Preventing bisphosphonate induced osteonecrosis of the jaw with a polyguanidine conjugate (GuaDex): A promising new approach.

Osteonecrosis of the jaw (ONJ) is a relatively rare side effect after prolonged use of bisphosphonates, which are drugs used to treat bone resorption in osteoporosis and certain cancers. This study introduces a novel ONJ model in rats by combining exposure to bisphosphonates, oral surgery, and bacterial inoculation. Potential ONJ preventive effects of polyguanidine (GuaDex) or antibiotics were evaluated. The study consisted of twenty-four male Wistar rats were divided into four groups. Groups 1 to 3 were given weekly doses of i.v. Zoledronic acid (ZA), four weeks before and two weeks after an osteotomy procedure on their left mandibular first molar. Group 4 was a negative control. Streptococcus gordonii bacteria were introduced into the osteotomy pulp chamber and via the food for seven days. On day eight, the rats were given different treatments. Group 1 was given a GuaDex injection into the osteotomy socket, Group 2 was given an intramuscular (i.m.) injection of clindamycin, Group 3 (positive control) was given an i.m. injection of saline, and Group 4 was given an i.m. injection of saline. Blood samples were taken two weeks after the osteotomy procedure, after which the rats were euthanized. Bone healing, bone mineral density, histology, and blood status were analyzed. The results showed that Group 1 (GuaDex) had no ONJ, extensive ongoing bone regeneration, active healing activity, vascularization, and no presence of bacteria. Group 2 (clindamycin) showed early stages of ONJ, avascular areas, and bacteria. Group 3 showed stages of ONJ, inflammatory infiltrates, defective healing, and bacterial presence, and Group 4 had normal healing activity and no bacterial presence. Conclusion: ZA treatment and bacterial inoculation after tooth extraction inhibited bone remodeling/healing and induced ONJ characteristic lesions in the rats. Only GuaDex apparently prevented ONJ development, stimulated bone remodeling, and provided an antimicrobial effect.

Cryotherapy plus low-dose oral isotretinoin vs cryotherapy only for the treatment of anogenital warts: a randomized clinical trial.

BACKGROUND: Anogenital warts are a common human papillomavirus infection. They cause emotional distress, especially when they are in the anogenital region. Cryotherapy is a first-line treatment. Previous clinical trials and case series have reported variable results with retinoids (isotretinoin) as adjuvant therapy. OBJECTIVE: To determine the safety and efficacy of low-dose oral isotretinoin as adjuvant treatment of anogenital warts. METHODS: Forty-six patients with anogenital warts were randomly assigned to isotretinoin + cryotherapy (n = 23) or only cryotherapy (n = 23). Patients were allocated via an interactive web-based randomization system. Evaluators were blinded to treatments. Isotretinoin 20 mg/daily + cryotherapy or cryotherapy were prescribed for 6 weeks. Patients were followed for 4 months. Genotyping of lesions was performed before treatment started. Dermatology Life Quality Index (DLQI) and Columbia-Suicide Severity Rating Scale (C-SSRS) were measured at the beginning and end of therapy. All patients completed the study. RESULTS: Both Groups had 50% clearance at the end of treatment. Recurrence in the combined group was not significantly lower than in the cryotherapy group (P = 0.59). Improvement was observed in the DLQI of all patients in both groups (P = 0.001). No suicidal intention was detected with the C-SSRS. Two patients (one in each group) had liver function test abnormalities after treatment. CONCLUSION: Combined therapy showed a slight not significant efficacy for anogenital warts in Hispanic patients. Low-dose isotretinoin seems to be safe even when it is used with cryotherapy on anogenital warts. TRIAL REGISTRATION: On April 25, 2019 with registration number DE19-00004, CONBIOÉTICA-19-CEI-001-20160404. Prospectively registered.

Combining ERBB family and MET inhibitors is an effective therapeutic strategy in cutaneous malignant melanoma independent of BRAF/NRAS mutation status.

Current treatment modalities for disseminated cutaneous malignant melanoma (CMM) improve survival; however, relapses are common. A number of receptor tyrosine kinases (RTKs) including EGFR and MET have been reported to be involved in CMM metastasis and in the development of resistance to therapy, targeting the mitogen-activated protein kinase (MAPK pathway). IHC analysis showed that patients with higher MET protein expression had a significantly shorter overall survival. In addition, silencing of MET caused an upregulation of EGFR and p-AKT, which was abrogated by concomitant silencing of MET and EGFR in CMM cells resistant to MAPK-targeting drugs. We therefore explored novel treatment strategies using clinically approved drugs afatinib (ERBB family inhibitor) and crizotinib (MET inhibitor), to simultaneously block MET and ERBB family RTKs. The effects of the combination were assessed in cell culture and spheroid models using established CMM and patient-derived short-term cell lines, and an in vivo xenograft mouse model. The combination had a synergistic effect, promoting cell death, concomitant with a potent downregulation of migratory and invasive capacity independent of their BRAF/NRAS mutational status. Furthermore, the combination attenuated tumor growth rate, as ascertained by the significant reduction of Ki67 expression and induced DNA damage in vivo. Importantly, this combination therapy had minimal therapy-related toxicity in mice. Lastly, the cell cycle G2 checkpoint kinase WEE1 and the RTK IGF1R, non-canonical targets, were altered upon exposure to the combination. Knockdown of WEE1 abrogated the combination-mediated effects on cell migration and proliferation in BRAF mutant BRAF inhibitor-sensitive cells, whereas WEE1 silencing alone inhibited cell migration in NRAS mutant cells. In summary, our results show that afatinib and crizotinib in combination is a promising alternative targeted therapy option for CMM patients, irrespective of BRAF/NRAS mutational status, as well as for cases where resistance has developed towards BRAF inhibitors.

Metastasis of Breast Lobular Carcinoma to Endometrium Presenting as Recurrent Abnormal Uterine Bleeding: A Case Report and Review of Literature.

There are few reports of breast cancer cases with uterine metastases. Here, we report a metastatic lobular carcinoma to endometrium presenting as abnormal uterine bleeding. Diagnosis was based in previous lobular breast carcinoma and immunohistochemistry.

Pirfenidone increases the epithelialization rate of skin graft donor sites.

BACKGROUND: Improving epithelialization of donor sites of split-thickness skin grafts (STSG) is extremely important in burned patients. We aimed to assess the efficacy of pirfenidone, a drug with anti-inflammatory, antifibrotic, and antioxidant effects, to accelerate wound healing. We hypothesized that pirfenidone accelerates the epithelialization rates in donor sites. METHODS: We included 28 patients requiring STSGs with donor sites of at least 7.5×10cm. After harvesting, the donor sites were randomly treated with either non-adherent gauze or topical pirfenidone and covered with non-adherent gauze. To assess epithelialization, biopsies were taken at day 7 and 10 on the pirfenidone group, and at day 10 on the control group. Percentage of epithelialization was assessed on the same days through clinical photographs. The pathologists and the clinical observer were blinded to the group and timepoint of the samples. RESULTS: 24 patients were included in the study, with a median age of 21(5-73) for control group and 28(9-61) for pirfenidone. The thickness of epithelium was 75.10±60µm at day 10 for the control group; and 98.21±6µm at day 7, and 108±22µm at day 10 for the pirfenidone group (p=<0.05). Epithelization rate was 83.58±14.09% at day 10 for the control group; and 98.7±1.8% at day 7, and 99.5±1.6% at day 10 for the pirfenidone group. CONCLUSIONS: Pirfenidone is efficient in reducing the healing times when applied in STSG donor sites, at both days 7 and 10.

Pediatric Papillary Renal Cell Carcinoma in a Horseshoe Kidney: A Case Report with Review of the Literature.

Renal cell carcinoma is the most common malignancy of the kidney in adults. In children, however, it only accounts for an estimated 1.8 to 6.3% of all pediatric malignant renal tumors. Papillary renal cell carcinoma is the second most common type of renal cell carcinoma in children. We present the case of a 12-year-old boy with a 2-month history of abdominal pain, unexplained weight loss, and gross hematuria. Computed tomography revealed a horseshoe kidney and a well-defined mass of 4 cm arising from the lower pole of the right kidney. Microscopically the tumor was composed of papillae covered with cells with abundant eosinophilic cytoplasm and high-grade nuclei with prominent nucleoli. Immunohistochemistry was performed; EMA, Vimentin, and AMACR were strongly positive while CK7, CD10, RCC antigen, TFE3, HMB-45, and WT-1 were negative. Currently, 10 months after the surgical procedure, the patient remains clinically and radiologically disease-free.