Association between endometriosis and gynecological cancers: a critical review of the literature

Endometriosis is one of the most common benign gynecological diseases with an occurrence approximately 10% in reproductive age. Endometriosis has been proposed as a possible precursor of certain ovarian carcinomas such as clear cell and endometrioid ovarian carcinomas. In addition to this pathogenic link, the association with other gynecological tumors and breast cancer has been studied on an epidemiological basis in several studies. The aim of this review was to critically present the recent published evidence on the association of endometriosis with gynecological cancer, and with a special emphasis on ovarian cancer. A search for eligible studies was conducted in three electronic databases, MEDLINE, EMBASE and CINAHL, for original research in humans published in any language. The present review includes studies examining the association between endometriosis and different types of gynecological cancer (i.e., 25 studies on ovarian cancer, 8 studies on breast cancer, 8 studies on endometrial cancer and 2 studies on cervical cancer). The present literature supports the pre-existing evidence suggesting an association between ovarian cancer and endometriosis and specifically its two histologic subtypes (endometrioid and ovarian clear cell cancer). The most recent population-based epidemiological studies cannot provide a clear association between endometriosis and endometrial, cervical or breast cancer.     

Intraperitoneal transfusion in severe, early-onset Rh isoimmunization

OBJECTIVE: To describe the management of five women with severe, early-onset Rh isoimmunization with a series of intraperitoneal transfusions. METHODS: Intraperitoneal transfusions were started at 15 to 16 weeks of pregnancy, with small volumes of blood given weekly until the umbilical cord could be successfully entered and further transfusions given intravascularly. RESULTS: The initial range of anti-D immune globulin levels was 24-244 international units, and all women had severe Rh isoimmunization complicating previous pregnancies. No fetus was severely anemic at the first intravascular transfusion (lowest hemoglobin 8.9 g/dL), and there were no fetal losses. Middle cerebral artery peak systolic velocity responded to treatment with intraperitoneal transfusions, suggesting that even at 15 to 16 weeks of gestation it correlates with fetal hemoglobin. CONCLUSION: This series shows that intraperitoneal transfusions can be used to successfully treat severe, early-onset Rhesus disease.     

B7-H4 is over-expressed in early-stage ovarian cancer and is independent of CA125 expression

OBJECTIVE: This study characterizes the expression of the novel biomarker B7-H4 in ovarian cancer tissue, normal ovaries, and benign ovarian tumors, and evaluates its relationship to CA125. METHODS: Ovarian tissue lysates from 251 patients with ovarian carcinoma were assessed for the levels of B7-H4 and CA125 by ELISA assays. For comparison, ovarian tissues from patients with benign ovarian tumors (n=43) and patients with normal ovaries (n=32) were tested. The marker concentrations were correlated with CA125 expression, clinicopathological variables, and patient outcome. RESULTS: Using a cut-off based on the 95th percentile of B7-H4 or CA125 concentration in the control group, B7-H4 was over-expressed in 48% of patients with stage I cancer, 55% of patients with stage II cancer, and 67% of patients with late stage cancer. CA125 was elevated in 31% patients with early stage cancer. B7-H4 was elevated in tumors of 30 patients with early stage cancer that were negative for CA125. The combination of B7-H4 and CA125 identified 56 early stage cancer patients (65%) as positive. Correlation of marker expression to clinical outcome showed that high B7-H4 levels were correlated with poor prognosis. However, the effect was not significant when outcome was adjusted for other clinicopathological variables. CONCLUSION: B7-H4 expression was low in normal ovaries and in benign tumors while half of early stage and two-thirds of late stage cancers over-expressed B7-H4. The data are consistent with previous observations and support further investigation of B7-H4 in the detection of early stage ovarian cancer either alone, or in combination with CA125.     

Reversible Deterioration in Hypophosphatasia Caused by Renal Failure With Bisphosphonate Treatment

Hypophosphatasia is an inborn error of metabolism caused by mutations in the ALPL gene. It is characterized by low serum alkaline phosphatase (ALP) activity and defective mineralization of bone, but the phenotype varies greatly in severity depending on the degree of residual enzyme activity. We describe a man with compound heterozygous mutations in ALPL, but no previous bone disease, who suffered numerous disabling fractures after he developed progressive renal failure (for which he eventually needed dialysis treatment) and was prescribed alendronate treatment. A bone biopsy showed marked osteomalacia with low osteoblast numbers and greatly elevated pyrophosphate concentrations at mineralizing surfaces. In vitro testing showed that one mutation, T117H, produced an ALP protein with almost no enzyme activity; the second, G438S, produced a protein with normal activity, but its activity was inhibited by raising the media phosphate concentration, suggesting that phosphate retention (attributable to uremia) could have contributed to the phenotypic change, although a pathogenic effect of bisphosphonate treatment is also likely. Alendronate treatment was discontinued and, while a suitable kidney donor was sought, the patient was treated for 6 months with teriparatide, which significantly reduced the osteomalacia. Eighteen months after successful renal transplantation, the patient was free of symptoms and the scintigraphic bone lesions had resolved. A third bone biopsy showed marked hyperosteoidosis but with plentiful new bone formation and a normal bone formation rate. This case illustrates how pharmacological (bisphosphonate treatment) and physiologic (renal failure) changes in the “environment” can dramatically affect the phenotype of a genetic disorder. © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research.     

Facilitating Breast-Conserving Surgery and Preventing Recurrence: Aromatase Inhibitors in the Neoadjuvant and Adjuvant Settings

Breast-conserving surgery (BCS) is an attractive option for many patients with early-stage breast cancer, because it provides a better cosmetic outcome than modified radical mastectomy, while reducing surgical morbidity. In patients with large, operable breast tumors who are ineligible for BCS, neoadjuvant therapy is a useful option for reducing the tumor size and for increasing the proportion of candidates for BCS. In patients with endocrine-responsive tumors, neoadjuvant endocrine therapy with either tamoxifen or an aromatase inhibitor (AI; anastrozole, letrozole, or exemestane) provides an alternative to neoadjuvant chemotherapy. Clinical trials have demonstrated the superiority of neoadjuvant AIs over tamoxifen in achieving a clinical response and increasing the frequency of BCS. In addition, adjuvant endocrine therapy with AIs, whether used as initial therapy instead of tamoxifen, in a switching strategy after 2–3 years of tamoxifen, or as extended adjuvant therapy after 5 years of adjuvant tamoxifen, has been shown in several randomized clinical trials to improve disease-free survival, reduce distant metastases and, in some cases, improve overall survival. The availability of the AIs for effective and well-tolerated neoadjuvant and/or adjuvant endocrine therapy represents an important advance in breast cancer treatment, and surgeons should be familiar with these new therapeutic options.     

Human herpesvirus 6 infection as a trigger of multiple sclerosis

We systematically reviewed the existing evidence to determine whether a relationship exists between infection with human herpesvirus 6 (HHV-6) and multiple sclerosis (MS) and, if so, to define the strength of that relationship. The following terms were used in searches of the Entrez-PubMed database (1966-2009): human herpes virus 6, HHV 6, demyelination, multiple sclerosis, pathogenesis, diagnosis, serology, cerebrospinal fluid, IgG antibodies, IgM antibodies, PCR, and lymphoproliferative techniques. Study quality was assessed using the criteria proposed by Moore and Wolfson and by the classification criteria used by the Canadian Task Force on the Periodic Health Examination. Studies were categorized both by experimental technique and by quality (high [A], intermediate [B], and low [C]) as determined by the Moore and Wolfson criteria. Overall, 25 (41%) of 61 studies, 15 (60%) of which were classified as A quality, reached a statistically significant result. According to the Canadian Task Force classification, all studies were categorized as evidence of quality II-1. Limitations of the available experimental techniques and perspectives for future research are discussed. The current review supports the need for further, objective, evidence-based examination of the relationship between HHV-6 infection and multiple sclerosis.     

Activated leukocyte cell adhesion molecule: A novel biomarker for breast cancer

Activated leukocyte cell adhesion molecule (ALCAM) has been implicated in tumorigenesis. Our goal was to examine the levels of ALCAM, in addition to the classical breast cancer tumor markers carbohydrate antigen 15‐3 (CA15‐3) and carcinoembryonic antigen (CEA), in serum by quantitative enzyme‐linked immunosorbent assay for diagnosis in breast cancer patients. The 3 proteins were measured in serum of 100 healthy women, 50 healthy men and 150 breast carcinoma patients. The diagnostic sensitivity and specificity of the tests were calculated and the association of serum marker concentrations with various clinicopathologic variables was examined using nonparametric Kruskal‐Wallis tests. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of the biomarkers. ALCAM, with area under the curve (AUC) of 0.78 [95% CI: 0.73, 0.84] outperformed CA15‐3 (AUC = 0.70 [95% CI: 0.64, 0.76]) and CEA (AUC= 0.63 [95% CI: 0.56, 0.70]). The incremental values of AUC for ALCAM over that for CA15‐3 were statistically significant (Delong test, p < 0.05). Combining CA15‐3 and ALCAM yielded a ROC curve with an AUC of 0.81 (95% CI [0.75, 0.87]). Serum ALCAM appears to be a new biomarker for breast cancer and may have value for disease diagnosis. © 2009 UICC     

Atrichia with papular lesions resulting from novel compound heterozygous mutations in the human hairless gene

Abstract:  Atrichia with papular lesions is a rare form of complete, irreversible alopecia that is inherited in an autosomal recessive manner. Several studies have implicated mutations in the human hairless gene as the underlying cause of this disorder. We describe two novel heterozygous mutations in exons 3 and 8 of the hairless gene in a 2-year-old Caucasian boy with complete alopecia of his scalp. These novel mutations add to the growing literature of mutations in the hairless gene found in nonconsanguineous families and expands the allelic series of mutations in this gene.     

Olfactory dysfunction in nasal polyposis: correlation with computed tomography findings

AIMS: This study evaluates if a computed tomography (CT) scan is useful to assess the olfactory loss in sinonasal disease, and if a preoperative CT scan has a predictive value for the long-term outcome regarding olfaction. METHODS: Thirty-one patients with nasal polyposis were included. Olfactory function was assessed with the 'Sniffin' Sticks' test and subjective perception recorded with a visual analogue scale. CT scans were assessed with the Lund-Mackay system and the Damm nasal segmentation. Patients were retested after endoscopic sinus surgery in a follow-up appointment at least 1 year later. RESULTS: Disease in the upper meatus and the posterior portion of the middle meatus strongly affects olfactory function. Lund-Mackay scores were significantly correlated with preoperative olfactory test results. Preoperative subjective ratings had a significant correlation only with present disease in the anterior upper meatus. Postoperative results were significantly decreased. Their relative percentage change was correlated only with the preoperative presence of disease in the anterior upper meatus. No correlation was found between the Lund-Mackay score and the postoperative olfactory results. CONCLUSIONS: Olfactory dysfunction in nasal polyposis is strongly related to specific obstructed nasal areas. A CT scan has no predictive value for the long-term surgical outcome regarding olfaction.     

Strategies for discovering novel cancer biomarkers through utilization of emerging technologies

The introduction of technologies such as mass spectrometry and protein and DNA arrays, combined with our understanding of the human genome, has enabled simultaneous examination of thousands of proteins and genes in single experiments, which has led to renewed interest in discovering novel biomarkers for cancer. The modern technologies are capable of performing parallel analyses as opposed to the serial analyses conducted with older methods, and they therefore provide opportunities to identify distinguishing patterns (signatures or portraits) for cancer diagnosis and classification as well as to predict response to therapies. Furthermore, these technologies provide the means by which new, single tumor markers could be discovered through use of reasonable hypotheses and novel analytical strategies. Despite the current optimism, a number of important limitations to the discovery of novel single tumor markers have been identified, including study design bias, and artefacts related to the collection and storage of samples. Despite the fact that new technologies and strategies often fail to identify well-established cancer biomarkers and show a bias toward the identification of high-abundance molecules, these technological advances have the capacity to revolutionize biomarker discovery. It is now necessary to focus on careful validation studies in order to identify the strategies and biomarkers that work and bring them to the clinic as early as possible.