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Most patients with gastric or gastroesophageal junction (GEJ) cancer are diagnosed with inoperable advanced or metastatic disease. In these cases, chemotherapy is the only treatment demonstrating survival benefit. The present study compares clinicopathologic characteristics and survival outcomes for patients with advanced esophageal, GEJ, and gastric adenocarcinoma treated with first-line chemotherapy [epirubicin-cisplatin-5-fluorouracil (ECF), epirubicin-cisplatin-capecitabine (ECX), or etoposide-leucovorin-5-fluorouracil (ELF)] or best supportive care (BSC) at our institution with those for historical controls. Methods We retrospectively reviewed medical information for 401 patients with newly diagnosed advanced esophageal, GEJ, or gastric adenocarcinoma treated with first-line chemotherapy (ECF, ECX, or ELF) or BSC from January 1, 2004, through December 31, 2010. Descriptive statistics were used to compare the data collected with data for historical control patients. Results Of the study patients, 93% were diagnosed with metastatic disease (n = 374), and 63% received BSC only (n = 251). The main reasons that patients received BSC only included poor Eastern Cooperative Oncology Group performance status (55%), patient decision (31%), and comorbidities (14%). Of the remaining patients, 98 (24%) received ECF or ECX and 52 (13%) received ELF as first-line treatment. Median overall survival was significantly longer in patients treated with ECF or ECX or with ELF than in those receiving BSC (12.7 months vs. 12.7 months vs. 5.5 months respectively). Chemotherapy also significantly reduced the risk of death (64% reduction with ECF or ECX, 58% with ELF). Conclusions We confirmed the substantial overall survival benefit of combination chemotherapy compared with BSC, with better survival in our patient population than in historical controls. However, novel treatment options are still warranted to improve outcomes in this patient population. [ABSTRACT FROM AUTHOR]

Introduction: Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) for muscle invasive urothelial carcinoma of the bladder improves survival. This study was undertaken to determine the rate of neoadjuvant gemcitabine and cisplatin use prior to RC and to assess its effect on the pathologic response rates and cancer-specific survival (CSS) and overall survival (OS)., Methods: This retrospective chart review examined all patients having a RC between January 1, 2007 and June 30, 2011. We collected patient demographics, pre-treatment clinical stage, type of chemotherapy, post-RC pathologic data and survival data., Results: A total of 251 RC were performed of which 160 were for stage cT2-T4 urothelial carcinoma of the bladder. Of the 160 patients, 91 (57%) received neoadjuvant gemcitabine and cisplatin (GC) and 69 (43%) went straight to RC. Patients receiving neoadjuvant GC had a greater chance of achieving a pathologically lower stage compared to the untreated population: pT0 at 21% vs. 3%; non-invasive cancer at 37% vs. 10%; and organ-confined cancer at 60% vs. 33% (p < 0.001). Survival correlated with pathological stage: ≤pT3a patients had a median OS and CSS of 48.8 and 51.2 months compared to an OS and a CSS in ≥pT3b patients of 21.8 and 28.1 months, respectively (p < 0.0001)., Conclusions: Neoadjuvant chemotherapy for urothelial carcinoma of the bladder is more frequently administered at our institution compared to the published literature. We have found that neoadjuvant chemotherapy increases the rate of down-staging, which is associated with a reduced the risk of death from urothelial carcinoma of the bladder.

Purpose: In pancreatic cancer, deoxycytidine kinase and the human equilibrative nucleoside transporter 1 have been validated as predictive markers for benefit from gemcitabine therapy. Gemcitabine is used with cisplatin or carboplatin as neoadjuvant chemotherapy for muscle invasive urothelial cancer of the bladder before radical cystectomy and patients rendered disease-free at surgery tend to have better outcomes. In this trial we examined if nucleoside transporter or deoxycytidine kinase protein abundance in biopsy specimens before chemotherapy is related to the response to neoadjuvant chemotherapy., Materials and Methods: A total of 62 consecutive patients undergoing neoadjuvant chemotherapy with platinum/gemcitabine at a single institution were accrued. Initial transurethral resection of bladder tumor specimens and cystectomy specimens were collected, and scored for nucleoside transporter and deoxycytidine kinase expression. Pathological response rates and survival data were collected., Results: Of the 62 patients 17 (27%) achieved a complete pathological response (pT0) to neoadjuvant chemotherapy. Nucleoside transporter and deoxycytidine kinase protein expression in the transurethral resection of bladder tumor specimens did not predict for pT0 status to neoadjuvant chemotherapy. Median overall survival was not reached for the group achieving pT0 status and was 46 months for those with persistent cancer at definitive surgery (p = 0.07). Median followup for the cohort was 30 months., Conclusions: Nucleoside transporter and deoxycytidine kinase expression in transurethral resection of bladder tumor samples do not predict for response to gemcitabine and platinum neoadjuvant chemotherapy. Patients should continue to be offered neoadjuvant chemotherapy before radical cystectomy based on clinical and pathological staging., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

We have studied male sexual differentiation of null mutant mice (-/-) for the thyroid-specific enhancer-binding protein (T/ebp or Nkx2.1) gene, a homeodomain transcription factor that plays a role in organogenesis of the thyroid, lung, ventral forebrain, and pituitary gland. Because the T/ebp/Nkx2.1 (-/-) mice do not develop the pituitary gland, their sexual differentiation, if any, must occur in the absence of action of gonadotropins and other pituitary hormones. The (-/-) mice survive only until birth (embryonic d 19-19.5 of pregnancy), and when their external and internal genitals were inspected at embryonic d 18.5, they were indistinguishable from the (+/-) and (+/+) control mice. The testis weights of (-/-) mice were 20% lower than in (+/+) and (+/-) mice. The testosterone content of the (-/-) testes (13.5 +/- 2.4 pg/gonad, mean +/- SEM, n = 11) was dramatically reduced, compared with (+/-) (165 +/- 22.5 pg, n = 14) and (+/+) (234 +/- 37.3 pg, n = 10) littermates. Light microscopy revealed no difference in seminiferous tubules, interstitial tissue, or relative proportions of the two-cell compartments between the (-/-) and (+/+) testes. However, electron microscopy confirmed that Leydig cells in the (-/-) testes were much smaller, with smaller mitochondria and proportion of smooth endoplasmic reticulum than found in the controls, which was in support of the low androgen content of the knockout testes. In conclusion, this study on T/ebp/Nkx2.1 knockout mice, devoid of the pituitary gland, demonstrates that pituitary hormone secretion is not needed for stimulation of sufficient fetal testicular androgen synthesis to induce male sexual differentiation. The endogenous testosterone level in the null mutant testes is 5-10% of the control level, which suggests that there is a considerable safety margin in the amount of testosterone that is needed for the male fetal masculinization.

To study the regulation of fetal testicular steroidogenesis in the rat, we examined effects of members of the natriuretic peptide family, that is, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), on testosterone production of dispersed Leydig cells of rat fetuses at Embryonic Day (E) 18.5. All three peptides stimulated testosterone production, with significant effect at concentrations > or =1 x 10(-8) mol/L of ANP, > or =1 x 10(-9) mol/L of BNP, and > or =1 x 10(-6) mol/L of CNP. Likewise, receptors for all three peptides (i.e., NPR-A, NPR-B, and NPR-C) were expressed in the fetal testis as early as E15.5. The natriuretic peptides had no effect on cAMP production by fetal Leydig cells. When tested in combination with two other peptides previously shown to stimulate fetal testicular steroidogenesis, vasoactive intestinal peptide and pituitary adenylate cyclase-stimulating polypeptide (PACAP-27), the combined effects did not differ significantly from the maximum effect with any one of the peptides alone. In conclusion, our present findings provide both functional and molecular evidences for NPR-A, NPR-B, and NPR-C in the fetal testis. Because ANP has previously been detected in fetal plasma and we now demonstrate the expression of BNP and CNP in fetal testes, these findings indicate involvement of the natriuretic peptides in endocrine and paracrine regulation during the early phase of fetal testicular steroidogenesis at E15.5--19.5 (i.e., before the onset of pituitary LH secretion).

Despite no evidence for desensitization of phospholipase C-coupled gonadotropin-releasing hormone (GnRH) receptors, we previously reported marked suppression of GnRH-mediated Ca(2+) responses in alphaT3-1 cells by pre-exposure to GnRH. This suppression could not be accounted for solely by reduced inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)) responses, thereby implicating uncoupling of Ins(1,4,5)P(3) production and Ca(2+) mobilization (McArdle, C. A., Willars, G. B., Fowkes, R. C., Nahorski, S. R., Davidson, J. S., and Forrest-Owen, W. (1996) J. Biol. Chem. 271, 23711-23717). In the current study we demonstrate that GnRH causes a homologous and heterologous desensitization of Ca(2+) signaling in alphaT3-1 cells that is coincident with a rapid (t((12)) < 20 min), marked, and functionally relevant loss of type I Ins(1,4,5)P(3) receptor immunoreactivity and binding. Furthermore, using an alphaT3-1 cell line expressing recombinant muscarinic M(3) receptors we show that the unique resistance of the GnRH receptor to rapid desensitization contributes to a fast, profound, and sustained loss of Ins(1,4,5)P(3) receptor immunoreactivity. These data highlight a potential role for rapid Ins(1,4,5)P(3) receptor down-regulation in homologous and heterologous desensitization and in particular suggest that this mechanism may contribute to the suppression of the reproductive system that is exploited in the major clinical applications of GnRH analogues.

Testicular steroidogenesis in the fetal rat is activated before the onset of pituitary gonadotropin secretion. We studied here whether the pituitary adenylate cyclase-activating polypeptide (PACAP) could regulate this early Leydig cell activity. Effects of the two PACAP forms, 27 and 38, were studied on cAMP and testosterone production of dispersed Leydig cells of embryonic Day (E) 18.5. Furthermore, PACAP and PACAP type I receptor mRNA expression were measured by reverse transcription-polymerase chain reaction (RT-PCR), and testicular PACAP concentations by RIA. The two peptides were highly potent stimulators of fetal testes. Doses as low as 10(-18) mol/L of PACAP-27 and 10(-17)-10(-16) mol/L of PACAP-38 significantly stimulated cAMP and testosterone production, with magnitude comparable to that evoked by hCG. These effects were specific for fetal Leydig cells, because PACAP-responsive control cells, including murine Sertoli and granulosa cell lines, only responded to concentrations >/=10(-12) mol/L. By RT-PCR, PACAP and its type I receptor mRNAs were expressed in fetal testis as early as E15.5. By Northern hybridization, PACAP mRNA was first detectable on Day 30 postpartum and increased thereafter. Both forms of PACAP peptides were clearly detectable in E17.5 testes, with decreasing levels thereafter. In conclusion, the steroidogenesis of fetal rat Leydig cells responds to very low concentrations of PACAP, which may be an important physiological regulator of this activity before the onset of pituitary LH secretion.

This study elaborates our recent preliminary finding that vasoactive intestinal peptide (VIP) has a specific stimulatory effect on fetal rat Leydig cells. We examined the dose-response relationship for the effect of VIP on cAMP and testosterone production by dispersed fetal Leydig cells isolated from rat testes on embryonic day (E) 18.5. Further, we used RT-PCR to examine the expression of the VIP gene in fetal brain and testes and that of the VIP receptor genes in fetal testes and used RIA to measure VIP in testes and plasma during the fetal period. VIP stimulated fetal testicular cAMP production at a dose of 10(-9) mol/liter, whereas a dose as low as 10(-12) mol/liter stimulated testosterone production. This suggests that VIP at low doses may stimulate testosterone production using second messenger pathways other than cAMP. RT-PCR analysis could not reveal either VIP messenger RNA (mRNA) in fetal tissues or VIP1 receptor mRNA in the fetal or newborn testes, whereas VIP2 receptor mRNA was detected in fetal testes as early as E15.5. Northern hybridization analysis showed that the level of expression of VIP2 receptor mRNA is very low in fetal and neonatal testes and increases with age. The testicular VIP content was unmeasurable by our RIA method (i.e. <1 fmol/testis), whereas the circulating level of VIP was 82.9 +/- 1.1 pmol/liter on E17.5 and decreased with advancing fetal age. In conclusion, our results suggest that VIP from an extratesticular source, possibly from the maternal compartment, may regulate fetal testicular steroidogenesis through type 2 receptors as early as E15.5. These findings may be of physiological significance, because the onset of fetal testicular steroidogenesis occurs at an age (E15.5-19.5) before the onset of pituitary LH secretion.

Unlabelled: The goal of the present study was to determine whether the onset of fetal Leydig cell steroidogenesis is dependent on gonadotropic stimulation. The relationships between the onset of pituitary LH synthesis and secretion, and the response of testicular steroidogenesis to LH and various putative paracrine factors were examined. We found by reverse transcription-polymerase chain reaction (RT-PCR) that the LHbeta-subunit gene expression in the fetal pituitary gland starts on embryonic day (E) 16.5. Plasma LH was very low (< 5.0 ng/L) until E19.5 and increased significantly thereafter. In contrast, the greatest increase in the testicular testosterone had already occurred between E18.5 and E19.5. Hence, fetal testicular steroidogenesis must start independent of LH stimulation. Basal testosterone production in incubations of fetal testis (E16.5-19.5) was high, 50-80% of the hCG-stimulated level. In contrast, in dispersed fetal Leydig cells, basal steroidogenesis was consistently low. This suggests the presence of paracrine factors in the intact testes that stimulate their steroidogenesis. Effects of various putative paracrine factors were thereafter tested on the fetal testis. We found for the first time that both vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP-27) markedly stimulated fetal, but not adult, Leydig cells., In Conclusion: 1) Pituitary LH cannot be the initial stimulus for fetal testicular steroidogenesis. 2) Some paracrine factor(s) probably turn on and maintain early fetal testicular steroidogenesis before the later onset of LH secretion, although a constitutive component in the onset of steroidogenesis is also possible. 3) VIP and PACAP-27 are likely candidates for a paracrine stimulus of the fetal testis.