ESPEN guidelines on nutrition in cancer patients

Over twenty years of intensive work toward improvement of cisplatin, and with hundreds of platinum drugs tested, has resulted in the introduction of the widely used carboplatin and of oxaliplatin used only for a very narrow spectrum of cancers. A number of interesting platinum compounds including the orally administered platinum drug JM216, nedaplatin, the sterically hindered platinum(II) complex ZD0473, the trinuclear platinum complex BBR3464, and the liposomal forms Lipoplatin and SPI-77 are under clinical evaluation. This review summarizes the molecular mechanisms of platinum compounds for DNA damage, DNA repair and induction of apoptosis via activation or modulation of signaling pathways and explores the basis of platinum resistance. Cisplatin, carboplatin, oxaliplatin and most other platinum compounds induce damage to tumors via induction of apoptosis; this is mediated by activation of signal transduction leading to the death receptor mechanisms as well as mitochondrial pathways. Apoptosis is responsible for the characteristic nephrotoxicity, ototoxicity and most other toxicities of the drugs. The major limitation in the clinical applications of cisplatin has been the development of cisplatin resistance by tumors. Mechanisms explaining cisplatin resistance include the reduction in cisplatin accumulation inside cancer cells because of barriers across the cell membrane, the faster repair of cisplatin adducts, the modulation of apoptotic pathways in various cells, the upregulation in transcription factors, the loss of p53 and other protein functions and a higher concentration of glutathione and metallothioneins in some type of tumors. A number of experimental strategies to overcome cisplatin resistance are at the preclinical or clinical level such as introduction of the bax gene, inhibition of the JNK pathway, introduction of a functional p53 gene, treatment of tumors with aldose reductase inhibitors and others. Particularly important are combinations of platinum drug treatments with other drugs, radiation and the emerging gene therapy regimens.

https://www.spandidos-publications.com/10.3892/or.10.6.1663/download

Cisplatin and platinum drugs at the molecular level. (Review).

Cancer metabolism: facts, fantasy, and fiction.

As p53 and its homologue p73 have significant sequence and functional similarities, p73 might also be expected to act as a tumour suppressor. However, p73 is activated after DNA damage in a way that is distinct from that of p53. The existence of ΔNp73 — an isoform of p73 that is encoded by a distinct promoter and that lacks the transactivation domain — further complicates matters. It seems to function as an oncogene by inhibiting both p73- and p53-induced apoptosis. So how can these opposing functions be reconciled in human tumours?

p73: Friend or foe in tumorigenesis

The tumor suppressor p53 is critically important in the cellular damage response and is the founding member of a family of proteins. All three genes regulate cell cycle and apoptosis after DNA damage. However, despite a remarkable structural and partly functional similarity among p53, p63, and p73, mouse knockout studies revealed an unexpected functional diversity among them. p63 and p73 knockouts exhibit severe developmental abnormalities but no increased cancer susceptibility, whereas this picture is reversed for p53 knockouts. Neither p63 nor p73 is the target of inactivating mutations in human cancers. Genomic organization is more complex in p63 and p73, largely the result of an alternative internal promoter generating NH2-terminally deleted dominant-negative proteins that engage in inhibitory circuits within the family. Deregulated dominant-negative p73 isoforms might play an active oncogenic role in some human cancers. Moreover, COOH-terminal extensions specific for p63 and p73 enable further unique protein-protein interactions with regulatory pathways involved in development, differentiation, proliferation, and damage response. Thus, p53 family proteins take on functions within a wide biological spectrum stretching from development (p63 and p73), DNA damage response via apoptosis and cell cycle arrest (p53, TAp63, and TAp73), chemosensitivity of tumors (p53 and TAp73), and immortalization and oncogenesis (DeltaNp73).

/pdf/p63-and-p73-roles-in-development-and-tumor-formation-3twt61x1jk.pdf

p63 and p73: roles in development and tumor formation.

Allelic deletion or transcriptional silencing of RASSF1, a putative tumor suppressor at 3p21.3, has been found in a considerable proportion of lung, breast, and ovarian cancers. In this study, we analyzed the expression and mutation status of three RASSF1 isoforms (-A, -B, and -C) in 55 primary bladder carcinomas and 10 bladder and prostate cancer cell lines. The RASSF1A transcript was not found in 80% (4 of 5) and 100% (4 of 4) of bladder and prostate cell lines, respectively. Compared with normal bladder tissues, loss or significant reduction of RASSF1A was identified in 62% (34 of 55) of primary bladder carcinomas and 10 (83%) of 12 matched sets showed tumor-specific alteration of RASSF1A expression. Moreover, loss or abnormal down-regulation of RASSF1A correlated with advanced tumor stage. RASSF1B was undetectable in 60% (3 of 5) of bladder cell lines and in 31% (17 of 55) of primary tumors, but none of these tumors showed altered expression exclusively in RASSF1B. RASSF1C transcript was detected in all cell lines and primary tumors we examined. Expression of RASSF1A and RASSF1B was reactivated in all nonexpressor cell lines by treatment with the demethylating agent 5-aza-2′-deoxycytidine. Bisulfite DNA sequencing analysis revealed that aberrant hypermethylation at the CpG island in the RASSF1A promoter is strongly associated with the loss of RASSF1A expression in cell lines and uncultured primary tumors. Methylation-specific PCR and BstUI digestion analyses also demonstrated that 97% (33 of 34) of RASSF1A-nonexpressing primary tumors are methylated. Although somatic mutations were not identified in RASSF1 transcripts expressed in unmethylated tumors, 24% (9 of 37) of methylated cell lines and primary tumors showed detectable reductions in genomic levels of RASSF1, suggesting that RASSF1A inactivation might be caused by both epigenetic and genetic mechanisms in a subset of bladder tumors. Together, our data suggest that RASSF1A inactivation may play a critical role in the malignant progression of human bladder carcinomas.

https://cancerres.aacrjournals.org/content/canres/61/18/6688.full.pdf

Frequent epigenetic inactivation of RASSF1A in human bladder carcinoma.

p73, a member of the p53 family at 1p36.3, has been demonstrated to be expressed monoallelically and induce apoptosis or G1 arrest of the cell cycle. To explore the candidacy of p73 as a suppressor in bladder tumorigenesis, we examined expression level, allelic origin, and mutation of p73 mRNA in 45 primary bladder carcinomas. Quantitative PCR analysis showed no allelic loss of the gene but showed various levels of mRNA expression in both carcinoma and noncancerous tissues. Elevated expression of p73 was frequently observed in carcinoma tissues [18 (40.0%) of 45] and showed a strong correlation with tumor stage or grade. Allotyping analysis using a StyI polymorphism detected biallelic expression in 12 (52.2%) of 23 heterozygous carcinomas but none in 4 noncancerous tissues. Tumor-specific biallelic expression was also identified from one matched set. In addition, 8 (66.7%) of these 12 expressed high levels of p73 mRNA, whereas only 2 (18.2%) of 11 monoallelic expressors showed high expression, which suggests that the increased expression of p73 might be caused by the transcriptional activation of a silent allele in carcinomas. Single-strand conformational polymorphism analysis of the entire coding region of p73 revealed no mutation, whereas 12 (26.7%) of the same set showed p53 alterations. No relationship between expression of p73 and p53 mutation or expression of p21Waf1 or MDM2 was identified. Taken together, our data argue that p73 does not play a role as a tumor suppressor in bladder carcinogenesis and suggest that the activation of a silent allele may contribute to the progression of bladder tumors.

https://cancerres.aacrjournals.org/content/canres/59/12/2791.full.pdf

Elevated and Biallelic Expression of p73 Is Associated with Progression of Human Bladder Cancer

The urachus is a fibrous cord that arises from the anterior bladder wall and extends cranially to the umbilicus. Traditionally, infection has been treated using a two-stage procedure that includes an initial incision and drainage which is then followed by elective excision. More recently, it has been suggested that a single-stage excision with improved antibiotics is a safe option. Thus, we intended to compare the effects of the two-stage procedure and the single-stage excision. We performed a retrospective review on nine patients treated between May 1990 and September 2005. The methods used in diagnosis were ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and cystoscopy. The study group was comprised of three males and six females with a mean age of 28.2 years (with a range from three to 71 years). Symptoms consisted of abdominal pain, abdominal mass, fever, and dysuria. The primary incision and drainage followed by a urachal remnant excision with a bladder cuff excision (two-stage procedure) was performed in four patients. The mean postoperative hospitalization lasted 5.8 days (with a range of three to seven days), and there were no reported complications. A primary excision of the infected urachal cyst and bladder cuff (single-stage excision) was performed in the other five patients. These patients had a mean postoperative hospitalization time of 9.2 days (with a range of four to 15 days), and complications included an enterocutaneous fistula, which required additional operative treatment. The best method of treating an infected urachal cyst remains a matter of debate. However, based on our results, the two-stage procedure is associated with a shorter hospital stay and no complications. Thus, when infection is extensive and severe, we suggest that the two-stage procedure offers a more effective treatment option.

/pdf/treatment-of-infected-urachal-cysts-390hw62pk6.pdf

Treatment of Infected Urachal Cysts

Expression of the human erythrocyte glucose transporter in transitional cell carcinoma of the bladder.

The purpose of this study was to assess the effectiveness of transrectal ultrasonographically guided needle aspiration in the treatment of prostatic abscess. Fourteen patients with prostatic abscess were evaluated with this technique and treated with sonographically guided needle aspiration. Using this technique, all cases (100%) had one or more hypoechoic areas within the prostate that contained inhomogeneous materials; in 10 patients (71.0%), the lesion showed internal septa or solid portion. The margins of the hypoechoic area were well defined and thick in 11 patients (79.0%) and poorly defined in 3 patients (21.0%). The estimated volume of the prostatic abscess ranged between 2 and 28 ml (mean, 12.0 ml). The presence of a pus collection within the prostate was confirmed by transrectal ultrasonographically guided aspiration in all patients. However, successful treatment of prostatic abscess with transrectal needle aspiration was done in 12 (86.0%) of 14 patients; the treatment failed in 2 (14.0%) of 14 patients. One patient was treated with perineal incision and drainage and the other with transurethral resection. The amount of pus drained ranged between 1 and 39 ml (mean, 12.0 ml). On follow-up transrectal ultrasonographic examination, no remaining abscess pocket was found within the prostate in any of the cases. One year later, the prostatic abscess recurred in one case. In conclusion, transrectal ultrasonographic guidance is useful in the diagnosis of prostatic abscess as well as in the guidance for aspiration and the drainage of such abscesses. Transrectal ultrasonographically guided needle aspiration could be an effective method for treating prostatic abscess.

Sung-Goo Chang

Papers

Frequent epigenetic inactivation of RASSF1A in human bladder carcinoma.

Elevated and Biallelic Expression of p73 Is Associated with Progression of Human Bladder Cancer

Treatment of Infected Urachal Cysts

Expression of the human erythrocyte glucose transporter in transitional cell carcinoma of the bladder.

Treatment of prostatic abscess: value of transrectal ultrasonographically guided needle aspiration.