Tolerance of Olaparib in a Patient With Unresectable Serous Gynecologic Cancer and End-Stage Renal Disease.

Poly (adenosine diphosphate-ribose) polymerase enzyme (PARP) inhibitors have risen in popularity for the treatment of gynecologic cancers, largely due to an expansion of applications with the discovery of more genetic mutations that manifest as homologous recombination deficiency. PARP inhibitors further represent an appealing management option as oral maintenance or monotherapy. While dose adjustments exist for mild kidney dysfunction, little is published about the use of PARP inhibitors in patients with severe renal dysfunction. We present a case of advanced, serous gynecologic cancer in a patient who was ineligible for surgery due to cardiac and renal comorbidities and treated with olaparib for nine months without direct adverse effects, despite a paucity of literature supporting the use or dosing of olaparib in patients requiring dialysis. Further studies are needed to better establish the safety, efficacy, and appropriate dose modification for patients with end-stage renal disease.

The impact of adjuvant antihormonal therapy versus observation on recurrence of borderline ovarian tumors: A retrospective cohort study.

Objectives: Adjuvant management of borderline ovarian tumors (BOT) after surgical diagnosis and staging is not standardized. While many patients undergo observation alone, some providers have introduced the use of adjuvant antihormonal therapy for BOT, extrapolating from studies suggesting improvement in progression-free survival in the low-grade serous ovarian carcinoma population. We hypothesized that adjuvant antihormonal therapy after surgical diagnosis of BOT would improve progression-free survival compared to surveillance alone. Methods: This is a retrospective review of BOT at one academic institution over thirteen years comparing management with antihormonal therapy, including aromatase inhibitors, progestins, and selective estrogen receptor modulators, to surveillance alone. Patients with concurrent malignancy were excluded. Data were abstracted from electronic medical records. Groups were compared by bivariate statistics. Results: We identified 193 patients with BOT. Of these, 17 (8.8%) were treated with adjuvant antihormonal therapy and 24 (12.4%) recurred. Patients treated with antihormonal therapy were more likely to be obese (64.7% vs 37.9%, p = 0.032), have advanced-stage disease (70.6% vs 11.4%, p < 0.001), serous histotype (94.1% vs 59.4%, p = 0.005) or microinvasion (29.4% vs 9.7%, p = 0.030), and less likely to have undergone fertility-sparing surgery (18.8% vs 51.7%, p = 0.012). Use of antihormonal therapy was not associated with a difference in recurrence or survival. Conclusions: This study is the first retrospective cohort review of adjuvant antihormonal therapy in BOT. We found that adjuvant antihormonal therapy for BOT is not associated with recurrence. While this single institution retrospective cohort study may lack the power to confirm or refute benefit, further studies could evaluate whether a subpopulation exists in whom antihormonal therapy is worthwhile.

Does Lymph Node Dissection Impact Adjuvant Treatment or Survival Outcomes in High-Risk Endometrial Cancers?

Objectives Lymphadenectomy does not improve overall survival outcomes in patients with low-risk endometrial cancers. Sentinel node mapping has a high detection rate and accuracy; however, its prognostic implications have not been well explored. We evaluated the overall survival and therapies received by patients undergoing varied lymph node dissection approaches for high-risk endometrial cancers. Methods Retrospective review of grade 3 endometrioid and high-grade non-endometrioid cancers at one institution over ten years. Patients who received neoadjuvant therapy and/or debulking of only grossly abnormal lymph nodes were excluded. Data was abstracted from electronic medical records. Chi-squared tests and survival analyses were used to compare groups. Results One hundred and fifty-three patients with grade 3 endometrioid, serous, clear cell, carcinosarcoma, or mixed high-grade on final pathology were identified; 16 had no lymph node dissection, 26 had sentinel lymph nodes, and 111 had complete lymph node dissection. Patients with open surgery were more likely to have complete nodes than sentinel nodes when compared to a minimally invasive approach (p<0.001). Sentinel nodal dissection significantly impacted the utilization of, or modality choice, in adjuvant therapy (p=0.051). Recurrence-free survival and cancer-specific overall survival were not significantly different across the three nodal-assessment groups. Conclusions  Sentinel lymph node dissection in high-risk endometrial cancers led to no significant differences in recurrence-free survival or cancer-specific overall survival. While limited by sample size and its retrospective nature, results from this single-institution study are hypothesis-generating and prompt consideration of non-inferiority trials. Performing the least invasive surgery possibly can lead to fewer complications while maintaining overall survival outcomes.

Composite Cellularized Structures Created from an Interpenetrating Polymer Network Hydrogel Reinforced by a 3D Woven Scaffold.

Biomaterial scaffolds play multiple roles in cartilage tissue engineering, including controlling architecture of newly formed tissue while facilitating growth of embedded cells and simultaneously providing functional properties to withstand the mechanical environment within the native joint. In particular, hydrogels-with high water content and desirable transport properties-while highly conducive to chondrogenesis, often lack functional mechanical properties. In this regard, interpenetrating polymer network (IPN) hydrogels can provide mechanical toughness greatly exceeding that of individual components; however, many IPN materials are not biocompatible for cell encapsulation. In this study, an agarose and poly(ethylene) glycol IPN hydrogel is seeded with human mesenchymal stem cells (MSCs). Results show high viability of MSCs within the IPN hydrogel, with improved mechanical properties compared to constructs comprised of individual components. These properties are further strengthened by integrating the hydrogel with a 3D woven structure. The resulting fiber-reinforced hydrogels display functional macroscopic mechanical properties mimicking those of native articular cartilage, while providing a local microenvironment that supports cellular viability and function. These findings suggest that a fiber-reinforced IPN hydrogel can support stem cell chondrogenesis while allowing for significantly enhanced, complex mechanical properties at multiple scales as compared to individual hydrogel or fiber components.

Conditional Macrophage Depletion Increases Inflammation and Does Not Inhibit the Development of Osteoarthritis in Obese Macrophage Fas-Induced Apoptosis-Transgenic Mice.

OBJECTIVE: To investigate whether short-term, systemic depletion of macrophages can mitigate osteoarthritis (OA) following injury in the setting of obesity. METHODS: CSF-1R-GFP+ macrophage Fas-induced apoptosis (MaFIA)-transgenic mice that allow conditional depletion of macrophages were placed on a high-fat diet and underwent surgery to induce knee OA. A small molecule (AP20187) was administrated to deplete macrophages in MaFIA mice. The effects of macrophage depletion on acute joint inflammation, OA severity, and arthritic bone changes were evaluated using histology and micro-computed tomography. Immunohistochemical analysis was performed to identify various immune cells. The levels of serum and synovial fluid cytokines were also measured. RESULTS: Macrophage-depleted mice had significantly fewer M1 and M2 macrophages in the surgically operated joints relative to controls and exhibited decreased osteophyte formation immediately following depletion. Surprisingly, macrophage depletion did not attenuate the severity of OA in obese mice; instead, it induced systemic inflammation and led to a massive infiltration of CD3+ T cells and particularly neutrophils, but not B cells, into the injured joints. Macrophage-depleted mice also demonstrated a markedly increased number of proinflammatory cytokines including granulocyte colony-stimulating factor, interleukin-1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor in both serum and joint synovial fluid, although the mice showed a trend toward decreased levels of insulin and leptin in serum after macrophage depletion. CONCLUSION: Our findings indicate that macrophages are vital for modulating homeostasis of immune cells in the setting of obesity and suggest that more targeted approaches of depleting specific macrophage subtypes may be necessary to mitigate inflammation and OA in the setting of obesity.