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Supplemental material, sj-docx-1-tam-10.1177_17588359221086911 for Topical heparin as an effective and safe treatment for patients with capecitabine-induced hand-foot syndrome: results of a phase IIA trial supported by proteomic profiling of skin biopsies by Analia Rodríguez-Garzotto, Lara Iglesias-Docampo, C. Vanesa Díaz-García, Isabel Ruppen, Pilar Ximénez-Embún, Carlos Gómez, J. Luis Rodríguez-Peralto, Javier Ortiz de Frutos, Jose A. Lopez-Martin, Cristina Grávalos, Hernán Cortés-Funes and M. Teresa Agulló-Ortuño in Therapeutic Advances in Medical Oncology

Supplemental material, sj-docx-2-tam-10.1177_17588359221086911 for Topical heparin as an effective and safe treatment for patients with capecitabine-induced hand-foot syndrome: results of a phase IIA trial supported by proteomic profiling of skin biopsies by Analia Rodríguez-Garzotto, Lara Iglesias-Docampo, C. Vanesa Díaz-García, Isabel Ruppen, Pilar Ximénez-Embún, Carlos Gómez, J. Luis Rodríguez-Peralto, Javier Ortiz de Frutos, Jose A. Lopez-Martin, Cristina Grávalos, Hernán Cortés-Funes and M. Teresa Agulló-Ortuño in Therapeutic Advances in Medical Oncology

Supplemental material, sj-docx-3-tam-10.1177_17588359221086911 for Topical heparin as an effective and safe treatment for patients with capecitabine-induced hand-foot syndrome: results of a phase IIA trial supported by proteomic profiling of skin biopsies by Analia Rodríguez-Garzotto, Lara Iglesias-Docampo, C. Vanesa Díaz-García, Isabel Ruppen, Pilar Ximénez-Embún, Carlos Gómez, J. Luis Rodríguez-Peralto, Javier Ortiz de Frutos, Jose A. Lopez-Martin, Cristina Grávalos, Hernán Cortés-Funes and M. Teresa Agulló-Ortuño in Therapeutic Advances in Medical Oncology

Study Objective: To compare operative and postoperative results of ovarian cortex retrieval by conventional laparoscopy (1cm umbilical site and 3 accessory 5-mm-reusable working ports) (HASS) versus single site laparoscopy (SSL). Design: Prospective cohort study. Setting: Fertility Preservation Programme at La Fe University Hospital-University of Valencia, Valencia, Spain, 2011 to 2012. Fertility Preservation Programme at La Fe University Hospital of Valencia, Valencia, Spain. Patients: Twenty-one patients with cancer (breast cancer: n = 17; Hodgkin's lymphoma: n = 3; and non-Hodgkin's lymphoma: n = 1). Intervention: Ovarian cortex retrieval either by conventional laparoscopy using an umbilical Hasson port and 3 accessory ports (HASS group: n = 11) or by SSL (SSL group: n = 10). Measurements and Main Results: Operative length, blood loss, postoperative pain (visual analog scale for pain at 6, 24, and 48 hours), need of additional analgesia, quality of life (European Quality of Life-5 Dimensions), cosmesis of the scar, and patient's self-perception were assessed at 24 and 48 hours and 3 months after surgery. Baseline characteristics were similar between groups. Estimated blood loss, operative length, and postoperative pain did not differ between groups. The start of chemotherapy was not delayed in either group, and cosmesis and image self-perception were also similar. Conclusion: The SSL approach can be considered a safe option compared with the classic multisite approach. (C) 2015 AAGL. All rights reserved.

Introduction In vitro activation and growth of primordial dormant follicles to produce fertilizable oocytes would provide a useful instrument for fertility preservation. The employment of Phosphatase and TENsin homolog (PTEN) inhibitors, in combination with Protein kinase B (Akt) stimulating molecules, has been previously employed to increase follicular activation through the stimulation of the PTEN-Akt pathway. Methods We aim to establish improved in vitro activation also for cancer patients whose ovarian tissue has already been cryopreserved. Fresh and previously cryopreserved human ovarian cortex were exposed to short-term, low-concentration and ovary-specific treatment with only a PTEN inhibitor. Results Our in vitro activation protocol enhances the activation mechanisms of primordial follicles in both fresh and cryopreserved samples, and enlarges growing populations without inducing apoptosis in either follicles or the surrounding stroma. Treatment augments estradiol secretion wand restores the expression levels of the previously diminished Anti-Mullerian hormone by means of cryopreservation procedures. Genomic modulation of the relative expression of PTEN pathway genes was found in treated samples. Conclusion The in vitro activation protocol offers new alternatives for patients with cryopreserved tissue as it increases the pool of viable activated follicles available for in vitro growth procedures. The combination of ovarian tissue cryopreservation and in vitro activation of primordial follicles, the main ovarian reserve component, will be a major advancement in fertility preservation.

BACKGROUND: Assisted reproduction technology (ART) has become a standard treatment for infertile couples. Increased success rates obtained over the years have resulted primarily from improved embryo quality, but implantation rates still remain lower than expected. The uterus, an important player in implantation, has been frequently neglected. While a number of uterine pathologies have been associated with decreased natural fertility, less information exists regarding the impact of these pathologies in ART. This report reviews the evidence to help clinicians advise ART patients. METHODS: An electronic search of PubMed and EMBASE was performed to identify articles in the English, French or Spanish language published until May 2014 which addressed uterine pathology and ART. Data from natural conception were used only in the absence of data from ART. Studies were classified in decreasing categories: RCTs, prospective controlled trials, prospective non-controlled trials, retrospective studies and experimental studies. Studies included in lower categories were only used if insufficient evidence was available. Pooled data were obtained from systematic reviews with meta-analyses when available. The summary of the evidence for the different outcomes and the degree of the recommendation for interventions were based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) statement recommendations. RESULTS: There is strong evidence that surrogacy is effective for uterine agenesia. For the remaining pathologies, however, there is very little evidence that the established treatments improve outcomes, or that these pathologies have a negative effect on ART. In the presence of an apparently normal uterus, assessing endometrial receptivity (ER) is the goal; however diagnostic tests are still under development. CONCLUSIONS: The real effect of different uterine/endometrial integrity pathologies on ART is not known. Moreover, currently proposed treatments are not based on solid evidence, and little can be done to assess ER in normal or abnormal conditions. No strong recommendations can be given based on the published experience, bringing an urgent need for well-designed studies. In this context, we propose algorithms to study the uterus in ART.

Objective: To determine whether there is any difference in the follicular fluid (FF) microRNA (miRNA) profiles from in vitro fertilization (IVF) patients according to their age and oocyte maturation stage. Design: Observational prospective study. Setting: IVF clinic/hospital facilities. Patients(s): We included 30 women with primary infertility undergoing intracytoplasmic sperm injection treatment and excluded patients with polycystic ovarian syndrome, endometriosis, severe male factor, and low ovarian reserve. Intervention(s): After the collection of FF and granulosa cells from each patient, the samples were processed for total RNA extraction. RNA was pooled into different groups (three samples per pool) for microarray analysis to evaluate the expression of a total of 866 human miRNAs. Individual samples were analyzed to validate the pooled microarray results using real-time polymerase chain reaction. Main Outcome Measure(s): Evaluation of the expression of a total of 866 human miRNAs in FF and granulosa cells. Result(s): We identified only one differentially expressed miRNA, hsa-miR-424, which is present in higher proportions in FF from patients with advanced age. When we compared the FF from metaphase II (MII) versus GV (germinal vesicle) oocytes, we found 13 differentially expressed miRNAs (two up-and 11 downregulated). When we compared FF from MII versus MI, we found seven differentially expressed miRNAs in MII (three up-and four downregulated). Conclusion(s): We have described the FF miRNA profiles according to IVF patients' age and the maturation stage of their oocytes. This descriptive study may aid our understanding of the physiology and regulation of oocyte maturation and could identify some potential miRNA biomarkers for this process. (C)2015 by American Society for Reproductive Medicine.

Objective: To develop a novel molecular panel of markers to detect breast cancer (BC) disseminated malignant cells in ovarian tissue, and to improve the safety of ovarian tissue transplantation. Design: Experimental study. Setting: University hospital. Patient(s): Ten ovarian biopsies from healthy patients, 13 biopsies with diagnosed BC metastasis, and 4 biopsies from primary BC tumor for designing a diagnostic panel of BC cell contamination; 60 ovarian biopsies from BC patients undergoing fertility preservation for validating the panel. Animal(s): Female nude mice. Intervention(s): A novel panel for BC malignant cell detection by reverse-transcription polymerase chain reaction (RT-PCR), inmmunohistochemical analysis, in vitro invasion assay and xenotransplantation assayed in ovarian tissue from BC patients. Main Outcome Measure(s): Expression of GCDFP15, MGB1, SBEM, MUC1, WT-1, and NY-BR-01, selected as markers, assessed by quantitative RT-PCR in samples with confirmed BC metastasis. The most sensitive markers were confirmed by immunohistochemistry, and tested in vitro and in vivo. Result(s): GCDFP15, MGB1, and SBEM were the most sensitive and specific markers to detect BC metastatic cells when at least one was expressed by quantitative RT-PCR. The panel was validated in 60 patients and confirmed in an in vitro invasion assay, where no invasive cells were observed. Samples negative for BC cells cannot develop disease when xenografted. Conclusion(s): GCDFP15, MGB1, and SBEM were the most sensitive molecules to create a diagnostic panel for BC malignant cell contamination, which may make ovarian tissue cryopreservation and transplantation a safe technique for fertility preservation in BC patients. (C) 2015 by American Society for Reproductive Medicine.

Objective: To investigate whether allogeneic uterine grafts in a rat model, with tacrolimus immunosuppression, can harbor pregnancies that result in offspring with normal postnatal growth. Design: Experimental animal study. Settingg: University hospital. Animals(s): Lewis rats as uterus donors and Piebald-Virol-Glaxo rats as recipients. Intrvention(s): Animals were allocated to one of the following three groups: allogeneic uterus transplantation with end-to-side anastomosis to the external iliac vessels and immunosuppression with tacrolimus (UT+Tac; n = 10); sham surgery and immunosuppression with tacrolimus (Sham+Tac; n = 10); or sham surgery (Sham; n = 10). The rats were subsequently introduced to male rats with proven fertility and in the event of resulting pregnancy cesarean sections were performed on day 22 of pregnancy. Main outcome measure(s): Graft viability, fertility rate, perinatal death, birth weight, postnatal birth trajectory. Results(s): Pregnancy rate was higher in the control groups (70% Sham and 80% Sham+Tac) than in the transplanted group (50% UT+Tac), although these differences did not reach the significance threshold. There were no differences between groups regarding number of living pups or neonatal deaths. Pups born from UT+Tac mothers had birth weights similar to external control animals from our breeding colony (BC): UT+Tac males 6.2 +/- 0.2 g, UT+Tac females 5.5 +/- 0.6 g, BC males 5.8 +/- 0.2 g, BC females 5.2 +/- 0.3 g; n.s. Evaluation of uteri and placentas of pregnant animals revealed a somewhat reduced vascular density in both tissues in the UT+Tac group, and that was not seen in the Sham+Tac group. Conclusion(s): Allogeneic uterus transplantation and immunosuppression with tacrolimus is compatible with normal pregnancy and perinatal outcome in a rat model. (C)2014 by American Society for Reproductive Medicine.

Uterus transplantation (UTx) has been proposed as a method to treat women with absolute uterine factor infertility. The aim of this study was to evaluate the viability of the transplanted rat uterus after exposure to long warm ischemic times, in order to mimic a time frame likely to occur in a human situation during complicated pelvic vascular anastomosis surgery.