Low-Volume Metastases in Apparent Early-Stage Endometrial Cancer: Prevalence, Clinical Significance, and Future Perspectives.

Endometrial cancer (EC) is the most diagnosed gynecologic malignancy, and its incidence and mortality are increasing. The prognosis is highly dependent on the disease spread. Surgical staging includes retroperitoneal evaluation to detect potential lymph node metastases. In recent years, systematic lymphadenectomy has been replaced by sentinel lymph node (SLN) biopsy and ultrastaging, allowing for the detection of macrometastases, micrometastases, and isolated tumor cells (ITCs). Micrometastases and ITCs have been grouped as low-volume metastases (LVM). The reported prevalence of LVM in studies enrolling more than one thousand patients with apparent early-stage EC ranges from 1.9% to 10.2%. Different rates of LVM are observed when patients are stratified according to disease characteristics and their risk of recurrence. Patients with EC at low risk for recurrence have low rates of LVM, while intermediate- and high-risk patients have a higher likelihood of being diagnosed with nodal metastases, including LVM. Macro- and micrometastases increase the risk of recurrence and cause upstaging, while the clinical significance of ITCs is still uncertain. A recent meta-analysis found that patients with LVM have a higher relative risk of recurrence [1.34 (95% CI: 1.07-1.67)], regardless of adjuvant treatment. In a retrospective study on patients with low-risk EC and no adjuvant treatment, those with ITCs had worse recurrence-free survival compared to node-negative patients (85.1%; CI 95% 73.8-98.2 versus 90.2%; CI 95% 84.9-95.8). However, a difference was no longer observed after the exclusion of cases with lymphovascular space invasion. There is no consensus on adjuvant treatment in ITC patients at otherwise low risk, and their recurrence rate is low. Multi-institutional, prospective studies are warranted to evaluate the clinical significance of ITCs in low-risk patients. Further stratification of patients, considering histopathological and molecular features of the disease, may clarify the role of LVM and especially ITCs in specific contexts.

Ataxia telangiectasia and rad3-related kinase contributes to cell cycle arrest and survival after cisplatin but not oxaliplatin.

The DNA cross-linking agents cisplatin and oxaliplatin are widely used in the treatment of human cancer. Lesions produced by these agents are widely known to activate the G1 and G2 cell cycle checkpoints. Less is known about the role of the intra-S-phase checkpoint in the response to these agents. In the present study, two different cell lines expressing a dominant-negative kinase dead (kd) version of the ataxia telangiectasia and rad3-related (ATR) kinase in an inducible fashion were examined for their responses to these two platinating agents and a variety of other DNA cross-linking drugs. The expression of the kdATR allele markedly sensitized the cells to cisplatin, but not to oxaliplatin, as assessed by inhibition of colony formation, induction of apoptosis, and cell cycle analysis. Similar differences in survival were noted for melphalan (ATR dependent) and 4-hydroperoxycyclophosphamide (ATR independent). Further experiments showed that ATR function is not necessary for removal of Pt-DNA adducts. The predominant difference between the responses to the two platinum drugs was the presence of a drug-specific ATR-dependent S-phase arrest after cisplatin but not oxaliplatin. These results indicate that involvement of ATR in the response to DNA cross-linking agents is lesion specific. This observation might need to be taken into account in the development and use of ATR or Chk1 inhibitors.

Racial and socioeconomic disparities in adherence to preventive health services for ovarian cancer survivors.

PURPOSE: To examine ovarian cancer survivors' adherence to evidence-based guidelines for preventive health care. METHODS: A case-control, retrospective study of Medicare fee-for-service beneficiaries diagnosed with stage I, II, or III epithelial ovarian cancer from 2001 to 2010 using the Surveillance, Epidemiology, and End Results-Medicare database. Survivors were matched 1:1 to non-cancer controls from the 5% Medicare Beneficiary file on age, race, state of residence, and follow-up time. Receipt of flu vaccination, mammography, and bone density tests were examined in accordance with national guidelines. Adherence was assessed starting 1 year after cancer diagnosis, across 2 years of claims. Interaction with the health care system, including outpatient and cancer surveillance visits, was tested as a potential mechanism for receipt of services. RESULTS: 2437 survivors met the eligibility criteria (mean age, 75; 90% white). Ovarian cancer survivors were more likely to be adherent to flu vaccination (5 percentage points (pp); < 0.001) and mammography guidelines (10 pp.; < 0.001) compared to non-cancer controls, but no differences were found for bone density test guidelines (- 1 pp.; NS). Black women were less likely to be adherent to flu vaccination and bone density tests compared with white women. Women dually eligible for Medicare and Medicaid were less likely to be adherent compared to those without such support. Adherence was not influenced by measures of outpatient visits. CONCLUSION: Ovarian cancer survivors are receiving preventive services with the same or better adherence than their matched counterparts. Minority and dual-eligible survivors received preventive services at a lower rate than white survivors and those with higher income. The number of outpatient visits was not associated with increased preventive health visits. IMPLICATIONS FOR CANCER SURVIVORS: Ovarian cancer survivors are receiving adequate follow-up care to be adherent to preventive health measures. Efforts to improve care coordination post-treatment may help reduce minority and low SES disparities.

MicroRNA-205 promotes cell invasion by repressing TCF21 in human ovarian cancer.

BACKGROUND: Ovarian cancer is the leading lethal, gynecological malignancy in the United States. No doubt, the continued morbidity and mortality of ovarian cancer reflects a poor understanding of invasive mechanisms. Recent studies reveal that ovarian cancers express aberrant microRNAs (miRNAs or miRs), some of which have oncogenic or tumor suppressor properties. Several studies suggested that miR-205 is involved in tumorigenesis. Presently, we investigate the molecular mechanisms and target of miR-205 in ovarian cancer. METHODS: Quantitative real-time polymerase chain reaction and western blot were performed to assess miR-205 and transcription factor 21 (TCF21) expression in ovarian cancer and normal ovary samples. The effect of miR-205 on TCF21 was determined by luciferase reporter assay and western blot. The effect of miR-205 and TCF21 on cell invasion was quantitated using transwell invasion assay. RESULT: miR-205 expression was increased in ovarian cancer and it promoted the invasive behavior of ovarian cancer cell lines (OVCAR-5, OVCAR-8 and SKOV-3). miR-205 directly targeted TCF21, which was significantly decreased in ovarian cancer tissue. miR-205 inhibited TCF21 expression and as a consequence blunted the inhibitory effect of TCF21 on cell invasion. Matrix Metalloproteinases (MMPs) play an important role in cancer invasion and metastasis. TCF21 inhibited MMP-2 and MMP-10 and decreased ovarian cancer cell invasion. Co-transfection of TCF21 expression plasmid with miR-205 mimic diminished the inhibitory effect of TCF21 on MMP-2 and MMP-10 in ovarian cancer cells. CONCLUSION: miR-205 appears to have an important role in the spread of ovarian cancer by targeting TCF21. These findings offer a new mechanism of ovarian cancer tumorigenesis, which could be useful for the development of new therapeutic approaches to ovarian cancer treatment.

Analysis of outcomes of microinvasive adenocarcinoma of the uterine cervix by treatment type.

OBJECTIVE: To estimate the risk of metastatic disease in microinvasive adenocarcinoma of the cervix in a large cohort. METHODS: Thirty-six cases were identified from the Mayo Clinic health information database, and 30 cases were identified using the University of Southern California gynecologic oncology patient database. Histopathology was reviewed by a single pathologist at each institution to confirm histologic subtype and grade of tumor, depth of invasion, linear extent of the tumor, the presence or absence of lymphovascular space invasion, margin status, parametrial involvement, and the presence of nodal metastasis. RESULTS: Fifty-two patients had stage IA1 cancers and 14 had stage IA2 cancers. Therapy ranged from cold knife conization to radical hysterectomy with lymphadenectomy. No parametrial involvement was noted in any of the patients who underwent parametrial resection. One patient with stage IA1 cancer had micrometastasis to a pelvic lymph node. No recurrences were noted with an average follow-up of 80 months. CONCLUSION: The management of microinvasive adenocarcinoma remains controversial, and radical therapy is applied more frequently to microinvasive adenocarcinoma than microinvasive squamous cell carcinoma of the cervix. The risk of extracervical disease is low and the risk of recurrence is not affected by the radicality of resection. Our data suggest that microinvasive adenocarcinoma is amenable to treatment with nonradical surgery. LEVEL OF EVIDENCE: III.