Ovulation is the strongest risk factor for ovarian high-grade serous carcinoma (HGSC) that largely originates from the fallopian tube fimbriae and always carries loss-of-function mutations of TP53 in both early and late lesions. Mature ovarian follicle contains high level of reactive oxygen species (ROS). When released from ovulation, follicular fluid (FF) bathes the fimbriae and may lead to DNA double-strand break (DSB) and neoplastic transformation. In this study, we examined the mutagenic and tumorigenic activities of human pre-ovulatory FFs. A subset (6/11) of FFs was found with high levels of ROS whereas the antioxidant capacities were indifferent. These ROS(high) FFs induced intracellular ROS and DSBs in the secretory cell population of fimbriae epithelium. When p53 and Rb were turned down, the FF-exposed secretory cells overcame apoptosis and expanded the population carrying ROS and DSB. The cancer initiation and promotion effects of FF were further recapitulated in Trp53 (-/-) mice. When introduced into the mammary fat pad, ROS(high) but not ROS(low) FFs induced early-onset B-cell lymphoma. Cotreatment with physiological concentration of melatonin, a potent antioxidant, ameliorated the mutagenic and tumorigenic effect of ROS(high) FF in vitro and in vivo. The study revealed ROS and mitogens in mature ovarian follicles could initiate the transformation of fimbria epithelium in the context of p53 loss and melatonin is a potent preventive agent.

Human papillomavirus (HPV) 58 accounts for a notable proportion of cervical cancers in East Asia and parts of Latin America, but it is uncommon elsewhere. The reason for such ethnogeographical predilection is unknown. In our study, nucleotide sequences of E6 and E7 genes of 401 HPV58 isolates collected from 15 countries/cities across four continents were examined. Phylogenetic relationship, geographical distribution and risk association of nucleotide sequence variations were analyzed. We found that the E6 genes of HPV58 variants were more conserved than E7. Thus, E6 is a more appropriate target for type-specific detection, whereas E7 is more appropriate for strain differentiation. The frequency of sequence variation varied geographically. Africa had significantly more isolates with E6-367A (D86E) but significantly less isolates with E6-203G, -245G, -367C (prototype-like) than other regions (p ≤ 0.003). E7-632T, -760A (T20I, G63S) was more frequently found in Asia, and E7-793G (T74A) was more frequent in Africa (p < 0.001). Variants with T20I and G63S substitutions at E7 conferred a significantly higher risk for cervical intraepithelial neoplasia grade III and invasive cervical cancer compared to other HPV58 variants (odds ratio = 4.44, p = 0.007). In conclusion, T20I and/or G63S substitution(s) at E7 of HPV58 is/are associated with a higher risk for cervical neoplasia. These substitutions are more commonly found in Asia and the Americas, which may account for the higher disease attribution of HPV58 in these areas.

Antiserum to a human prostate-specific antigen was raised in a rabbit and utilized by immunoperoxidase staining to evaluate its potential value as a diagnostic histologic marker for tumors of prostatic origin. All primary and metastatic prostatic malignancies reacted positively, whereas nonprostatic neoplasms did not stain with this procedure. This is the first immunohistochemical marker for prostate gland epithelium which does not represent prostatic acid phosphatase.

Background The fallopian tube fimbria is regarded as the main tissue of origin and incessant ovulation as the main risk factor of ovarian high-grade serous carcinoma. Previously, we discovered the tumorigenesis activity of human ovulatory follicular fluid (FF) upon injection to the mammary fat pad of Trp53-null mice. We also found a mutagenesis activity of FF-ROS and a apoptosis-rescuing activity of Hb from retrograde menstruation. However, neither of them can explain the tumorigenesis activities of FF. Methods From two cohorts of ovulatory FF retrieved from IVF patients, the main growth factor responsible for the transformation of human fimbrial epithelial cells was identified. Mechanism of activation, ways of signal transduction of the growth factor, as well as the cellular and genetic phenotypes of the malignant transformation was characterized. Findings In this study, we showed that insulin-like growth factor (IGF)-axis proteins, including IGFBP-bound IGF2 as well as the IGFBP-lytic enzyme PAPP-A, are abundantly present in FF. Upon engaging with glycosaminoglycans on the membrane of fimbrial epithelial cells, PAPP-A cleaves IGFBPs and releases IGF2 to bind with IGF-1R. Through the IGF-1R/AKT/mTOR and IGF-1R/AKT/NANOG pathways, FF-IGF leads to stemness and survival, and in the case of TP53/Rb or TP53/CCNE1 loss, to clonal expansion and malignant transformation of fimbrial epithelial cells. By depleting each IGF axis component from FF, we proved that IGF2, IGFBP2/6, and PAPP-A are all essential and confer the majority of the transformation and regeneration activities. Interpretation This study revealed that the FF–IGF axis functions to regenerate tissue damage after ovulation and promote the transformation of fimbrial epithelial cells that have been initiated by p53- and Rb-pathway disruptions. Fund The study was supported by grants of the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-303-001-MY2; MOST 105-2314-B-303-017-MY2; MOST 107-2314-B-303-013-MY3), and Buddhist Tzu Chi General Hospital, Taiwan (TCMMP104-04-01).

High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells. Here we show that P4, via P4 receptors (PRs), induces necroptosis in Trp53 mouse oviduct epithelium and in immortalized human p53-defective fimbrial epithelium through the TNF-α/RIPK1/RIPK3/MLKL pathway. Necroptosis occurs specifically at diestrus, recovers at the proestrus phase of the estrus cycle, and can be augmented with P4 supplementation. These results reveal the mechanism of the well-known ability of progesterone to prevent ovarian cancer.

To determine whether the status of human-papillomavirus (HPV) infection affects the clinical outcome of cervical carcinoma (CC), HPV genotype was prospectively determined in 94 consecutive CC cases subsequently followed for a median duration of 37.5 months. With a consensus PCR-RFLP method of HPV genotyping, 81 (86.2%) cancers were positive for HPV DNA. They were classified, according to the phylogenic similarities, into HPV-16-related (type 16, n ‫؍‬ 45; type 31, n ‫؍‬ 2), HPV-58-related (type 58, n ‫؍‬ 17; type 33, n ‫؍‬ 3; type 52, n ‫؍‬ 2) and HPV-18-related (type 18, n ‫؍‬ 8; type 68, n ‫؍‬ 1) groups, and analyzed in relation to clinical outcome. The following results were observed: (i) Type-58-related HPVs were more prevalent in the old age (older than the median age of 52) group than in the young age group (41% vs. 14.6%, p ‫؍‬ 0.045); (ii) 63% (5/8) of patients with advanced stages (III and IV) were HPV-negative, a figure much higher than that Cervical carcinoma (CC) is one of the most common malignancies both in incidence and in mortality in women worldwide. Epidemiologic and laboratory studies have revealed a multifactorial and multi-step process, with infection of oncogenic types of human papillomavirus (HPV) standing for the predominant role (zur Hausen, 1991; Muñoz et al., 1992). The integration of HPV DNA into host genome and over-expression of the E6 and E7 oncogenes appear to be critical steps in cancer development (Phelps et al., 1988). Consequently, HPV DNA is present in most high-grade squamous intra-epithelial lesions (HSIL) and invasive cancers of the uterine cervix (Muñoz et al., 1992).On the basis of differences in DNA sequences, more than 70 types of HPV have been identified, and about 20 of them are associated with CC. They were grouped, according to their prevalence in SIL and CC, into intermediate-risk types (31, 33, 35, 51, 52 and 58) and high-risk types (16, 18, 45 and 56) (Lorincz et al., 1992). But the biologic behavior and clinical relevance of this classification have not been confirmed. However, several reports have noted that HPV genotypes associated with lesions of similar pathologies are phylogenetically related (De Villiers, 1989;Chan et al., 1992;Bernard et al., 1994), and indicated amino-acid-sequencedependent oncogenic behavior of HPV. Accordingly, a phylogenetic study has related, by order of phylogenic branching, HPV types 58/33/67/52, types 16/31/35 and, in remote branches, types 56/51 and 18/68/45 (Bernard et al., 1994).A number of studies of the influence of HPV status on the clinical features of cervical cancers have produced conflicting results. HPV 16 was found to be more prevalent in welldifferentiated carcinomas (Riou et al., 1990), while HPV 18 was associated with adenocarcinoma (AC) and adenosquamous carcinoma (ASC) (Higgins et al., 1991;Chen et al., 1994) and younger age (Higgins et al., 1991;Lorincz et al., 1992;Nakagawa et al., 1996). In addition, HPV-18-positive CCs were found to have a poor prognosis (Rose et al., 1991;Nakagawa et al., 1996;Lombard et al...

The prognostic and postoperative monitoring capabilities of the CEA assay were compared to pathological staging of the operative specimens, clinical followup including endoscopy, radiology and scanning techniques, as well as DNCB skin testing and laboratory enzyme determinations (alkaline phosphatase and transaminase). A total of 46 patients with curative resection for colorectal carcinoma were studied. This included 23 patients with recurrent tumors compared to 23 long-term survivors without signs of recurrence at the time of the study. Preoperative CEA determinations were a good prognostic tool comparable to pathological staging of the specimen. Post operative CEA monitoring was the earliest sign of recurrence in 14 of 23 patients and was positive at the time of recurrence determined by other methods in 20; it was negative in only three cases. The incidence of false positive results among the non recurrent group became a lesser problem when repeated elevated values were required before considering the patient as having a recurrence. From these data, it seems reasonable to propose the use of a second-look operation in patients with maintained elevation of circulating CEA and no clinical signs of tumor presence, if we are to treat recurrence at an early stage. Chemotherapy would be an alternative way to deal with this problem, since the absence of clinical signs in general correlate with small bulk of tumor which at this time may be more susceptible to chemotherapeutic agents.

Human papillomavirus (HPV) genotype 52 is commonly found in Asian cases of cervical cancer but is rare elsewhere. Analysis of 611 isolates collected worldwide revealed a remarkable geographical distribution, with lineage B predominating in Asia (89.0% vs 0%-5.5%; P(corrected) < .001), whereas lineage A predominated in Africa, the Americas, and Europe. We propose that the name "Asian lineage" be used to denote lineage B, to signify this feature. Preliminary analysis suggested a higher disease risk for lineage B, although ethnogeographical confounders could not be excluded. Further studies are warranted to verify whether the reported high attribution of disease to HPV52 in Asia is due to the high prevalence of lineage B.