Skeletal Muscle-Derived Cell Implantation for the Treatment of Fecal Incontinence: A Randomized, Placebo-Controlled Study.

BACKGROUND AND AIMS: Fecal incontinence (FI) improvement following injection of autologous skeletal muscle-derived cells has been previously suggested. This study aimed to test the efficacy and safety of said cells through a multicenter, placebo-controlled study, to determine an appropriate cell dose, and to delineate the target patient population that can most benefit from cell therapy. METHODS: Patients experiencing FI for at least 6 months were randomized to receive a cell-free medium or low or high dose of cells. All patients received pelvic floor electrical stimulation before and after treatment. Incontinence episode frequency (IEF), FI quality of life, FI burden assessed on a visual analog scale, Wexner score, and parameters reflecting anorectal physiological function were all assessed for up to 12 months. RESULTS: Cell therapy improved IEF, FI quality of life, and FI burden, reaching a preset level of statistical significance in IEF change compared with the control treatment. Post hoc exploratory analyses indicated that patients with limited FI duration and high IEF at baseline are most responsive to cells. Effects prevailed or increased in the high cell count group from 6 to 12 months but plateaued or diminished in the low cell count and control groups. Most physiological parameters remained unaltered. No unexpected adverse events were observed. CONCLUSIONS: Injection of a high dose of autologous skeletal muscle-derived cells followed by electrical stimulation significantly improved FI, particularly in patients with limited FI duration and high IEF at baseline, and could become a valuable tool for treatment of FI, subject to confirmatory phase 3 trial(s). (ClinicalTrialRegister.eu; EudraCT Number: 2010-021463-32).

Hemorrhoidal disease and chronic venous insufficiency: Concomitance or coincidence; results of the CHORUS study (Chronic venous and HemORrhoidal diseases evalUation and Scientific research).

BACKGROUND AND AIM: The CHORUS study (Chronic venous and HemORrhoidal diseases evalUation and Scientific research) was conducted to provide data on patients presenting with hemorrhoidal disease (HD) in clinical practice and to explore the frequency with which it coexists with chronic venous disease (CVD) and shared risk factors. METHODS: This international, noninterventional study enrolled adult patients attending a consultation for hemorrhoidal complaints. The questionnaire completed by physicians established the subjects' demographic and lifestyle characteristics and collected information on HD grade and symptoms and signs of CVD. RESULTS: A total of 5617 patients were analyzed. Symptoms commonly reported were bleeding (71.8%), pain (67.4%), swelling (55.0%), itching (44.1%), and prolapse (36.2%). Multivariate analysis revealed the variables with the strongest association with HD severity were older age, higher CVD CEAP (Clinical manifestations, Etiologic factors, Anatomic distribution of disease, and underlying Pathophysiology) class, constipation, and male gender (all P < 0.0001). Elevated BMI was a risk factor for HD recurrence. Among women, number of births had a significant association with both HD grade and recurrence. The presence of CVD, reported in approximately half the patients (51.2%), was strongly associated with advanced grade of HD (P < 0.0001). Treatments most commonly prescribed were venoactive drugs (94.3%), dietary fiber (71.4%), topical treatment (70.3%), analgesics (26.3%), and surgery (23.5%). CONCLUSIONS: CHORUS provides a snap shot of current profiles, risk factors, and treatments of patients with HD across the globe. The coexistence of HD and CVD in more than half the study population highlights the importance of examining for CVD among patients with a hemorrhoid diagnosis, particularly when shared risk factors are present.

Anal verrucous carcinoma is not related to infection with human papillomaviruses and should be distinguished from giant condyloma (Buschke-Löwenstein tumour).

AIMS: Verrucous carcinoma (VC) is a variant of well-differentiated squamous cell carcinoma and in the anal region is regarded as synonymous with giant condyloma (Buschke-Löwenstein tumour) (BLT). Aetiology, diagnostic criteria and clinical behaviour of both lesions are controversial. Recent studies suggest that VC at other sites is not associated with human papillomaviruses (HPV). We hypothesized that anal VC is also not related to HPV, while BLT is a HPV-induced lesion. METHODS AND RESULTS: Ten cases of VC and four cases of BLT were included. Several techniques were used for HPV detection: in-situ hybridization for HPV6, 11, 16 and 18, six different polymerase chain reaction (PCR) protocols for detection of at least 89 HPV types from alpha-, beta-, gamma- and mu-PV genera and in-situ hybridization for high-risk HPV E6/E7 mRNA; p16 immunohistochemistry and morphometric analysis were also performed. Alpha-, gamma- and mu-PVs were not found in any case of VC, while HPV6 was detected in all cases of BLT. p16 overexpression was not present in any of the lesions. Among microscopic features, only the absence of koilocytosis and enlarged spinous cells seem to be useful to distinguish VC from BLT. CONCLUSIONS: Our results suggest that anal VC, similarly to VC at other sites, is not associated with HPV infection, and must be distinguished from BLT, which is associated with low-risk HPV. Only with well-set diagnostic criteria will it be possible to ascertain clinical behaviour and optimal treatment for both lesions.

Tumor-specific and gender-specific pre-vaccination distribution of human papillomavirus types 6 and 11 in anogenital warts and laryngeal papillomas: a study on 574 tissue specimens.

Anogenital warts and laryngeal papillomas are two most important benign tumors etiologically linked with HPV. In the study, which included both the largest number of laryngeal papilloma tissue specimens (152 specimens from 152 patients) to date and the largest number of prospectively collected and histologically confirmed tissue specimens of anogenital warts obtained from both genders (422 specimens from 315 patients), HPV DNA was detected in 413/422 (97.9%) of anogenital warts and 139/152 (91.4%) of laryngeal papillomas. HPV-6 and/or HPV-11 were detected in 291/315 (92.4%) patients with anogenital warts and in 138/152 (90.8%) patients with laryngeal papillomas, indicating that the great majority of both tumors could be prevented with prophylactic quadrivalent vaccine. The HPV-6 gender-specific distribution in both anogenital warts and laryngeal papillomas was not statistically significant. In contrast, HPV-11 was found almost three times more often in males than in females with anogenital warts (16.5% vs. 6.3%; P = 0.008), with a gender neutral HPV-11 type distribution in laryngeal papillomas. The overall HPV DNA prevalence in anogenital warts was significantly different from that in laryngeal papillomas (97.1% vs. 91.4%; P = 0.01). In the first comparison of the HPV-6/HPV-11 type-specific distribution between patients suffering from anogenital warts and laryngeal papillomas with the same geographic and ethnic background, a significant imbalance in tumor-specific distribution of HPV-6 and HPV-11 was identified: HPV-6 was statistically more often present in anogenital warts than in laryngeal papillomas (79.0% vs. 59.2%; P = 0.000013), whereas HPV-11 was statistically more frequent in laryngeal papillomas than in anogenital warts (28.9% vs. 12.4%; P = 0.00003).

Flavonoids to reduce bleeding and pain after stapled hemorrhoidopexy: a randomized controlled trial.

INTRODUCTION: Control of postoperative symptoms is of paramount importance in ambulatory surgery. This trial was conducted to evaluate whether a micronized purified flavonoid fraction (MPFF) (Detralex((R))) reduces postoperative bleeding, pain and consumption of analgesics after ambulatory stapled hemorrhoidopexy, as reported in trials after classic hemorrhoidectomy. Phlebotropic activity, protective effect on the capillaries and anti-inflammatory properties of this drug have been reported in several studies. METHODS: Sixty-three patients with third-degree hemorrhoids had ambulatory stapled hemorrhoidopexy under spinal anesthesia in the period of one year. The patients were randomized, with 30 receiving Detralex 500 mg (2 tablets 3 times daily for 5 days after the operation) and 33 forming the control group. The patients were asked to daily self-assess the presence of blood on defecation, degree of pain and consumption of analgesics for the first week after the operation. RESULTS: There was no significant difference between the two groups in duration of presence of blood, degree of pain or analgesics requirement. No major complications, such as bleeding requiring transfusion or hospitalization, sepsis, anal stenosis or urgent defecation, were noted in the follow-up period. There were no side effects from Detralex treatment. DISCUSSION: In our study we could not demonstrate any positive effect of prescribing flavonoids after stapler hemorrhoidopexy. This procedure may not be sufficiently aggressive and is associated with too few postoperative complications to show any protective influence of flavonoids.

Genetic diversity of HPV-6 in concurrent multiple anogenital warts.

INTRODUCTION: Anogenital warts (AGW) are the most common benign tumors in the anogenital area. They are etiologically associated with alpha human papillomaviruses (HPV), in more than 90% of cases with HPV-6 and HPV-11. AGW frequently displays a multifocal and multicentric appearance. However, it is not clear whether the occurrence of multiple AGW in a particular patient is a consequence of infection with single or multiple HPV genomic variants of a given HPV genotype. METHODS: Forty-five HPV-6 isolates from fresh-frozen AGW tissue specimens, obtained from 18 patients with concurrent multiple AGW, were included. The entire HPV-6 L1, E5a, E5b ORFs, and LCR genomic region was sequenced. RESULTS: Fourteen different HPV-6 L1-LCR-E5a-E5b genomic variants were identified among 18 patients with concurrent multiple AGW. In 17 out of 18 patients, a single identical HPV-6 L1-E5a-E5b-LCR genomic variant was identified in all concurrent multiple AGW collected in an individual patient. Co-infection with two different HPV-6 genomic variants was identified in one patient. DISCUSSION: The presence of an identical HPV genomic variant in all concurrently present multiple AGW within an individual patient supports the hypothesis that the occurrence of multiple concurrent AGW is a consequence of infection with a single HPV-6 genomic variant, rather than infection with multiple genomic variants of HPV-6.

Distribution of HPV genotypes in Slovenian patients with anal carcinoma: preliminary results.

The aim of the present study was to obtain first data on the distribution of human papillomavirus (HPV) genotypes in patients with anal cancer (AC) in Slovenia. A total of 21 samples of AC (16 archival FFPE samples and 5 fresh-frozen tissue samples) collected from the same number of patients were analysed. All samples were tested for the presence of HPV DNA using a consensus GP5+/ GP6+ PCR and HPV genotypes determined by the INNO LiPA HPV Genotyping Extra test, capable of recognizing 28 different alfa-HPV genotypes. All 21 AC samples were HPV DNA positive. The most frequent HPV genotype, found in 19/21 AC samples, was HPV-16. Only low-risk HPV-6 was detected in one sample and infection with high-risk HPV-52 and low-risk HPV-61 was identified in one sample. Prophylactic HPV vaccination with currently available vaccines could potentially prevent the great majority of anal cancers in Slovenia.

Genomic distribution of beta papillomaviruses in single eyebrow hair samples and pools of eyebrow hair samples.

Human beta papillomaviruses (beta-HPVs) are frequently detected in hairs and the majority of people are infected with multiple beta-HPV genotypes. This study was conducted to investigate for the first time the distribution of beta-HPV genotypes in single hair specimens and to estimate the contribution of a single hair to the beta-HPV profile obtained from a specimen made of multiple hairs pooled together. A total of 85 eyebrow hair specimens, representing 64 single hairs and 21 pools of hairs, obtained from 21 immunocompetent individuals, were tested using a reverse-line blot-based beta-HPV genotyping assay that allows identification of 25 different beta-HPVs. Overall, beta-HPV DNA was detected in 82/84 (97.6%) samples. The great majority of hair pools (19/21; 90.5%) contained multiple beta-HPVs, the mean number of identified beta-HPV genotypes per hair pool was 5.2 (ranging from 1 to 12). In individual hairs, the great majority of individual hairs (43/63; 68.3%) contained multiple beta-HPVs, the mean number of identified beta-HPV genotypes was 4 (ranging from 1 to 12). Overall, HPV-23 was the most prevalent genotype, followed by HPV-24 and HPV-38. A comparison of beta-HPV genotype distribution in pooled hair specimens and in at least one individual hair within a single patient revealed that 5/20 patients had a complete match between the number and profile of identified genotypes, 2/20 patients had the same/similar number of HPV genotypes but different genotype profile, 9/20 patients had more HPV genotypes identified in pools than in the majority of individual hairs and 4/20 patients had at least one individual hair with more HPV genotypes identified than in the corresponding pool. Our results suggest that beta-HPVs are unevenly distributed over the eyebrows and even pools made of several hairs do not necessarily provide information on the whole spectrum of HPV genotypes present in eyebrows.