Is There Room for Liposomal Irinotecan in Biliary Tract Cancer? A Meta-analysis of Randomised Trials.

AIMS: The combination of 5-fluorouracil/leucovorin (5-FU/LV) plus oxaliplatin (FOLFOX) is widely acknowledged as the standard regimen for second-line treatment in patients with advanced biliary tract cancer. Nanoliposomal irinotecan (nal-IRI) has demonstrated its activity in patients with advanced pancreatic cancer. Recent studies have investigated the activity of nal-IRI in combination with 5-FU/LV for biliary tract cancer. However, the results have been contradictory. We conducted a meta-analysis to assess survival outcomes and response rates in randomised trials investigating the activity of nal-IRI in previously treated biliary tract cancer patients. MATERIALS AND METHODS: We systematically collected potentially relevant findings from PubMed/Medline, the Cochrane library and EMBASE. Abstracts presented at major international oncological meetings were also reviewed. We extracted hazard ratios and 95% confidence intervals for progression-free survival and overall survival, as well as odds ratios and 95% confidence intervals for objective response rate. The outcomes of the accessible randomised studies evaluating the activity of nal-IRI plus 5-FU/LV were analysed. RESULTS: The combination therapy exhibited a statistically significant decrease in the risk of progression (hazard ratio 0.70; 95% confidence interval 0.50-0.97) when compared with 5-FU/LV alone. Additionally, the dual regimen yielded longer overall survival and a higher objective response rate. CONCLUSION: Our meta-analysis showed that nal-IRI plus 5-FU/LV had a superior activity in comparison with 5-FU/LV. Further investigations are required to elucidate the role of nal-IRI in this setting and to identify subgroups of patients who could derive the greatest benefit from its administration.

Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling.

BACKGROUND: Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions. METHODS: We studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS),Results:We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPOCM) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSCCM) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPOCM induced the overexpression and the nuclear translocation of the Frizzled family member receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells. CONCLUSIONS: We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer.

TAK1-regulated expression of BIRC3 predicts resistance to preoperative chemoradiotherapy in oesophageal adenocarcinoma patients.

BACKGROUND: About 20% of resectable oesophageal carcinoma is resistant to preoperative chemoradiotherapy. Here we hypothesised that the expression of the antiapoptotic gene Baculoviral inhibitor of apoptosis repeat containing (BIRC)3 induced by the transforming growth factor ß activated kinase 1 (TAK1) might be responsible for the resistance to the proapoptotic effect of chemoradiotherapy in oesophageal carcinoma. METHODS: TAK1 kinase activity was inhibited in FLO-1 and KYAE-1 oesophageal adenocarcinoma cells using (5Z)-7-oxozeaenol. The BIRC3 mRNA expression was measured by qRT-PCR in 65 pretreatment frozen biopsies from patients receiving preoperatively docetaxel, cisplatin, 5-fluorouracil, and concurrent radiotherapy. Receiver operator characteristic (ROC) analyses were performed to determine the performance of BIRC3 expression levels in distinguishing patients with sensitive or resistant carcinoma. RESULTS: In vitro, (5Z)-7-oxozeaenol significantly reduced BIRC3 expression in FLO-1 and KYAE-1 cells. Exposure to chemotherapeutic agents or radiotherapy plus (5Z)-7-oxozeaenol resulted in a strong synergistic antiapoptotic effect. In patients, median expression of BIRC3 was significantly (P<0.0001) higher in adenocarcinoma than in the more sensitive squamous cell carcinoma subtype. The BIRC3 expression significantly discriminated patients with sensitive or resistant adenocarcinoma (AUC-ROC=0.7773 and 0.8074 by size-based pathological response or Mandard's tumour regression grade classifications, respectively). CONCLUSIONS: The BIRC3 expression might be a valid biomarker for predicting patients with oesophageal adenocarcinoma that could most likely benefit from preoperative chemoradiotherapy.

Abnormal p53 expression is rare in clinically localized human prostate cancer: comparison between immunohistochemical and molecular detection of p53 mutations.

BACKGROUND: We assessed the frequency and molecular basis of p53 mutations in clinically localized prostatic adenocarcinoma. METHODS: Prostate specimens were examined from 100 patients with clinically localized prostatic adenocarcinoma and 13 patients with benign prostatic hyperplasia (BPH). Mutations producing nuclear accumulation of p53 were detected immunohistochemically. Exon-specific mutations were analyzed by polymerase chain reaction amplification and single strand conformation polymorphism (PCR-SSCP) and sequenced. RESULTS: p53 accumulation was detected in 5 tumors using antibody DO-1, and in 4 of these using antibody PAb 1801, but not in BPH. PCR-SSCP detected mutations in all 5 tumors, with alterations in exon 5 for 1 tumor, exon 6 for 3 tumors, and exon 7 for 1 tumor. An exon 6 mutation was also found in a tumor with no anti-p53 staining. CONCLUSIONS: p53 mutations are uncommon in clinically localized prostatic adenocarcinoma and absent from BPH. 5 of the 6 mutations were derived from locally invasive, prostate carcinomas, supporting the hypothesis that mutation of p53 is a late event in prostate carcinoma progression.

Transforming growth factor-beta 3 is expressed in nondividing basal epithelial cells in normal human prostate and benign prostatic hyperplasia, and is no longer detectable in prostate carcinoma.

BACKGROUND: We investigated the role of the transforming growth factor beta (TGF-beta) family in the neoplastic progression of the human prostate. METHODS: Expression of TGF-beta mRNA was measured by Northern blot analysis of tissue extracts, and TGF-beta protein by immunohistochemical analysis of tissue sections. Proliferating cells were detected by their expression of Ki-67 antigen. RESULTS: The level of TGF-beta 1 mRNA was equal among normal prostate, benign prostatic hyperplasia (BPH), and prostate carcinoma. TGF-beta 2 mRNA was not detectable, and TGF-beta 3 mRNA was expressed 20-fold lesion in carcinoma compared to BPH and normal prostate. TGF-beta 1 protein was expressed in the stromal cells in all three tissues and TGF-beta 3 protein in the basal layer of epithelial cells, but not in carcinoma. Proliferating epithelial cells fail to express TGF-beta 3. CONCLUSIONS: TGF-beta 1 and TGF-beta 3 are independently regulated, and carcinoma of the prostate is characterized by the loss of basal epithelial cells expressing TGF-beta 3.

TGF-beta 3 expression correlates with epithelial cell death in normal, hyperplastic and malignant prostate.

Cytokines of the TGF beta family are thought to be involved in cellular growth control and are therefore likely candidates to regulate homeostasis of the prostate. We have analyzed immunohistochemically the expression of TGF-beta 3 in normal prostate (NP), benign prostate hyperplasia (BPH) and prostate cancer (PCa). Its expression was correlated to cell death and cell proliferation using double labeling techniques with terminal transferase and anti-Ki67 antibodies, respectively. TGF-beta 3 expression, localized to the basal cell layer of glandular epithelium, was found in NP and BPH. In TGF-beta 3 positive regions cell death was frequently detected, while proliferating cells were only observed in TGF-beta 3 negative areas. Moreover, cell death was not observed in the absence of TGF-beta 3. PCa was characterized by high cell proliferation and the absence of cell death. TGF-beta 3 expression could not be detected in PCa. Hormonal ablation is the main therapeutic protocol used today suffering, however, from a high relapse rate. We have used the rat as a model system to show that castration, resulting in massive cell death of glandular epithelial cells, induces overall expression of TGF-beta 3 in the basal cell layers. Interestingly, investigation of tumor material from patients received after hormonal ablation revealed the simultaneous presence of TGF-beta 3 positive, hyperplastic regions undergoing cell death and TGF-beta 3 negative highly proliferating malignant foci. Our results suggest that the expression of TGF-beta 3 strictly correlates with cell death in normal and hyperplastic prostate and that disappearance of TGF-beta 3 indicates high cell proliferation and the establishment of the malignant phenotype.

No evidence of osteopenia 5 to 8 years after ileal orthotopic bladder substitution.

PURPOSE: The use of bowel segments as bladder substitutes may result in chronic, impaired vitamin D and calcium metabolism, and ultimately in bone demineralization. MATERIALS AND METHODS: Bone metabolism was examined in 14 patients who lived for 5 to 8 years with an ileal low pressure bladder substitute after radical cystectomy for bladder cancer. Bone mineral density was measured using dual energy x-ray absorptiometry of the total skeleton, lumbar spine, femoral neck, and tibial epiphysis and diaphysis. Laboratory studies included serum levels of 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, intact parathyroid hormone, plasma alkaline phosphatase, electrolytes, creatinine and blood gas analysis. RESULTS: Bone mineral density was normal in all patients. There was no evidence of deficient vitamin D stores. There was a tendency toward slightly elevated serum creatinine values in patients with preexisting impaired renal function, including 1 who also had slight acidosis. No patient had hyperchloremia. CONCLUSIONS: We found no evidence of osteomalacia, osteoporosis or significant metabolic acidosis in 14 patients with an ileal bladder substitute for 5 to 8 years. However, it is not known whether the absence of osteopenia would also apply to patients with poor renal function, to those not followed meticulously and, thus, at risk for major long-term functional or metabolic disturbances from the ileal bladder substitute or to patients with orthotopic bladder substitutes made from longer or other bowel segments than we used.

Experience in 100 patients with an ileal low pressure bladder substitute combined with an afferent tubular isoperistaltic segment.

Between April 1985 and April 1993, 100 consecutive men underwent lower urinary tract reconstruction after cystectomy. An ileal low pressure reservoir using the Goodwin cup-patch principle was combined with an afferent ileal tubular segment. The early complication rate was 11%, including 2 postoperative deaths due to septicemia. After a median followup of 27 months (range 3 to 96) 14 patients required surgery for late complications (intestinal obstruction, urethral stricture or tumor recurrence, hernia or ureteral stenosis). A total of 32 patients died of metastatic bladder cancer and 7 died of other causes. The functional capacity of the bladder substitute was increased to the desired 450 to 500 ml. after 3 to 12 months, which was paralleled by improving urinary continence. After 1 year 92% of the patients were continent by day and after 2 years 80% were continent at night. Upper tract surveillance with excretory urography, renal ultrasound and serum creatinine estimation has shown 4 left ureteral strictures but not significant upper tract deterioration or ureteral recurrence. Significant reflux was not observed during video urodynamics unless the reservoir was overfilled. During voiding, by outlet relaxation and straining if necessary, the intra-abdominal pressure increase with straining acted equally on the reservoir and ureters. Therefore, unlike voiding with a normal bladder, no isolated intravesical pressure increase occurred and, thus, there was no reflux from the reservoir. The combination of an ileal low pressure reservoir with an afferent isoperistaltic ileal segment and an open end-to-side ureteroileal anastomosis allows for radical cancer surgery with resection of the ureters where they cross the iliac vessels and minimizes the risk of ureteral stenosis. The unidirectional peristalsis of the ureters and the afferent tubular ileal segment seem to protect the upper urinary tract sufficiently. The surgical technique is straightforward and allows for later conversion to an ileal conduit if necessary. The functional results of the bladder substitute are comparable to other similar reservoir techniques, provided that the patients are carefully selected, well rehabilitated and meticulously followed.

Analysis of early failures after intravesical instillation therapy with bacille Calmette-Guérin for carcinoma in situ of the bladder.

OBJECTIVE: To analyse the clinical and therapeutic consequences of early treatment failure after bacille Calmette-Guérin (BCG) instillation therapy for carcinoma in situ of the bladder. PATIENTS AND METHODS: A total of 115 patients with carcinoma in situ (Tis) of the bladder were treated by intravesical instillation of living BCG vaccine (Immun BCG Pasteur F). Twenty five patients had primary Tis and 90 had secondary Tis with synchronous or prior superficial papillary tumours. All papillary tumours were resected before instillation of BCG. All patients completed one series of 6 weekly instillations of 120 mg BCG. RESULTS: Twenty-two of 25 patients (88%) with primary Tis responded completely, with negative cytology and cystoscopy findings within a median follow-up period of 44 months. Three of the 25 (12%) had cytological evidence of disease within 9 months of therapy and were considered to be early treatment failures. One patient had muscle-invasive bladder cancer, one had Tis and invasive cancer of the prostatic urethra, and the last, in whom a second BCG course also failed, had Tis of both ureters. Seventy of 90 patients (78%) with secondary Tis had a complete response after treatment with BCG, with repeated negative cytology and cystoscopy examinations within a median follow-up time of 40 months. Twenty of the 90 (22%) with secondary Tis had positive cytology within 9 months after BCG therapy and were considered early treatment failures. Five of these 20 had a cystectomy, three for persistent Tis of the bladder and two for a solid urothelial carcinoma of the prostate. The remaining 15 early failures received a second course of BCG. Four of these 15 patients responded and the remaining 11 failed the second course. The 11 failures included two patients with multifocal T1 G3 bladder cancers. four with invasive bladder cancer, two with solid urothelial carcinomas of the prostatic urethra, and three with Tis of the upper urinary tract. CONCLUSIONS: According to these data, early treatment failure after 6 weekly instillations of 120 mg Immun BCG Pasteur F is an alarming signal which requires immediate re-assessment of the patient to exclude a muscle-invasive bladder cancer or an extravesical carcinoma in situ, either in the upper urinary tract or in the prostatic urethra.

Mesenchymal-epithelial interactions and transforming growth factor-beta expression during mouse prostate morphogenesis.

To explore the role of transforming growth factor-beta (TGF beta) isoforms and other growth-related genes during prostate morphogenesis in the mouse, we examined mRNA levels in fetal day 17 urogenital sinus, mesenchyme (UGM), and epithelium (UGE) as well as in the ventral, dorsal, and anterior lobes of the adult prostate. In addition, we used antiserum specific for extracellular TGF beta 1 in immunohistochemical studies to localize accumulation of the TGF beta 1 isozyme in the above tissues as well as those derived from fetal day 19 and neonatal mouse prostate. Differential patterns of expression in fetal and adult tissues were seen. TGF beta 1, -beta 2, and -beta 3 expression was substantially elevated in UGM compared to that in UGE, yet only TGF beta 1, not TGF beta 2 or TGF beta 3, mRNA levels were sustained in adult prostate tissues. High levels of accumulation of TGF beta 1 were demonstrated by immunohistochemistry in the mesenchymal compartment compared to those in the epithelial compartment throughout development. Interestingly, the highest levels of TGF beta 1 appeared in areas of active epithelial duct formation and delineated the mesenchymal architectural changes necessary for ductal network formation. Additional studies revealed that levels of mRNAs for other genes involved in tissue remodeling and growth were also elevated in UGM compared to those in UGE. Tissue plasminogen activator, urokinase plasminogen activator, androgen receptor, and c-myc mRNA levels were also elevated in UGM compared to UGE. Interestingly, whereas tissue plasminogen activator mRNA levels, like those of TGF beta 2 and -beta 3, were barely detectable in adult prostatic tissues, mRNA levels for urokinase plasminogen activator, androgen receptor, and c-myc were readily detected and expressed in a lobe-specific fashion. Overall, these data indicate that expression of TGF beta 1 isoforms and other growth-related genes is associated with mesenchymal cells in areas of active morphogenesis during prostate development and provide objective molecular and cellular information regarding mediators of mesenchymal-epithelial interactions in prostate.

Differential expression of transforming growth factor-beta 1 and beta 3 as well as c-fos mRNA in normal human prostate, benign prostatic hyperplasia and prostatic cancer.

The discrepancy between the incidence of latent prostate cancer and that of clinically overt carcinoma suggests that there can be different courses in the biological progression of prostate cancer. As this cancer is detected increasingly at an infraclinical stage, markers are needed to indicate which lesions will progress and lead to the patient's death. To investigate the possibility that specific growth factors and/or proto-oncogenes are expressed differentially, we measured mRNA levels of transforming growth factors beta 1 (TGF-beta 1), TGF-beta 2 and TGF-beta 3 and of the c-fos and c-jun oncogenes by Northern blotting in normal prostate, benign prostatic hyperplasia (BPH) and prostate cancer. Our data demonstrate that expression of TGF-beta 1 increased, whereas that of TGF-beta 3 fell to an almost undetectable level in carcinoma. Expression of c-fos followed the TGF-beta 1 pattern, whereas no difference could be seen in c-jun expression in cancer as compared with BPH and normal prostate. The differential expression of TGF-beta 1, TGF-beta 3 and c-fos could possibly be used to improve the characterisation of prostate cancer. Long-term follow-up of patients may indicate whether mRNA levels of these growth factors and oncogenes correlate clinically and whether they can be used as markers for progression in human prostate cancer.

Elevated transforming growth factor-beta 1 and beta 3 mRNA levels are associated with ras + myc-induced carcinomas in reconstituted mouse prostate: evidence for a paracrine role during progression.

Mouse prostate reconstitution is a useful model for studying the progression of ras + myc-induced carcinomas. When these oncogenes were introduced into both the epithelial and the mesenchymal compartments, poorly differentiated adenocarcinomas resulted. Restricted introduction of both oncogenes into the epithelium produced epithelial hyperplasia. Malignancies were produced in two out of 17 cases of selectively transformed epithelium, suggesting that the hyperplastic condition represents a premalignant phenotype. Restricted introduction of both oncogenes into the mesenchyme produced only mesenchymal dysplasia. Transforming growth factor-beta 1 (TGF-beta 1) and beta 3 (TGF-beta 3) mRNA levels were elevated in the ras + myc-induced carcinomas when compared to the normal controls or to the epithelial hyperplasias. In contrast, TGF-beta 2 mRNA levels were similar in all control and ras + myc-induced carcinomas. Elevated TGF-beta 1 mRNA levels were also found in mesenchymal dysplasia pointing to a potential paracrine activity by the ras + myc transformed mesenchyme. We conclude that elevated TGF-beta 1 and beta 3 are correlated with progression to malignancy and that mesenchyme derived TGF-beta 1 may play an important role in the promotion of ras + myc-induced carcinomas in this model system.

Experimental oncogene induced prostate cancer.

The mouse prostate reconstitution model exploits the ability of the fetal urogenital sinus to differentiate into a mature prostate when grafted under the renal capsule of an adult isogenic male host. By use of a recombinant retroviral vector, the ras and myc oncogenes are introduced singly or in combination into the fetal urogenital sinus--resulting in distinct phenotypes of prostatic pathology: dysplasia (caused by ras), hyperplasia (caused by myc) and frank carcinomas (caused by a combination of ras+myc). This unique experimental model creates in vivo conditions that mimic the natural initiation and progression of cancer. An expanded MPR protocol allows restricted retrovirus infection of the mesenchyme or epithelial compartments to evaluate paracrine activities. It enables almost unparalleled flexibility in addressing fundamental questions in prostate cancer. We have identified genetic variance in the susceptibility to tumour induction between two different strains of mice (mimicking the observation of racial variability in the predisposition to clinical prostate cancer). The MPR model supports data from other tumour models and implicates TGF-beta 1 and TGF-beta 3 as being strongly associated with tumour progression. Finally, with this model, we have established clonal prostate adenocarcinomas to study directly the affects of castration on gene expression. Not only are TGF-beta 1 and TGF-beta 3 mRNA levels increased in association with malignancy but they are also further enhanced by castration treatment. Based on these experimental studies, we believe that TGF-beta 1 and TGF-beta 3 expression strongly influences the progression of prostate cancer. This information will hopefully impact on the development of more effective therapy for this important malignancy.

[Clinical experiences with extracorporeal shockwave lithotripsy]. / Klinische Erfahrungen mit der extrakorporellen Stosswellenlithotripsie (ESWL).

Clinical experience with 2738 patients treated by extracorporeal shock wave lithotripsy between March 1985 and December 1988 is reported. All treatments were performed with the Dornier HM-3 lithotriptor. 34% of the patients needed auxiliary measures, consisting primarily of urological manipulation to improve urinary drainage or for better localization and/or focussing of the stones. Severe complications were rare; urosepticemia occurred in 0.3%, 2 patients had to undergo nephrectomy because of abscessing pyelonephritis, and there was one death due to recurrent pulmonary embolism in a patient with polycythemia vera. ESWL was used for stones in the entire upper urinary tract. The stone free rate for pelvic calculi smaller than 2 cm was 79% three months after treatment; a further 16% showed desintegrated material smaller than 5 mm, augmenting the success rate to 95%. The success rate dropped to 74% for very large renal stones of more than 4 cm. A stone free rate of 84-96% was ascertained for ureteral calculi 3 months after ESWL. Absolute contraindications for ESWL are acute pyelonephritis, coagulation disorders and pregnancy. The patients must tolerate anesthesia, as most treatments with this lithotriptor must be carried out under peridural or general anesthesia and only in a few exceptional cases is treatment in sedoanalgesia possible. ESWL is now generally accepted in view of its negligible invasiveness, low morbidity and the high success rate. Modern treatment of urinary calculi is inconceivable without considering ESWL.

[Conservative treatment of splenic injuries in the adult]. / Traitement conservateur des traumatismes spléniques chez l'adulte.

Because of the risk of overwhelming post-splenectomy infection, the current trend favors conservative treatment for splenic trauma. Out of a total of 70 cases of splenic trauma in adults seen over the last 5 1/2 years, 19 spleens were preserved, 13 with, 6 without operations. Ten operated spleens were examined by Duplex-sonography, on average 38 months after surgery. The results show that in all cases, the spleen was morphologically and hemodynamically restored to normal.