the endothelium in hyperacute and acute vascular rejection usually necessitates the use of in vivo models. Conventional in vitro or ex vivo systems require either serum, plasma or anti-coagulated whole blood, making analysis of coagulation-mediated effects difficult. Here a novel in vitro microcarrier-based system for the study of endothelial cell (EC) activation and damage, using non-anticoagulated whole blood is described. Once established, the model was used to study the effect of the characterized complement- and coagulation inhibitor dextran sulfate (DXS, MW 5000) for its EC protective properties in a xenotransplantation setting. METHODS: Porcine aortic endothelial cells (PAEC), grown to confluence on microcarrier beads, were incubated with non-anticoagulated whole human blood until coagulation occurred or for a maximum of 90 min. PAEC-beads were either pre- or co-incubated with DXS. Phosphate buffered saline (PBS) experiments served as controls. Fluid phase and surface activation markers for complement and coagulation were analyzed as well as binding of DXS to PAEC-beads. RESULTS: Co- as well as pre-incubation of DXS, followed by washing of the beads, significantly prolonged time to coagulation from 39 +/- 12 min (PBS control) to 74 +/- 23 and 77 +/- 20 min, respectively (P < 0.005 vs. PBS). DXS treatment attenuated surface deposition of C1q, C4b/c, C3b/c and C5b-9 without affecting IgG or IgM deposition. Endothelial integrity, expressed by positivity for von Willebrand Factor, was maintained longer with DXS treatment. Compared with PBS controls, both pre- and co-incubation with DXS significantly prolonged activated partial thromboplastin time (>300 s, P < 0.05) and reduced production of thrombin-antithrombin complexes and fibrinopeptide A. Whilst DXS co-incubation completely blocked classical pathway complement activity (CH50 test) DXS pre-incubation or PBS control experiments showed no inhibition. DXS bound to PAEC-beads as visualized using fluorescein-labeled DXS. CONCLUSIONS: This novel in vitro microcarrier model can be used to study EC damage and the complex interactions with whole blood as well as screen 'endothelial protective' substances in a xenotransplantation setting. DXS provides EC protection in this in vitro setting, attenuating damage of ECs as seen in hyperacute xenograft rejection.     

Prolonged imiquimod treatment and graft-versus-host reaction: histological mimicry in the skin infiltration pattern of the monocyte-macrophage-dendrocyte lineage

Factor-XIIIa-positive dendrocytes belong to the monocyte-macrophage-dendrocyte (MMD) lineage which is considered to play a pivotal role in the skin response to the immune response modifier imiquimod. The same cells are also boosted in low-grade graft-versus-host reaction (GVHR) with skin manifestations. Both conditions are characterized by specific epidermal damage. The aim of the present study was to compare them using immunohistochemistry to identify MMD subsets and other inflammatory cells in the dermis. We compared 3 cases of long-term (4, 9 and 11 months) imiquimod topical applications on normal skin, 25 low-grade GVHR controlled by immunosuppressive therapy and 25 control cases with normal skin. Compared to the normal dermis, cells of the MMD lineage were considerably boosted in the dermis of GVHR and at the imiquimod-treated sites. By contrast, only minimal accumulations of lymphocytes and Langerhans cells were disclosed in the dermis. The pattern of dermal infiltration by MMD cells was similar in GVHR and after imiquimod treatment. However, intraindividual differences in densities were obvious irrespective of the skin condition. In conclusion, there is great mimicry in the MMD involvement in the dermis during low-grade GVHR and after chronic applications of imiquimod.     

Naturally death-resistant precursor cells revealed as the origin of retinoblastoma

The molecular mechanisms and the cell-of-origin leading to retinoblastoma are not well defined. In this issue of Cancer Cell, Bremner and colleagues describe the first inheritable model of retinoblastoma, revealing that loss of the pocket proteins pRb and p107 deregulates cell cycle exit in retinal precursors. The authors show that a subset of these precursors contain an inherent resistance to apoptosis, and that while most terminally differentiate, some are likely to acquire additional mutations, leading to tumor formation. Thus, this work defines the cell-of-origin of retinoblastoma and suggests that mutations giving increased proliferative capacity are required for retinoblastoma development.