Katherine Moxley

Multiple Biopsies and Detection of Cervical Cancer Precursors at Colposcopy

PURPOSEnWomen with abnormal cervical cancer screening results are referred to colposcopy and biopsy for diagnosis of cervical cancer precursors (high-grade squamous intraepithelial lesions [HSILs]). Colposcopy with a single biopsy can miss identification of HSILs. No systematic study has quantified the improved detection of HSIL by taking multiple lesion-directed biopsies.nnnMETHODSnThe Biopsy Study was an observational study of 690 women referred to colposcopy after abnormal cervical cancer screening results. Up to four directed biopsies were taken from distinct acetowhite lesions and ranked by colposcopic impression. A nondirected biopsy of a normal-appearing area was added if fewer than four directed biopsies were taken. HSIL identified by any biopsy was the reference standard of disease used to evaluate the incremental yield and sensitivity of multiple biopsies.nnnRESULTSnIn the overall population, sensitivities for detecting HSIL increased from 60.6% (95% CI, 54.8% to 66.6%) from a single biopsy to 85.6% (95% CI, 80.3% to 90.2%) after two biopsies and to 95.6% (95% CI, 91.3% to 99.2%) after three biopsies. A significant increase in sensitivity of multiple biopsies was observed in all subgroups. The highest increase in yield of HSIL was observed for women with a high-grade colposcopic impression, HSIL cytology, and human papillomavirus (HPV) type 16 positivity. Only 2% of all HSILs diagnosed in the participants were detected by biopsies of normal-appearing transformation zone.nnnCONCLUSIONnCollection of additional lesion-directed biopsies during colposcopy increased detection of histologic HSIL, regardless of patient characteristics. Taking additional biopsies when multiple lesions are present should become the standard practice of colposcopic biopsy.

Ovarian cancer in the octogenarian: Does the paradigm of aggressive cytoreductive surgery and chemotherapy still apply?

OBJECTIVEnThe cornerstone of therapy for advanced ovarian cancer is cytoreductive surgery (CRS) followed by platinum based chemotherapy. Optimal management for very elderly women (>80) is unclear. This study sought to review the experience with treating ovarian cancer in this population.nnnMATERIALS AND METHODSnThis is a retrospective analysis of patients treated between 1991 and 2006. Outcomes included post-operative complications, chemotherapy received and overall survival. Statistical analysis was performed with SAS v.9.1.nnnRESULTSn85 patients were identified with a mean age of 84 years. 86% of patients presented with advanced disease. Primary CRS was performed on 80%. Among patients with advanced disease who underwent either primary (68) or interval debulking (2), 74% were left with <1 cm residual disease. Post-operative complications were common with 15% of patients suffering cardiac or pulmonary complications, over 10% with prolonged ileus, wound complications or mental status changes and over 30% requiring transfusion or antibiotics. Death prior to hospital discharge and within 60 days of surgery occurred in 13% and 20%. Among patients who underwent CRS, 13% were unable to receive indicated adjuvant therapy. Among those who were treated, 25% were treated with single agent platinum and 43% completed <3 cycles. Two-year overall survival for those who underwent CRS followed by adjuvant therapy is 51%.nnnCONCLUSIONSnOur data suggests that patients >80 may not tolerate combination surgery and chemotherapy. The extremely high proportion of post-operative complications and relatively high proportion of post-operative deaths argues for a more prudent approach to this group of patients.

Do uterine risk factors or lymph node metastasis more significantly affect recurrence in patients with endometrioid adenocarcinoma

OBJECTIVESnControversy continues over the importance of lymph node (LN) status in treating and predicting recurrence in endometrial cancer. Several predictive models are available which use uterine factors to stratify risk groups. Our objective was to determine how LN status affects recurrence and survival compared to uterine factors alone.nnnMETHODSnA retrospective review was performed of patients undergoing complete surgical staging for clinical stage 1 endometrioid adenocarcinoma of the uterus. Patients were assessed based on PORTEC 1 high intermediate risk (H-IR) criteria (2 factors : age>60, grade 3, >50% DOI), GOG-99 H-IR criteria (age >70+1 factor, age 50-70+2 factors, any age +3 factors: grade 2 or 3, LVSI, >50% DOI), and PORTEC 2 criteria. Rates of nodal involvement, recurrence rates, PFS, and OS were compared.nnnRESULTSnWe identified 352 clinical stage I patients with positive LN in 24% (87). 175 patients met PORTEC 1 eligibility and 66 met H-IR criteria. Rates of LN positivity were similar among groups (18.4% vs 19.7%, p=0.83) but recurrence rates were dissimilar (7.4% vs 27.3%, p=0.0004). Only 93 met PORTEC 2 criteria for treatment with no association between LN status, recurrence, and eligibility. 188 patients met H-IR eligibility criteria for GOG-99 with LN positive and recurrence rates higher in the H-IR group compared to GOG-99 eligible (34.6% vs 16.3%, p=0.0004, 28.3% vs. 10.6%, p=0.0002).nnnCONCLUSIONSnPatients with H-IR disease based on uterine characteristics alone have substantial risk of nodal involvement. Knowledge of LN status may better define risk, prognosis, and postoperative treatment.

Endometrial Carcinoma: A Review of Chemotherapy, Drug Resistance, and the Search for New Agents

The article examines current treatment options in patients with endometrial carcinoma, the role of drug resistance, and the rationale for the use of epothilones in treating this disease.

Malignant melanoma of the vulva: An extension of cutaneous melanoma?

OBJECTIVEnTo determine the prognostic significance of the 2002 revisions of the American Joint Committee on Cancer (AJCC) Staging System for cutaneous melanoma in melanoma of the vulva and review the current surgical utilized for treatment of this neoplasm.nnnMETHODSnDemographic, surgical and outcomes data were obtained from the records of vulvar melanoma patients treated from 1990 to 2006 at five academic medical centers. The 2002 modifications of the AJCC staging system for cutaneous melanoma, Breslow thickness and Clark level, were applied to all subjects. Kaplan-Meier Modeling and Linear Regression analysis were utilized for data analysis. Statistics were performed with SAS v 9.1.nnnRESULTSnSeventy-seven patients were identified with a median age of 62 years. 73% had Stage I/II disease. Surgical radicality did not impact recurrence rates or survival. Breslow thickness was associated with recurrence (p=0.002) but not survival. Only the 2002 modified AJCC staging criteria were predictive of overall survival (p=0.006) in patients with malignant melanoma of the vulva.nnnCONCLUSIONSnIn the largest multi-site series of vulvar melanoma, the AJCC-2002 staging system for cutaneous malignant melanoma appears to be applicable to primary vulvar melanoma. Moreover, surgical radicality was associated with significant morbidity but not with improvement in survival. Utilization of standard operative staging and resection principles in cutaneous melanoma should be used for all vulvar melanoma patients. Moreover, these patients should also be considered for enrollment in cutaneous melanoma clinical trials.

Stage I, grade 3 endometrioid adenocarcinoma of the endometrium: An analysis of clinical outcomes and patterns of recurrence

OBJECTIVEnTo study patterns of recurrence and survival outcomes in patients with surgical stage I, grade 3 endometrioid adenocarcinoma of the endometrium (EA) treated with various treatment modalities.nnnMETHODSnA retrospective multi-institutional study of surgical stage I, grade 3 EA patients diagnosed between 1988 and 2006 was performed. Demographic, clinicopathologic, treatment and outcome data were collected. After surgery, patients were treated with either observation or radiotherapy (vaginal brachytherapy, whole pelvic or both).nnnRESULTSnOne hundred seventy-six patients were collected with a median age of 68 years. Twenty-six (15%) were stage IA, 96 (54%) IB and 54 (31%) IC. Sixty-one patients (35%) had lymphovascular space invasion (LVSI) and a mean of 18.9 lymph nodes (LNs) was removed. Seventy-eight patients (44%) were observed while 98 (56%) were treated with radiotherapy, the majority (n=51) receiving brachytherapy. After a median follow-up of 58 months, 20 recurrences (11%) were noted. Ninety percent of recurrences occurred in Stage IB/IC patients. The median time to recurrence was 22.5 months (5-74.5) and 80% of recurrences were extra-pelvic. There was no significant difference in recurrence based upon treatment modality or LVSI. Majority of recurrences were not salvaged as 75% (12/16) died of their disease with a median time of recurrence to death of 8 months.nnnCONCLUSIONSnPatients with stage IB/IC, grade 3 endometrioid adenocarcinoma have a significant risk for extra-pelvic recurrence. Most patients will not be salvaged and will succumb to their disease, suggesting that current loco-regional adjuvant treatment strategies are not optimal and evaluation of more systemic therapies is warranted.

Exosomes: A Role for Naturally Occurring Nanovesicles in Cancer Growth, Diagnosis and Treatment

Exosomes are 30-100 nm bodies secreted from almost all types of cells into the extracellular spaces. They enclose in their lumen active genetic information in the form of messenger RNA (mRNA), micro RNA (miRNA), DNA and active peptides that are representative of the parental cell and can be isolated from different body fluids. Exosomes can participate in inter-cellular communication by trafficking molecules to their target cells. Because they can stably carry cargo including miRNA, mRNA, and proteins and can pass through stringent biological barriers (e.g., blood brain barrier) without eliciting an immune response, they are considered as an ideal acellular vehicle for drug delivery. In this review, we describe the structure and biogenesis of exosomes and new directions related to their role in diagnosis and treatment of diseases, especially for cancer. We also discuss potential challenges associated with exosomes that should be addressed before exosome-based therapy can be applied to clinical settings.

Phase II Evaluation of Dalantercept, a Soluble Recombinant Activin Receptor-Like Kinase 1 (ALK1) Receptor Fusion Protein, for the Treatment of Recurrent or Persistent Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study 0229N

OBJECTIVEnThis two-stage phase II study assessed activity of single agent dalantercept in patients with recurrent/persistent endometrial carcinoma (EMC).nnnMETHODSnEligible patients had persistent/recurrent EMC after 1-2 prior cytotoxic regimens, measurable disease (RECIST 1.1), and GOG performance≤2. Dalantercept 1.2mg/kg subcutaneous was administered once every 3weeks until disease progression (PD)/development of prohibitory toxicity. Primary objectives were to estimate the proportion of patients with persistent/recurrent EMC, who survive progression-free without receiving non-protocol therapy (TPFS) for at least 6months and to estimate the proportion having objective tumor response.nnnRESULTSnAll 28 enrolled patients were eligible and evaluable. Median age: 62years. Most common histologies: 32% Grade 1/2 endometrioid and 54% serous tumors. Prior treatment: 1 or 2 regimens in 82% and 18% of patients, respectively. Eighteen patients received prior radiation therapy. Patients received 1-12 cycles of dalantercept, and 46% of patients received ≤2cycles. The most common adverse events (AE) were fatigue, anemia, constipation and peripheral edema. Grade 3/4 AEs occurred in 39% and 4% of patients. One grade 5 gastric hemorrhage in a patient with a history of radiation fibrosis/small bowel obstruction was deemed possibly dalantercept-related. All patients are off study: 86% for PD. No ORs were observed; 57% had stable disease and 11% had TPFS>6 mos. Median progression-free and overall survival: 2.1months (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.0-17.5), respectively.nnnCONCLUSIONSnDalantercept has insufficient single agent activity in recurrent EMC to warrant further investigation at this dose level and schedule.

Resolution of hydrops secondary to cytomegalovirus after maternal and fetal treatment with human cytomegalovirus hyperimmune globulin

BACKGROUND: Congenital cytomegalovirus (CMV) is a common infection with limited treatment options. Vertical transmission can lead to fetal death or long-term neurologic injury. We present a case wherein fetal hydrops resolved after maternal and fetal intravenous administration of CMV hyperimmune globulin. CASE: A 20-year-old gravida 3, para 0 was referred for Level II ultrasonography secondary to hydrops fetalis. Amniocentesis demonstrated in utero CMV infection. Resolution of hydrops occurred after the administration of CMV hyperimmune globulin to the patient and then to her fetus. CONCLUSION: Resolution of hydrops secondary to congenital CMV was temporally related to the administration of maternal and fetal hyperimmune globulin.

Induction of death receptor ligand-mediated apoptosis in epithelial ovarian carcinoma: The search for sensitizing agents

OBJECTIVEnTo assess the abilities of cisplatin, paclitaxel, and flexible heteroarotinoid (Flex-Het) compound (SHetA2) to sensitize ovarian cancer cells to induction of the extrinsic apoptosis pathway by death receptor ligands, tumor necrosis factor alpha (TNFalpha), and TNF-related apoptosis-inducing ligand (TRAIL).nnnSTUDY DESIGNnThe effects of various combinations of TNFalpha, TRAIL, cisplatin, paclitaxel, and SHetA2 on viability and apoptosis in two established ovarian cancer cell lines, A2780 and SK-OV-3, and normal human primary endometrial cultures were measured with a cytotoxicity assay, flow cytometric analysis of annexin-V, and propidium iodide staining and Western blot analysis of caspase 8 and 3 activation.nnnRESULTSnOvarian cancer and normal cells were resistant to TNFalpha and TRAIL. Cisplatin and paclitaxel did not increase sensitivity to these agents in either cell type. In contrast, combination of SHetA2 with TNFalpha or TRAIL induced a synergistic induction of apoptosis in cancer cells that involved activation of the extrinsic pathway caspase 8 and executioner caspase 3. The TRAIL combination was more potent than the TNFalpha combination. SHetA2 did not harm the viability of normal cells as a single agent or in combination with the death receptor ligands.nnnCONCLUSIONSnSHetA2, but not cisplatin or paclitaxel, can overcome resistance of ovarian cancer cells to TNFalpha and TRAIL without increasing sensitivity of normal cells to these death receptor ligands.