BACKGROUND The incidence and distribution pattern of retroperitoneal lymph node metastasis in patients with cervical carcinoma should be investigated based on data from systematic pelvic lymph node (PLN) and paraaortic lymph node (PAN) dissection, so that a basis can be established for determining the site of selective lymph node dissection or sampling. METHODS A total of 208 patients with Stages IB, IIA, and IIB cervical carcinoma who underwent radical hysterectomy and systematic pelvic and PAN dissection were investigated for lymph node metastasis and histopathologic risk factors for lymph node metastasis. RESULTS Fifty‐three patients (25.5%) had lymph node metastasis. The obturator lymph nodes were most frequently involved, with a rate of 18.8% (39/208). Forty‐nine of 53 node‐positive patients had lymph node metastasis in the obturator, internal iliac, or common iliac lymph nodes. Of 26 solitary lymph node metastases confined to one node group, 18 were in the obturator, 3 in the internal iliac, 3 in the parametrial, and 2 in the common iliac lymph nodes. A multiple logistic regression analysis revealed that deep cervical stromal invasion and lymph‐vascular space invasion were related to PLN metastasis. It was also shown that metastasis to bilateral PLNs (excluding the common iliac lymph nodes) as well as metastasis to the common iliac lymph nodes were significantly related to PAN metastasis. CONCLUSIONS The results of this study suggest that the obturator lymph nodes can be sentinel lymph nodes of cervical carcinoma. PAN metastasis appears to occur secondarily to wide‐spread PLN metastasis. These results provide a basis for determining the site of selective lymph node dissection and for estimating the existence of PAN metastasis from the pattern of metastasis in PLN in patients with cervical carcinoma. Cancer 1999;85:1547–54. © 1999 American Cancer Society.

Sperm entry in mammalian oocytes triggers intracellular Ca2+ oscillations that initiate resumption of the meiotic cell cycle and subsequent activations. Here, we show that phospholipase C zeta 1 (PLCζ1) is the long-sought sperm-borne oocyte activation factor (SOAF). Plcz1 gene knockout (KO) mouse spermatozoa fail to induce Ca2+ changes in intracytoplasmic sperm injection (ICSI). In contrast to ICSI, Plcz1 KO spermatozoa induced atypical patterns of Ca2+ changes in normal fertilizations, and most of the fertilized oocytes ceased development at the 1–2-cell stage because of oocyte activation failure or polyspermy. We further discovered that both zona pellucida block to polyspermy (ZPBP) and plasma membrane block to polyspermy (PMBP) were delayed in oocytes fertilized with Plcz1 KO spermatozoa. With the observation that polyspermy is rare in astacin-like metalloendopeptidase (Astl) KO female oocytes that lack ZPBP, we conclude that PMPB plays more critical role than ZPBP in vivo. Finally, we obtained healthy pups from male mice carrying human infertile PLCZ1 mutation by single sperm ICSI supplemented with Plcz1 mRNA injection. These results suggest that mammalian spermatozoa have a primitive oocyte activation mechanism and that PLCζ1 is a SOAF that ensures oocyte activation steps for monospermic fertilization in mammals.

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Interstitial collagen gives fetal membranes tensile strength, and membrane rupture has been attributed to collagen degradation. A polymorphism at ؊1607 in the matrix metalloproteinase-1 (MMP-1) promoter (an insertion of a guanine (G)) creates a core Ets binding site and increases promoter activity. We investigated whether this polymorphism is functionally significant for MMP-1 expression in amnion cells and whether it is associated with preterm premature rupture of the membranes (PPROM). The 2G promoter had >2-fold greater activity than the 1G allele in amnion mesenchymal cells and WISH amnion cells. Phorbol 12-myristate 13-acetate (PMA) increased mesenchymal cell nuclear protein binding with greater affinity to the 2G allele. Induction of MMP-1 mRNA by PMA was significantly greater in cells with a 1G/2G or 2G/2G genotype compared with cells homozygous for the 1G allele. When treated with PMA, the 1G/2G and 2G/2G cells produced greater amounts of MMP-1 protein than 1G/1G cells. A significant association was found between fetal carriage of a 2G allele and PPROM. We conclude that the 2G allele has stronger promoter activity in amnion cells, that it confers increased responsiveness of amnion cells to stimuli that induce MMP-1, and that this polymorphism contributes to the risk of PPROM.Complications resulting from idiopathic preterm birth, defined as delivery before 37 weeks of gestation, account for the majority of perinatal deaths of infants without anomalies in developed nations (1, 2). Preterm premature rupture of the membranes (PPROM) 1 occurs in ϳ1% of all pregnancies and is associated with 30 -40% of preterm deliveries (3). PPROM is thus the leading identifiable cause of preterm birth and its complications, including respiratory distress syndrome, neonatal infection, and intraventricular hemorrhage (3, 4). Consequently, identification of markers that identify patients at risk for PPROM is a subject of considerable interest.Interstitial collagens (type I and type III collagen) of the amnion confer upon the fetal membranes tensile strength (5). Rupture of fetal membranes at term as well as preterm has been attributed, in part, to degradation of the collagens in the extracellular matrix. The breakdown of the interstitial collagens is mediated by matrix metalloproteinases (MMPs). The first step in interstitial collagen catabolism is catalyzed by collagenases including matrix metalloproteinase 1 (MMP-1), the primary collagenase elaborated by fibroblasts (6). It is also produced by monocytic cells (7). MMP-1 is produced as a proenzyme; after proteolytic activation, it cleaves through the fibrillar triple helix at a specific site, producing fragments that can be further degraded by other MMPs, including the gelatinases MMP-2 and MMP-9 (8 -12). Evidence that MMP activity is important for fetal membrane rupture includes the observation that fetal membrane MMP expression increases at the time of parturition (13, 14). Moreover, MMP levels are elevated in human amniotic fluid in association with PPROM (15-18).A single n...

Purpose: The objective of this study was to evaluate the efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B 12 in pretreated Japanese patients with advanced non-small cell lung cancer (NSCLC). Experimental Design: Patients with an Eastern Cooperative Oncology Group performance status 0 to 2, stage III or IV, and who received previously one or two chemotherapy regimens were randomized to receive 500 mg/m 2 pemetrexed (P500) or 1,000 mg/m 2 pemetrexed (P1000) on day 1every 3 weeks. The primary endpoint was response rate. Results: Of the 216 patients evaluable for efficacy (108 in each arm), response rates were 18.5 % (90 % confidence interval, 12.6-25.8 %) and 14.8 % (90 % confidence interval, 9.5-21.6%), median survival times were 16.0 and 12.6 months, 1-year survival rates were 59.2% and 53.7%, and median progression-free survival were 3.0 and 2.5 months for the P500 and P1000, respectively. Cox multiple regression analysis indicated that pemetrexed dose was not a significant prognostic factor. Drug-related toxicity was generally tolerable for both doses; however, the safety profile of P500 showed generally milder toxicity. Main adverse drug reactions of severity grade 3 or 4 were neutrophil count decreased (20.2%) and alanine aminotransferase (glutamine pyruvic transaminase) increased (15.8%) in P500 and neutrophil count decreased (24.3%), WBC count decreased (20.7%), and lymphocyte count decreased (18.0%) in P1000. One drug-related death from interstitial lung disease occurred in the P500. Conclusion: P500 and P1000 are similarly active with promising efficacy and acceptable safety outcomes in pretreated patients with NSCLC. These results support the use of P500 as a second-and third-line treatment of NSCLC.