Sequence of treatment in locally advanced and metastatic renal cell carcinoma

The spectrum of drugs that have shown activity in advanced or metastatic renal cell carcinoma (RCC) has led to a debate on the optimal sequence of treatments. There is agreement on recommending targeted agents as the standard of care in this disease. Uncertainty, however, remains on the best first-line drug choice. Physicians and patients may select sunitinib, bevacizumab in combination with interferon-alpha (IFN-α), pazopanib, or—in poor risk patients—temsirolimus. There are also a variety of therapies with proven efficacy on hand in the second-line setting: sorafenib, pazopanib, axitinib, and everolimus. While most randomized RCC trials assessed progression free survival (PFS) as primary endpoint, some agents were shown to improve median overall survival (OS), and given in sequence they have extended the life expectancy of RCC patients from 13 months in the cytokine era to over 30 months. Despite the progress made, there are sobering aspects to the oncologic success story in RCC, as the new treatments do not obtain an objective response or disease stabilization (SD) in all patients. There are also as yet no predictors to select patients who might benefit and those who are primary resistant to specific drugs, and ultimately almost all patients will experience disease progression. Bearing inevitable treatment failure in mind, availability of further drugs and switching therapy while the patient is in a condition to continue pharmacotherapy is essential. Of note, depending on the setting, only 33-59% of patients receive second-line treatment. In this review we present data on first-, second-, and third-line treatment in RCC, and discuss the difficulties in their interpretation in the context of treatment sequence. We summarize biological aspects and discuss mechanisms of resistance to anti-angiogenic therapy and their implications for treatment selection.     

Altered Visual Function in a Larval Zebrafish Knockout of Neurodevelopmental Risk Gene pdzk1

PurposeThe human PDZK1 gene is located in a genomic susceptibility region for neurodevelopmental disorders. A genome-wide association study identified links between PDZK1 polymorphisms and altered visual contrast sensitivity, an endophenotype for schizophrenia and autism spectrum disorder. The PDZK1 protein is implicated in neurological functioning, interacting with synaptic molecules including postsynaptic density 95 (PSD-95), N-methyl-d-aspartate receptors (NMDARs), corticotropin-releasing factor receptor 1 (CRFR1), and serotonin 2A receptors. The purpose of the present study was to elucidate the role of PDZK1.MethodsWe generated pdzk1-knockout (pdzk1-KO) zebrafish using CRISPR/Cas-9 genome editing. Visual function of 7-day-old fish was assessed at behavioral and functional levels using the optomotor response and scotopic electroretinogram (ERG). We also quantified retinal morphology and densities of PSD-95, NMDAR1, CRFR1, and serotonin in the synaptic inner plexiform layer at 7 days, 4 weeks, and 8 weeks of age. Standard RT-PCR and nonsense-mediated decay interference treatment were also performed to assess genetic compensation in mutants.ResultsRelative to wild-type, pdzk1-KO larvae showed spatial frequency tuning functions with increased amplitude (likely due to abnormal gain control) and reduced ERG b-waves (suggestive of inner retinal dysfunction). No synaptic phenotypes, but possible morphological retinal phenotypes, were identified. We confirmed that the absence of major histological phenotypes was not attributable to genetic compensatory mechanisms.ConclusionsOur findings point to a role for pdzk1 in zebrafish visual function, and our model system provides a platform for investigating other genes associated with abnormal visual behavior.     

Combined massive allograft and intramedullary vascularized fibula transfer: the Capanna technique for treatment of congenital pseudarthrosis of the tibia

Background and purpose — Congenital pseudarthrosis of the tibia (CPT) is caused by local periosteal disease that can lead to bowing, fracturing, and pseudarthrosis. Current most successful treatment methods are segmental bone transport and vascularized and non-vascularized bone grafting. These methods are commonly hampered by discomfort, reoperations, and long-term complications. We report a combination of a vascularized fibula graft and large bone segment allograft, to improve patient comfort with similar outcomes.Patients and methods — 7 limbs that were operated on in 6 patients between November 2007 and July 2018 with resection of the CPT and reconstruction with a vascularized fibula graft in combination with a bone allograft were retrospectively studied. The mean follow-up time was 5.4 years (0.9–9.6). Postoperative endpoints: time to discharge, time to unrestricted weight bearing, complications within 30 days, consolidation, number of fractures, and secondary deformities.Results — The average time to unrestricted weight bearing with removable orthosis was 3.5 months (1.2–7.8). All proximal anastomoses consolidated within 10 months (2–10). 4 of the 7 grafts fractured at the distal anastomosis between 6 and 14 months postoperatively. After reoperation, consolidation of the distal anastomosis was seen after 2.8 months (2–4). 1 patient required a below-knee amputation.Interpretation — This case series showed favorable results of the treatment of CPT through a combination of a vascularized fibula graft and large bone segment allograft, avoiding the higher reintervention rate and discomfort with ring frame bone transport, and the prolonged non-weight bearing with vascularized fibula transfer without reinforcement with a massive large bone segment allograft.

Congenital pseudarthrosis of the tibia (CPT) is a rare disease affecting the development of the diaphysis of the tibia with a reported incidence ranging between 1 in 140,000 to 250,000 newborns (Ruggieri and Huson 2001, Horn et al. 2013). CPT is characterized by local periosteal disease, often leading to bowing and fracturing of the tibia and/or fibula, followed by the development of a pseudarthrosis (Stevenson et al. 1999). The etiology behind CPT remains largely unelucidated. Many theories regarding the influence of vascular, genetic, and mechanical factors have been proposed over the years, but none provides an entirely satisfactory explanation for the pathological features or its typical location (Hefti et al. 2000, Hermanns-Sachweh et al. 2005). However, there is a clear association with type 1 neurofibromatosis (NF1), as the prevalence of NF1 in CPT patients exceeds 50% (Van Royen et al. 2016).The challenge in cases of pseudarthrosis in CPT is obtaining solid union of the tibia with minimal limb length discrepancy and angular deformity (Grill et al. 2000). The most used treatments today are resection of the CPT part of the bone and vertical bone transport or the use of a pedicled or free vascularized fibula graft (Kesireddy et al. 2018). A multinational study from Japan, which included both the Ilizarov technique combined with diaphyseal transfer and vascularized fibula grafting, found high rates of union among both treatment groups and concluded that both approaches should be considered (Ohnishi et al. 2005).For the Ilizarov technique with diaphyseal transfer through proximal metaphyseal corticotomy and distraction at a distance from the dystrophic area, success rates between 50% and 90% have been reported (Paley et al. 1992, Ghanem et al. 1997, Romanus et al. 2000, Choi et al. 2011). Drawbacks of this technique are multiple interventions and prolonged discomfort of the patient due to many months of wearing a ring frame around the lower leg with pins and K-wires moving through muscle compartments. Also, pin tract infections and surgery to induce healing at the docking side of the bone transport lead to restrictions in social and psychological functioning (Ramaker et al. 2000, Patterson 2006).Studies on vascularized fibula grafts report union rates up to over 90% (Weiland et al. 1990, Erni et al. 2010). Drawbacks of this method include the prolonged period of non-weight bearing due to the lack of primary mechanical strength, resulting in graft fractures requiring reoperations prior to consolidation and hypertrophy of the graft (Weiland et al. 1990, Bos et al. 1993, Romanus et al. 2000, Ohnishi et al. 2005).In 1993, Capanna et al. reported on his “Capanna technique” in the resection of bone tumors in which the use of a vascularized autograft is combined with the use of a solid bone segment allograft in order to achieve instant stability with solid bone during consolidation and subsequent hypertrophy of the vascularized fibula during growth (Capanna et al. 1993).In order to avoid the drawbacks and discomfort of bone transport or vascularized fibula transfer without adding initial additional stability, we introduced this technique for the treatment of pseudarthrosis in CPT. Paley (2019) recently published the outcomes of his cross-union concept, reporting union in all 17 treated patients without refracturing with his latest technique, with follow-up to 11 years. If these outcomes prove to be reproducible, this will probably make the cross-union technique the gold standard for treating CPT. We report a retrospective case series on the Capanna technique in patients with CPT as reference for future strategies in this disease.     

Kinsey revisited,part II: Comparisons of the sexual socialization and sexual behavior of black women over 33 years

Kinsey's findings regarding the sexual behavior of black women were compared with data from a more recent study of sexual socialization and experiences among women in Los Angeles County, Ca. The study examined responses from two groups of college-educated black women, ages 18 to 36, 196 women from the original Kinsey sample and 64 women from the new sample. Log-linear analyses were used to control for differences between the samples on age and marital status. Comparisons were conducted in the areas of childhood family characteristics; sexual socialization and education; sexual behavior in childhood, adolescence, and adulthood; contraceptive practices; and child sexual abuse. Results reflected changes that have taken place in society and in patterns of sexual behavior. Differences in sexual socialization pointed to the increased role of the media and the schools and to more relaxed attitudes about nudity in the home. Shifts in sexual behavior were particularly dramatic. As compared to women in the Kinsey sample, newer subjects began intercourse earlier, were less likely to have a fiance or husband as their first partner, reported a higher number of sexual partners, and participated in a broader range of sexual behaviors. Contraceptive practices differed considerably, especially among never-married women. Women in this study were slightly more likely to report instances of child sexual abuse. Methdological and social factors contributing to the findings are discussed.This research was supported by the Center for the Prevention and Control of Rape, NIMH, MH 33603 and through a Research Scientist Career Development Award (MH 00269), to the first author.