Stefan Mohr

Toward cell therapy using placenta-derived cells: disease mechanisms, cell biology, preclinical studies, and regulatory aspects at the round table

Among the many cell types that may prove useful to regenerative medicine, mounting evidence suggests that human term placenta-derived cells will join the list of significant contributors. In making new cell therapy-based strategies a clinical reality, it is fundamental that no a priori claims are made regarding which cell source is preferable for a particular therapeutic application. Rather, ongoing comparisons of the potentiality and characteristics of cells from different sources should be made to promote constant improvement in cell therapies, and such comparisons will likely show that individually tailored cells can address disease-specific clinical needs. The principle underlying such an approach is resistance to the notion that comprehensive characterization of any cell type has been achieved, neither in terms of phenotype nor risks-to-benefits ratio. Tailoring cell therapy approaches to specific conditions also requires an understanding of basic disease mechanisms and close collaboration between translational researchers and clinicians, to identify current needs and shortcomings in existing treatments. To this end, the international workshop entitled Placenta-derived stem cells for treatment of inflammatory diseases: moving toward clinical application was held in Brescia, Italy, in March 2009, and aimed to harness an understanding of basic inflammatory mechanisms inherent in human diseases with updated findings regarding biological and therapeutic properties of human placenta-derived cells, with particular emphasis on their potential for treating inflammatory diseases. Finally, steps required to allow their future clinical application according to regulatory aspects including good manufacturing practice (GMP) were also considered. In September 2009, the International Placenta Stem Cell Society (IPLASS) was founded to help strengthen the research network in this field.

A Comparison of Radiocolloid and Indocyanine Green Fluorescence Imaging, Sentinel Lymph Node Mapping in Patients with Cervical Cancer Undergoing Laparoscopic Surgery

AbstractBackground and Purpose99TC combined with blue-dye mappingn is considered the best sentinel lymph node (SLN) mapping technique in cervical cancer. Indocyanine green (ICG) with near infrared fluorescence imaging has been introduced as a new methodology for SLN mapping. The aim of this study was to compare these two techniques in the laparoscopic treatment of cervical cancer.MethodsMedical records of patients undergoing laparoscopic SLN mapping for cervical cancer with either 99Tc and patent blue dye (Group 1) or ICG (Group 2) from April 2008 until August 2012 were reviewed. Sensitivity, specificity, and overall and bilateral detection rates were calculated and compared.ResultsFifty-eight patients were included in the study—36 patients in Group 1 and 22 patients in Group 2. Median tumor diameter was 25 and 29xa0mm, and mean SLN count was 2.1 and 3.7, for Groups 1 and 2, respectively. Mean non-SLN (NSLN) count was 39 for both groups. SLNs were ninefold more likely to be affected by metastatic disease compared with NSLNs (pxa0<xa00.005). Sensitivity and specificity were both 100xa0%. Overall detection rates were 83 and 95.5xa0% (pxa0=xa0nonsignificant), and bilateral detection rates were 61 and 95.5xa0% (pxa0<xa00.005), for Groups 1 and 2, respectively. In 75xa0% of cases, SLNs were located along the external or internal iliac nodal basins.ConclusionsICG SLN mapping in cervical cancer provides high overall and bilateral detection rates that compare favorably with the current standard of care.

Laparoscopic Indocyanine Green Sentinel Lymph Node Mapping in Endometrial Cancer

BackgroundIn endometrial cancer (EMCA), indocyanine green (ICG) sentinel lymph node (SLN) mapping has been reported, mainly in conjunction with robotic surgery.ObjectiveWe aimed to evaluate detection rates, sensitivity, and false negative (FN) rate of laparoscopic ICG SLN mapping in EMCA, and to evaluate differences in surgical outcomes between patients subjected to SLN biopsy only versus lymphadenectomy.MethodsA retrospective analysis of EMCA patients undergoing ICG SLN mappingxa0±xa0pelvic (PLND) and/or para-aortic lymphadenectomy (PALND) was performed. Detection rates were calculated for the entire cohort. Sensitivity and FN rates were calculated for patients undergoing lymphadenectomy after SLN mapping, and surgical outcome was compared among patients undergoing SLN mapping only versus lymphadenectomy.ResultsOf 75 patients, 33 underwent SLN mapping and 42 underwent SLN mapping followed by PLND/PALND. Overall and bilateral detection rates were 96xa0% (72/75) and 88xa0% (66/75), respectively, and the median number of removed SLNs, pelvic non-SLNs (NSLN) and para-aortic NSLNs was 3, 27, and 19, respectively. With a FN rate of 8.3xa0%, only one patient had bilateral FN SLNs and a metastatic para-aortal NSLN. Estimated blood loss (EBL) and operative (OR) time were significantly lower in patients undergoing SLN mapping only. No differences in complication rates between patients undergoing SLN mapping only and patients undergoing lymphadenectomy were recorded.ConclusionsLaparoscopic ICG SLN mapping has excellent overall and bilateral detection rates and a low FN rate. Compared with lymphadenectomy, SLN biopsy is associated with significantly lower EBL and shorter OR time.

Bulking agents: an analysis of 500 cases and review of the literature

Introduction and hypothesisStress urinary incontinence (SUI) is common, impacts women’s quality of life, and generates high costs. Physiotherapy is the first-line therapy, and if it fails, suburethral slings are the gold standard in SUI surgery. Bulking agents injected periurethrally might be a beneficial alternative, but there is a paucity of data on bulking therapy. The aim of this study was to prospectively analyze the efficacy and safety of bulking agents in the setting of a tertiary referral center.MethodsIn the last 13xa0years, 514 elderly women with SUI were treated by injection therapy with either collagen (Contigen®), hyaluronic acid (Zuidex®), ethylene vinyl alcohol (Tegress®), or polyacrylamide hydrogel (Bulkamid®). Subjective and objective outcome was recorded at the 12-month postoperative appointment using the King’s Health Questionnaire, visual analogue scale (VAS) describing their incontinence severity, standardized pad test, and urethral pressure profile.ResultsDemographic data were equally distributed in all four groups of agents used. Sixty-one patients were lost to follow-up (10.6xa0%). Statistically significant changes were found for maximum urethral closure pressure (MUCP), pad weight, and VAS before and after bulking for the four agents used. Pad test was negative in 73.2xa0% of patients after bulking therapy. Subjective assessment showed improvements in general health and role limitations. The overall complication rate was low for all agents.ConclusionsThis study shows improvement in incontinence after bulking therapy according to subjective and objective outcomes in an elderly population. In contrast to earlier reports, side effects due to injections were few and mild. We can advocate bulking therapy for treating SUI, as it is simple, safe, and shows both objective and subjective improvement and relief.

Generation of an osteogenic graft from human placenta and placenta-derived mesenchymal stem cells.

The objecitve of the study was to determine the feasibility of generating a biodegradable, stem cell-loaded osteogenic composite graft from human placenta. Initially, a scaffold from human chorion membrane was produced. Human placenta mesenchymal stem cells (MSCs) derived from either first-trimester chorionic villi or term chorion membrane were differentiated osteogenically on this scaffold. Outgrowth, adherence, and osteogenic differentiation of cells were assessed by immunohistochemistry (IHC), scanning electron microscopy, protein expression, and real-time polymerase chain reaction (RT-PCR). Our results showed that a cell-free extracellular matrix scaffold can be generated from human chorion. Seeded MSCs densely adhered to that scaffold and were osteogenically differentiated. Calcium and alkaline phosphatase were detected in the cell-scaffold constructs as a proof of mineralization and findings were confirmed by IHC and RT-PCR results. This study shows for the first time that generation of an osteogenic composite graft using placental tissue is feasible. It might allow therapeutic application of autologous or allogeneic grafts in congenital skeletal defects by means of a composite graft.

FIGO stage IIIC endometrial cancer identification among patients with complex atypical hyperplasia, grade 1 and 2 endometrioid endometrial cancer: laparoscopic indocyanine green sentinel lymph node mapping versus frozen section of the uterus, why get around the problem?

PurposeTo compare two surgical strategies used to identify lymph node metastases in patients with preoperative diagnosis of complex atypical hyperplasia (CAH), grade 1 and 2 endometrial cancer (EC).MethodsData on patients with preoperative diagnosis of CAH, grade 1 and 2 EC undergoing laparoscopic indocyanine green (ICG) sentinel lymph node (SLN) mapping followed by frozen section of the uterus were collected. When risk factors were identified at frozen section, patients were subjected to a systematic lymphadenectomy. False negative (FN) rates, negative predictive values (NPV), positive predictive values (PPV) and correlation with stage IIIC EC were calculated for the systematic lymphadenectomy based on frozen section of the uterus and for the SLN mapping.ResultsSix (9.5%) out of 63 patients had lymph nodal metastases. Based on frozen section of the uterus, 22 (34.9%) and 15 (22.2%) patients underwent a pelvic and a pelvic and paraaortic lymphadenectomy, respectively. Five patients with stage IIIC disease were identified with a FN rate of 16.7% and a NPV and PPV of 97.6 and 27.3%, respectively. Overall and bilateral detection rates of ICG SLN mapping were 100 and 97.6%, respectively; no FN were recorded. The identification of patients with stage IIIC disease with ICG SLN mapping showed a NPV and PPV of 100%. Correlation between indication to lymphadenectomy and stage IIIC disease was poor (κxa0=xa00.244) when based on frozen section of the uterus and excellent (κxa0=xa01) when based on SLN mapping.ConclusionsICG SLN mapping reduces the number of unnecessary systematic lymphadenectomies and the risk of underdiagnosing patients with metastatic lymph nodes.

Painful Love—“Hispareunia” after Sling Erosion of the Female Partner

INTRODUCTIONnSling erosion/extrusion is a complication after suburethral sling insertion for female stress urinary incontinence that occurs in approximately 6% of patients. Symptoms may include vaginal discharge, infections, postcoital bleeding, and alterations of the sexual function. Little is known about the effect of sling erosion on the sexual function of the male partner.nnnAIMnThe aim of this study was to determine male sexual function in partners of women who had undergone sling insertion for stress urinary incontinence and who developed sling erosion postoperatively.nnnMAIN OUTCOME MEASURESnMain outcome measures were the Brief Male Sexual Function Inventory (BMSFI) and visual analog scale (VAS) scores.nnnMETHODSnMale partners of patients who presented with sling erosion for various reasons were addressed and asked to fill in the BMSFI and assess sexual pain using the VAS before and 6 months after the sling erosion of their female partners was treated. Participants gave informed consent and those who had undergone prostate surgery during the past 12 months were excluded. For statistical analyses, SPSS version 10.0 (SPSS Inc., Chicago, IL, USA) was used.nnnRESULTSnThirty-two males were included in the study and produced a full set of data. VAS scores as a measurement for hispareunia improved from a median score of 8 before to a median score of 1 after intervention. Some domains of male sexual function (sexual interest, sexual drive, ejaculation, and erection) were significantly improved whereas the strength of erection, problems with ejaculation, and problems with lack of interest were not statistically significantly changed.nnnCONCLUSIONSnChanges of male sexual function and particularly pain after sling insertion in their female partners may be due to sling exposure. Sexual interest and drive may be negatively influenced. Male dyspareunia is a complaint that can be treated effectively by correcting the sling exposure.

Laparoscopic Indocyanine Green Sentinel Lymph Node Mapping in Pregnant Cervical Cancer Patients.

We present cases of 2 pregnant patients with early-stage cervical cancer who have undergone indocyanine green (ICG) sentinel lymph node (SLN) mapping followed by laparoscopic SLN biopsy, pelvic lymphadenectomy, and cervical conization. Eight milliliters of ICG were injected in the 4 quadrants of the cervix after having obtained an adequate pneumoperitoneum and having inspected the abdominal cavity. SLNs were identified in both hemipelvises in both patients. In the final pathologic analysis, both SLNs and non-SLNs were negative for metastatic disease. No adverse events from ICG injection were recorded. ICG SLN mapping seems to be feasible in pregnant cervical cancer patients.

Sexual function after vaginal and abdominal fistula repair

OBJECTIVEnThe purpose of this study was to compare clinical outcomes and sexual function between transvaginal and transabdominal repairs of vesicovaginal fistulae (VVF).nnnSTUDY DESIGNnParticipants (99 women with VVF at a tertiary referral center) were treated with urinary catheterization for 12 weeks and, if the procedure was unsuccessful, underwent repair using either the transvaginal (Latzko) or transabdominal technique. Objective clinical parameters were analyzed; subjective outcomes were recorded prospectively before surgery and at the 6-month follow-up examination with the use of the female sexual function index to evaluate sexual function and the visual analog scale to measure general disturbance by the fistula.nnnRESULTSnAfter bladder drainage for 12 weeks, 8 patients had spontaneous fistula closure. Demographic variables were similar in the transvaginal (n = 60) and transabdominal (n = 31) repair groups. The transvaginal procedure showed significantly shorter operation times, less blood loss, and shorter hospital stay. Continence rates 6 months after surgery were 82% (transvaginal) and 90% (transabdominal). Sexual function in the 64 sexually active patients was significantly improved, and overall disturbance by the fistula was reduced with both operative techniques. Neither surgical intervention was superior to the other regarding sexual function or visual analog scale.nnnCONCLUSIONnFistula repair improves sexual function and quality of life with no difference attributable to surgical route. Given this and that operating time, blood loss and length of stay are less with the transvaginal approach, the transvaginal approach is preferred in VVF repair if fistula and patient characteristics are suitable.

Indocyanine Green Fluorescence Imaging in the Surgical Management of an Iatrogenic Lymphatic Fistula: Description of a Surgical Technique

We present a case of laparoscopic surgical management of an iatrogenic lymphorrhea using indocyanine green (ICG). A case of a patient who developed recurrent symptomatic lymphorrhea after laparoscopic radical hysterectomy and bilateral pelvic lymphadenectomy for an early stage cervical cancer is presented. Intraoperative bipedal interdigital subcutaneous injection of ICG exactly localized the disrupted lymphatic duct on fluorescence imaging performed with a near-infrared laparoscopic fluorescent optic device, thus allowing a successful surgical repair.