Treatment of Human Immunodeficiency Virus Infection With Tenofovir Disoproxil Fumarate–Containing Antiretrovirals Maintains Low Bone Formation Rate,But Increases Osteoid Volume on Bone Histomorphometry

Bone mineral density (BMD) loss is a known complication of human immunodeficiency virus (HIV) infection and its treatment, particularly with tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimens. Although renal proximal tubular dysfunction and phosphaturia is common with TDF, it is unknown whether BMD loss results from inadequate mineralization. We evaluated change in BMD by dual-energy X-ray absorptiometry (DXA) and bone histomorphometry by tetracycline double-labeled transiliac crest biopsies in young men living with HIV before (n = 20) and 12 months after (n = 16) initiating TDF/lamivudine/efavirenz. We examined relationships between calciotropic hormones, urinary phosphate excretion, pro-inflammatory and pro-resorptive cytokines, and bone remodeling-related proteins with changes in BMD and histomorphometry. Mean age was 29.6 ± 5.5 years, with mean CD4 + T cell count of 473 ± 196 cells/mm³. At baseline, decreased bone formation rate and increased mineralization lag time were identified in 16 (80%) and 12 (60%) patients, respectively. After 12 months, we detected a 2% to 3% decrease in lumbar spine and hip BMD by DXA. By histomorphometry, we observed no change in bone volume/total volume (BV/TV) and trabecular parameters, but rather, increases in cortical thickness, osteoid volume, and osteoblast and osteoclast surfaces. We did not observe significant worsening of renal phosphate excretion or mineralization parameters. Increases in PTH correlated with decreased BMD but not histomorphometric parameters. Overall, these data suggest abnormalities in bone formation and mineralization occur with HIV infection and are evident at early stages. With TDF-containing antiretroviral therapy (ART), there is an increase in bone remodeling, reflected by increased osteoblast and osteoclast surfaces, but a persistence in mineralization defect, resulting in increased osteoid volume. © 2019 American Society for Bone and Mineral Research.     

Field evaluation of a dual rapid Human Immunodeficiency Virus and treponemal syphilis rapid test in community-based clinics in Los Angeles and New York

Introduction

Dual human immunodeficiency virus/syphilis rapid diagnostic devices can play an important role in prevention efforts. The field performance of the INSTI Multiplex HIV-1/HIV-2/Syphilis Antibody Test (Multiplex) was evaluated.

A model for prediction of parametrial involvement and feasibility of less radical resection of parametrium in patients with FIGO stage IB1 cervical cancer

Objective

The objective of this study was to evaluate the potential risk factors associated with parametrial invasion and to identify preoperatively a subgroup of patients at low risk for parametrial involvement who could be appropriate candidates for less radical surgery in FIGO stage IB1 cervical cancer.

Methods

We retrospectively reviewed the medical records of 317 FIGO stage IB1 cervical cancer patients undergoing class III radical hysterectomy and bilateral pelvic lymphadenectomy. Clinocopathologic factors associated with parametrial invasion were analyzed and the risk criteria predicting parametrial involvement were calculated using a logistic regression model.

Results

Of 317 patients, 17 patients (5.4%) had parametrial involvement. Tumor size > 3 cm (OR, 3.80; [95% CI, 1.19-12.06]; p = 0.02) and pelvic lymph node metastasis (OR, 3.02; [95% CI, 1.04-8.79]; p = 0.04) were independent pathologic factors for parametrial invasion on multivariate analysis. Significant preoperative factors associated with parametrial involvement were tumor size > 3 cm (OR, 4.29; [95% CI, 1.43-12.89]; p < 0.01) and serum SCC Ag level > 1.40 ng/mL (OR, 3.27; [95% CI, 1.11-9.69]; p = 0.03). We identified 185 low-risk (tumor size ≤ 3 cm and SCC ≤ 1.4 ng/mL) and 132 high-risk (tumor size > 3 cm and/or SCC > 1.4 ng/mL) patients. The rates of parametrial involvement in low- and high-risk patients were 1.1% and 11.4%, respectively (p < 0.01).

Conclusions

In this dataset, a model using tumor size and SCC Ag level is highly predictive of parametrial involvement in patients with stage IB1 cervical cancer and may identify candidates for less radical parametrial resection.     

Audit-induced change reduces complications of the Ganz trochanteric flip approach

INTRODUCTION

The Ganz trochanteric flip approach aims to avoid the potential risk of avascular necrosis in hip conserving surgery and may reduce the risk of femoral neck fractures, neck thinning and femoral head implant migration in hip resurfacing. Our initial audit revealed the complications of non-union and trochanteric screw irritation to be associated with this approach. We, therefore, modified our selection criteria and re-audited our results.

SUBJECTS AND METHODS

The initial audit (IA) ran between January 2003 and November 2007 after which an age limit of 50 years was recommended. The re-audit (RA) ran between November 2007 and December 2008 where one of the senior authors stopped using the approach in the over 50 year age group whilst the other senior author continued on selected patients over 50 years.

RESULTS

There were 545 hips in the IA and 152 hips in the RA group. The incidence of non-union decreased in the RA after the change of selection criteria (6.2% [IA] vs 1.3% [RA]). In both audit groups, the incidence of non-union increased with age, and in the RA no non-unions were observed under the age of 50 years. The incidence of screw irritation and the necessity for removal remained relatively unchanged (20.7% [IA] vs 28.3% [RA]) with a combined incidence of 22.4%.

CONCLUSIONS

The trochanteric flip approach to the hip can be used safely with an acceptable complication rate in young adult impingement and resurfacing surgery. Caution must, however, be exercised in patients over 50 years of age as they have a higher incidence of trochanteric non-union. In addition, all patients should be consented for the possibility of screw removal as a second procedure.     

High-volume ovarian cancer care: Survival impact and disparities in access for advanced-stage disease

Objective

To characterize the impact of hospital and physician ovarian cancer case volume on survival for advanced-stage disease and investigate socio-demographic variables associated with access to high-volume providers.

Methods

Consecutive patients with stage IIIC/IV epithelial ovarian cancer (1/1/96–12/31/06) were identified from the California Cancer Registry. Disease-specific survival analysis was performed using Cox-proportional hazards model. Multivariate logistic regression analyses were used to evaluate for differences in access to high-volume hospitals (HVH) (≥ 20 cases/year), high-volume physicians (HVP) (≥ 10 cases/year), and cross-tabulations of high- or low-volume hospital (LVH) and physician (LVP) according to socio-demographic variables.

Results

A total of 11,865 patients were identified. The median ovarian cancer-specific survival for all patients was 28.2 months, and on multivariate analysis the HVH/HVP provider combination (HR = 1.00) was associated with superior ovarian cancer-specific survival compared to LVH/LVP (HR = 1.31, 95%CI = 1.16–1.49). Overall, 2119 patients (17.9%) were cared for at HVHs, and 1791 patients (15.1%) were treated by HVPs. Only 4.3% of patients received care from HVH/HVP, while 53.1% of patients were treated by LVH/LVP. Both race and socio-demographic characteristics were independently associated with an increased likelihood of being cared for by the LVH/LVP combination and included: Hispanic race (OR = 1.72, 95%CI = 1.22–2.42), Asian/Pacific Islander race (OR = 1.57, 95%CI = 1.07–2.32), Medicaid insurance (OR = 2.51, 95%CI = 1.46–4.30), and low socioeconomic status (OR = 2.84, 95%CI = 1.90–4.23).

Conclusions

Among patients with advanced-stage ovarian cancer, the provider combination of HVH/HVP is an independent predictor of improved disease-specific survival. Access to high-volume ovarian cancer providers is limited, and barriers are more pronounced for patients with low socioeconomic status, Medicaid insurance, and racial minorities.     

The prognostic significance of pre- and post-treatment CA-125 in grade 1 serous ovarian carcinoma: A Gynecologic Oncology Group study

Objectives

The study objective was to determine the prognostic significance of serum CA-125 levels in patients with grade 1 serous ovarian carcinoma (SOC) enrolled in a Phase III study.

Methods

An ancillary analysis of a phase III study of women with advanced epithelial ovarian cancer treated with carboplatin/paclitaxel versus triplet or sequential doublet regimens. Grade 1 SOC was used as a surrogate for low-grade serous carcinoma.

Results

Among 3686 enrolled patients, 184 (5%) had grade 1 disease and CA-125 levels available. For those with grade 1 SOC, the median patient age was 56.5; 87.3% had Stage III disease. Median follow-up was 102 months and there was no difference in pre-chemotherapy CA-125 by treatment arm (P = 0.91). Median pretreatment CA-125 for those with grade 1 SOC was lower (119.1) than for patients with grade 2–3 SOC (246.7; P < 0.001). In those with grade 1, pretreatment CA-125 was not prognostic of outcome. However, patients with CA-125 levels that normalized after cycle 1, 2 or 3 were 60–64% less likely to experience disease progression as compared to those who never normalized or normalized after 4 cycles (P ≤ 0.024). Normalization of CA-125 levels before the second cycle was negatively associated with death, with a HR of 0.45 (P = 0.025).

Conclusions

Pretreatment CA-125 level was significantly lower in women with grade 1 SOC compared to those with high-grade SOC. While pretreatment CA-125 was not associated with survival, serial CA-125 measurements during chemotherapy treatment were prognostic, with normalization before the second chemotherapy cycle associated with a decreased risk of death.     

Tumor senescence and radioresistant tumor-initiating cells (TICs): let sleeping dogs lie!

Preclinical data from cell lines and experimental tumors support the concept that breast cancer-derived tumor-initiating cells (TICs) are relatively resistant to ionizing radiation and chemotherapy. This could be a major determinant of tumor recurrence following treatment. Increased clonogenic survival is observed in CD24^-/low/CD44⁺ TICs derived from mammosphere cultures and is associated with (a) reduced production of reactive oxygen species, (b) attenuated activation of γH2AX and CHK2-p53 DNA damage signaling pathways, (c) reduced propensity for ionizing radiation-induced apoptosis, and (d) altered DNA double-strand or DNA single-strand break repair. However, recent data have shed further light on TIC radioresistance as irradiated TICs are resistant to tumor cell senescence following DNA damage. Taken together, the cumulative data support a model in which DNA damage signaling and repair pathways are altered in TICs and lead to an altered mode of cell death with unique consequences for long-term clonogen survival. The study of TIC senescence lays the foundation for future experiments in isogenic models designed to directly test the capacity for senescence and local control (that is, not solely local regression) and spontaneous metastases following treatment in vivo. The study also supports the targeting of tumor cell senescence pathways to increase TIC clonogen kill if the targeting also maintains the therapeutic ratio.