Evaluation of optimum classification measures used to define textbook outcome among patients undergoing curative-intent resection of gastric cancer.

BACKGROUND: Textbook outcome (TO) is a composite measure reflecting various aspects of services provided to patients with solid malignancies. We sought to evaluate the importance of various TO components previously proposed for gastric cancer. METHODS: Prospectively maintained electronic databases of 1,743 patients treated in two academic surgical centres were reviewed. Six candidate definitions of TO were evaluated based on their ability to accurately predict patients' prognosis by Cox proportional hazards modelling. RESULTS: TO definition combining 10 measures corresponding to complete tumour resection with an uneventful postoperative course showed the best goodness of fit by achieving the lowest values of Akaike (AIC) and Bayesian (BIC) information criteria and the best predictive performance based on the highest value of c-index. The overall median survival was significantly longer for patients with than without textbook outcome (69.0 vs 20.1 months, P < 0.001). TO maintained its prognostic value in a multivariate model controlling for age, sex, comorbidities, treatment, and tumour related variables and was associated with a 39% lower risk of death (HR 0.61, 95%CI 0.51 - 0.73, P < 0.001). Nine variables identified as predictors of TO were used to develop a nomogram showing very good correlation between the predicted and actual probability of achieving TO. The AUC of ROC obtained from the nomogram was 0.752 (95% CI 0.727 to 0.781). CONCLUSIONS: A uniform definition of textbook outcome provides clinically relevant prognostic information and could be used in quality improvement programs for gastric cancer patients.

Nomogram-Based Prognostic Evaluation of Gastric Cancer Patients with Low Counts of Examined Lymph Nodes Outperforms the Predictive Ability of the 7th and 8th Editions of the American Joint Committee on Cancer Staging System.

BACKGROUND: The American Joint Committee on Cancer (AJCC) staging system has limited accuracy in predicting survival of gastric cancer patients with inadequate counts of evaluated lymph nodes (LNs). We therefore aimed to develop a prognostic nomogram suitable for clinical applications in such cases. METHODS: A total of 1511 noncardia gastric cancer patients treated between 1990 and 2010 in the academic surgical center were reviewed to compare the 7th and 8th editions of the AJCC staging system. A nomogram was developed for the prediction of 5-year survival in patients with less than 16 LNs evaluated (n = 546). External validation was performed using datasets derived from the Polish Gastric Cancer Study Group (n = 668) and the SEER database (n = 11,225). RESULTS: The 8th edition of AJCC staging showed better overall discriminatory power compared to the previous version, but no improvement was found for patients with < 16 evaluated LNs. The developed nomogram had better concordance index (0.695) than the former (0.682) or latest (0.680) staging editions, including patients subject to neoadjuvant treatment, and calibration curves showed excellent agreement between the nomogram-predicted and actual survival. High discriminatory power was also demonstrated for both validation cohorts. Subsequently, the nomogram showed the best accuracy for the prediction of 5-year survival through the time-dependent ROC curve analysis in the training and validation cohorts. CONCLUSIONS: A clinically relevant nomogram was built for the prediction of 5-year survival in patients with inadequate numbers of LNs evaluated in surgical specimens. The predictive accuracy of the nomogram was validated in two Western populations.

Impact of anastomotic leakage on long-term survival after total gastrectomy for carcinoma of the stomach.

BACKGROUND: Recent studies suggest that anastomotic leak may adversely affect long-term survival in patients undergoing surgery for gastrointestinal malignancies. Data relating to total gastrectomy for gastric cancer are scarce. METHODS: An electronic database of all patients with resectable gastric cancer treated between January 1999 and December 2004 at seven university surgical centres cooperating in the Polish Gastric Cancer Study Group was reviewed. RESULTS: Anastomotic leakage was diagnosed in 41 (5.9 per cent) of 690 patients who underwent total gastrectomy. The prevalence of surgical and general complications, and mortality rates were significantly higher in patients diagnosed with anastomotic leakage. The only two independent risk factors for leakage were Eastern Cooperative Oncology Group performance status of 2 or 3 (odds ratio 5.09, 95 per cent confidence interval (c.i.) 2.29 to 11.32) and splenectomy (odds ratio 2.58, 95 per cent c.i. 1.08 to 6.13). Two Cox proportional hazards models including all the patients and excluding in-hospital deaths identified anastomotic leakage as an independent predictor of survival with hazard ratios of 3.47 (95 per cent c.i. 1.82 to 6.64) and 3.14 (1.51-6.53) respectively. CONCLUSION: The occurrence of anastomotic leakage was a major independent prognostic factor for long-term survival.

Adjuvant chemotherapy with etoposide, adriamycin and cisplatin compared with surgery alone in the treatment of gastric cancer: a phase III randomized, multicenter, clinical trial.

OBJECTIVE: The aim of this study was to evaluate the efficacy of adjuvant chemotherapy with etoposide, Adriamycin and cisplatin (EAP) after potentially curative resections for gastric cancer. METHODS: After surgery, patients were randomly assigned to the EAP or control arm. Chemotherapy included 3 courses, administered every 28 days. Each cycle consisted of doxorubicin (20 mg/m(2)) on days 1 and 7, cisplatin (40 mg/m(2)) on days 2 and 8, and etoposide (120 mg/m(2)) on days 4, 5, and 6. RESULTS: Of 309 eligible patients, 141 were allocated to chemotherapy and 154 to the supportive care group. Four (2.8%) treatment-related deaths were recorded, including 3 due to septic complications of myelosuppression and 1 due to cardiocirculatory failure. Grade 3 or 4 toxicities were found in 17 (22%) patients. According to the intention-to-treat analysis, the median survival was 41.3 months (95% confidence interval, 24.5-58.2) and 35.9 months (95% confidence interval, 25.5-46.3) in the chemotherapy and control group, respectively (p = 0.398). Subgroup analysis revealed survival benefit from chemotherapy in patients with tumors infiltrating the serosa and in those with 7-15 metastatic lymph nodes. CONCLUSION: Three cycles of EAP regimen postoperatively offer no survival advantage in gastric cancer patients.

Ratio of metastatic to resected lymph nodes for prediction of survival in patients with inadequately staged gastric cancer.

BACKGROUND: Staging is inadequate in up to 70 per cent of patients with gastric cancer in Western countries owing to the small number of lymph nodes dissected during surgery. The aim was to determine whether using the ratio of metastatic to resected lymph nodes (LNR) might improve accuracy. METHODS: Data were analysed from patients with gastric cancer who had gastrectomy in several centres between 1986 and 1998, with dissection of 15 or fewer lymph nodes. LNRs and other prognostic factors were evaluated. RESULTS: From a total of 738 patients, the median number of resected nodes was 8 (range 1-15) and median LNR was 42.8 per cent. The number of metastatic nodes significantly affected survival only in univariable analysis. In a Cox proportional hazards model, patient age, depth of tumour infiltration, tumour location, and LNR were identified as independent prognostic factors. Compared with node-negative patients, the hazard ratio for an LNR of 0.1-40.0 per cent was 1.85 (P < 0.001), increasing to 2.93 (P < 0.001) when the LNR exceeded 40.0 per cent. CONCLUSION: The LNR cannot be used as a substitute for staging with adequate lymphadenectomy. It may help to stratify patients in terms of prognosis when the number of resected lymph nodes is limited.

Intraoperative ultrasonography in detecting and assessment of colorectal liver metastases.

OBJECTIVE: to assess the clinical value of intraoperative ultrasonography (IOUS) in detecting and assessment of liver metastatic tumours in colorectal cancer patients. METHODS: a study is a retrospective analysis of 388 patients operated on for colorectal carcinoma between 1997 and 2004. In all the patients intraoperative ultrasound was performed. The authors analyzed of sensitivity, specificity, PPV, NPV and accuracy of pre- and intraoperative ultrasonography in detecting and staging of colorectal metastatic lesions. RESULTS: Intraoperative ultrasonography showed the highest sensitivity, specificity and accuracy in both, tumor detection (99.1, 98.5 and 98.9%, respectively) and assessment (95.4, 99.5 and 99.1%, respectively). Overall sensitivity of IOUS was significantly better in detection and staging compared with preoperative ultrasonography 91.1 and 72.2%, respectively). CONCLUSIONS: IOUS should be used as routine diagnostic modality in colorectal cancer patients with hepatic metastases or suspected metastases. Transabdominal ultrasonography cannot be used as the only diagnostic tool in the evaluation of liver lesions, but may be helpful in preoperative screening.

Differences in prognosis of Siewert II and III oesophagogastric junction cancers are determined by the baseline tumour staging but not its anatomical location.

BACKGROUND: The anatomical Siewert classification for adenocarcinoma of the oesophagogastric junction (OGJ) was dictated by the potential differences in tumour epidemiology and pathology. However, there are some uncertainties whether the distinction of true carcinoma of the cardia (type II) and subcardial gastric cancer (type III) is of clinical value. METHODS: Using a multicentre data set, we studied 243 patients with OGJ adenocarcinomas who underwent gastric resections between 1998 and 2008. Postoperative complications and long-term survival were compared to evaluate the potential differences in clinically relevant outcomes. RESULTS: A group of 109 patients with Siewert type II and 134 with Siewert type III OGJ adenocarcinoma was identified. Both groups showed similar baseline characteristics, including clinical symptoms and duration of diagnostic delay. However, the prevalence of node-negative cancers and superficial (T1-T2) lesions was significantly higher among type II tumours, i.e. 42% vs 21% (P = 0.003) and 43% vs 20% (P = 0.045), respectively. Morbidity and mortality rates were 25% and 3.7%, respectively, but types and incidence of postoperative complications were not affected by the anatomical location of the tumour. The overall median survival was significantly longer for Siewert type II tumours (42 vs 16 months; P < 0.001). However, only patients' age >70 years, depth of tumour infiltration, lymph node metastases, distant metastases, and radical resection were identified as independent prognostic factors using the Cox proportional hazards model. CONCLUSION: The topographic-anatomic sub-classification of OGJ adenocarcinomas does not correspond to relevant differences in clinical parameters of safety and efficacy of surgical treatment.

Description and analysis of clinical pathways for oesophago-gastric adenocarcinoma, in 10 European countries (the EURECCA upper gastro intestinal group - European Registration of Cancer Care).

AIMS: Outcomes for patients with oesophago-gastric cancer are variable across Europe. The reasons for this variability are not clear. The aim of this study was to describe and analyse clinical pathways to understand differences in service provision for oesophageal and gastric cancer in the countries participating in the EURECCA Upper GI group. METHODS: A questionnaire was devised to assess clinical presentation, diagnosis, staging, treatment, pathology, follow-up and service frameworks across Europe for patients with oesophageal and gastric cancer. The questionnaire was issued to experts from 14 countries. The responses were analysed quantitatively and qualitatively and compared. RESULTS: The response rate was (10/14) 71.4%. The approach to diagnosis was similar. Most countries established a diagnosis within 3 weeks of presentation. However, there were different approaches to staging with variable use of endoscopic ultrasound reflecting availability. There has been centralisation of treatments in most countries for oesophageal surgery. The most consistent area was the approach to pathology. There were variations in access to specialist nurse and dietitian support. Although most countries have multidisciplinary teams, their composition and frequency of meetings varied. The two main areas of significant difference were research and audit and overall service provision. Observations on service framework indicated that limited resources restricted many of the services. CONCLUSION: The principle approaches to diagnosis, treatment and pathology were similar. Factors affecting the quality of patient experience were variable. This may reflect availability of resources. Standard pathways of care may enhance both the quality of treatment and patient experience.

Circular dichroism study of the interaction of mitoxantrone, ametantrone and their Pd(II) complexes with deoxyribonucleic acid.

The interaction of mitoxantrone, ametantrone and their Pd(II) complexes with DNA have been studied using absorption and circular dichroism spectroscopy. We have shown that mitoxantrone forms with Pd(II) a complex in which two Pd(II) ions are bound to two molecules of drug (D1 and D2). One Pd(II) ion is bound to the two nitrogens of the side chain on C-5 of molecule D1 and to the two nitrogens of the side chain on C-5 of molecule D2, whereas the second Pd(II) ion is bound to the nitrogens of the side chain on C-8 of molecule D1 and of molecule D2. The same complex is formed between Pd(II) and ametantrone. The stability constants for these complexes are, respectively, beta M = (1.4 +/- 0.5).10(19) and beta A = (2.5 +/- 0.5).10(18). They display antitumor activity against P 388 leukemia which compares with that of the free drugs. Interactions of the free drugs with DNA have been studied. Mitoxantrone and ametantrone are not optically active by themselves. However, through interaction with DNA, there is an induction of optical activity within the electronic transitions of both drugs. At a nucleotide/drug molar ratio lower than about 5 a CD signal of the couplet type is observed, suggesting that there is a coupling between the pi----pi transitions of the molecules of drugs intercalated between the base pairs. This coupling disappears when the molar ratio is increased. The interactions of the Pd(II) complexes with DNA do not give rise to induction of optical activity within the electronic transition of the drugs, indicating that the presence of the metal ion prevents the intercalation of the drugs between the base pairs.

The value of imaging techniques in the staging of pancreatic cancer.

BACKGROUND: The aim of this study was to assess the clinical value of endoscopic ultrasound (EUS) in the staging of pancreatic carcinoma and to compare it to ultrasonography (US) and CT. METHODS: We evaluated 45 patients (21 women and 24 men with a mean age of 62.1 years) who had undergone surgical treatment for pancreatic cancer between 1994 and 2004. Out analysis focused on the overall accuracy, sensitivity, and specificity of routine and Doppler US, CT, and EUS. RESULTS: Endoscopic ultrasound was the most accurate modality for local tumor staging (93.1%), vascular infiltration (90%), and lymph node assessment (87.5%). Routine US was the least accurate (82.5%, 67.5%, and 72.5%, respectively). The accuracy rates for CT and Doppler US were similar (88.1%, 82.5% and 80.0%, respectively). CONCLUSIONS: Endoscopic ultrasound is the most accurate method available to stage pancreatic cancer in the preoperative period. However, the advantage of EUS over CT and US does not justify its routine use due to its high cost, low availability, and invasiveness.

Outcome of gastric cancer surgery in elderly patients.

BACKGROUND/AIMS: The aim of the study was to review cases of gastric cancers in elderly adults (70 years of age and older), and compare demographic, clinical, pathologic features and outcomes of surgical treatment with younger patients (below 70 years of age). METHODOLOGY: The analysis included 3431 patients treated for gastric cancer between 1977 and 1998 at eight university surgical centers cooperating for the Polish Gastric Cancer Study Group (PGCSG). Patients were analyzed retrospectively according to data obtained from standardized forms and divided into two groups: group I--patients 70 years of age and over, group II--younger patients. RESULTS: There were no significant differences between these two groups in clinical symptoms at the time of diagnosis and tumor advancement. The incidence of the intestinal type according to Lauren (55.9% vs. 43.9%;p<0.05) and distally-located cancers (40.8% vs. 31.3%; p<0.05) was higher in group I. Total gastrectomies and extended lymph node dissection were performed more often in younger patients. There were no significant differences in postoperative complications between both groups, except the higher incidence of abdominal abscesses in the younger group. The overall 5-year survival was 24% and 35% for group I and II, respectively (p<0.05), and increased to 35% and 53% after radical resections, respectively. However, there were no statistically significant differences in stage-specific survival between both groups. CONCLUSIONS: Surgical resection is the method of choice in the treatment of gastric cancer. Age of the patients is not a contraindication to surgical treatment of gastric cancer.

The clinical value of parenteral immunonutrition in surgical patients.

BACKGROUND & AIM: To analyze the clinical impact and cost-effectiveness of parenteral immunonutrition (PN). METHODS: Prospective clinical trial of a group of 105 patients operated on for gastric carcinoma between 2001-2003. During the postoperative period, patients were randomly allocated to one of three groups: standard PN (A), PN + glutamine (B) and PN + omega-3-FA (C). The rate and type of complications, hepatic and renal function, cost and treatment tolerance in all groups were analyzed. RESULTS: Postoperative complications were observed in 11 patients (36.6%) in group A, in 7 (23.3%) in B and in 8 (26.6%) in C. The most common complication was pneumonia. Prealbumin concentration and TLC increased faster in groups B and C. The length of hospital stay was significantly shorter in the immunonutrition groups. The cost of PN was highest in C group, while cost of hospital stay was longer in A. CONCLUSIONS: Immunostimulating parenteral nutrition helps to reduce the number of infectious complications, improves the function of the immune system, and has no influence on surgical complications, hepatic and renal function and protein synthesis. The cost of immunostimulating treatment based on omega-3-unsaturated fatty acids is higher than standard.

Enzymatic oxidative activation and transformation of the antitumor agent mitoxantrone.

Ambient temperature incubation of the anticancer agent mitoxantrone with horseradish peroxidase and hydrogen peroxide converts it into a hexahydronaphtho[2,3-f]quinoxaline-7,12-dione in which one side chain has cyclized to the chromophore. The structure of this cyclic metabolite was secured by independent synthesis. This peroxidative conversion of mitoxantrone, the progress of which can be followed spectrophotometrically, is accompanied by formation of a free radical species. The EPR characteristics, and dependence on pH of the latter, suggest it exists as a radical cation. The enzymatic oxidation of mitoxantrone is totally irreversible. The purified cyclic metabolite is a substrate for the peroxidase affording the unstable fully oxidized diimino compound and this reaction is fully reversible upon addition of ascorbate or other biological reductants. Admixture of the fully oxidized diimino product with the reduced cyclic metabolite generates the corresponding radical cation species by disproportionation-comproportionation processes. Independent kinetic studies confirm that reaction of the peroxidase with the cyclic metabolite proceeds more rapidly than with mitoxantrone itself. A derivative of mitoxantrone, in which the side-chain secondary amine functions are acylated, generates a radical cation upon treatment with the peroxidase-H2O2 system but does not cyclize subsequently. Derivatives without phenolic hydroxyls or those in which the phenolic hydroxyls are blocked also undergo peroxidative reaction. These observations suggest that initial peroxidative attack occurs at the aromatic nitrogens of mitoxantrone. The possible relevance of these results to the anticancer action of mitoxantrone and the implications for suppression of lipid peroxidation in vivo are discussed.

Photosensitization by antitumor agents. 5. Daunorubicin-photosensitized oxidation of NAD(P)H in aqueous and N,N-dimethylformamide/aqueous solutions--an electron paramagnetic resonance study.

An EPR spectrum of the semiquinone radical of daunorubicin (D) was recorded upon illumination (480 nm) of the drug and NAD(P)H in deaerated aqueous and DMF/aqueous solutions. In the latter solvent system, an EPR spectrum with hyperfine structure was recorded. The kinetics of the photoinduced generation and decrease of the EPR signal intensity in the dark were measured. Second order rate constants for the radical recombination were derived for the two solvent systems. Photosensitized production of the superoxide radical, upon illumination of daunorubicin and NAD(P)H, in aerated aqueous or DMF/aqueous solutions, is evidenced by employing a spin trap DMPO (5,5-dimethyl-1-pyrroline-N-oxide) and an SOD assay. 5-Iminodaunorubicin (5-ID), in contrast to the parent compound (D), does not possess photosensitizing properties.

Inflammatory fibroid polyp of the stomach. A special reference to an immunohistochemical profile of 42 cases.

Forty two cases (46 lesions) of inflammatory fibroid polyp (IFP) of the stomach were reviewed histologically and studied immunohistochemically. The paraffin sections were stained with a panel of antibodies against alpha-smooth-muscle actin, HHF-35, desmin, vimentin, lysozyme, alpha-1-antitrypsin, alpha-1-antichymotrypsin, KP1, Mac 387, S-100 protein, neuron-specific enolase, factor VIII RAg, and with Ulex europaeus agglutinin I. The lesions ranged in size from 0.3 to 3.5 cm with a mean of 1.2 cm. Forty (87.0%) IFPs occurred in the antrum, five in the gastric body, and one in the cardia. In all but two lesions, the mucosal layer was involved, and 20 (43.5%) lesions were entirely restricted to the mucosa. All 46 IFPs tested diffusely positive with vimentin. Positive reactions for alpha-smooth-muscle actin and HHF-35 were observed in 12 (26.1%) and 10 (21.7%) IFPs, respectively. Two lesions with alpha-smooth-muscle actin and one lesion with HHF-35 showed a diffuse staining. Seventeen (37.0%) lesions were focally positive for KP1, and seven (15.2%) IFPs were focally positive for Mac 387. All other antibodies and agglutinin were negative with the proliferating cells. The results of this study confirmed (a) the presence of myofibroblastic and histiocytic lines of differentiation in addition to the main fibroblastic features for the main cellular component in IFP, and (b) the heterogeneity of the immunoprofile of IFP.

Enzymatic studies of the effect of Cu (II) on oxygen radical production stimulated by daunorubicin and ametantrone.

Daunorubicin can bind Cu (II) in Tris-HCl buffer (pH 7.4) and in the presence of NADH (100 microM). The complex is very stable. Cu (II) is not removed from the complex by cytochrome c reductase. The complexation of Cu (II) to daunorubicin gives rise to a modification of its redox properties. The complex, unlike the free drug, does not stimulate oxygen radical production. Ametantrone can also form a complex with Cu (II) in the conditions of enzymatic assays. Nevertheless, this complex is not stable in the presence of cytochrome c reductase. It dissociates immediately after the addition of the enzyme with releasing the metal ion.

Enzymatic oxidative activation of 5-iminodaunorubicin. Spectrophotometric and electron paramagnetic resonance studies.

Horseradish peroxidase catalyzed oxidation of the antitumor agent 5-iminodaunorubicin by hydrogen peroxide was studied with both spectrophotometric and electron paramagnetic resonance methods. Kinetics of oxidation of the drug at pH 3, 6 and 8 were determined. Rapid formation of a nitrogen-centered free radical metabolite was demonstrated with electron paramagnetic resonance employing the 15N-labeled drug and by deuterium exchange techniques. This enzymatic oxidative activation of 5-iminodaunorubicin suggests an alternative mode of metabolism and mechanism of action of this less cardiotoxic anticancer agent. By contrast, the parent compound, daunorubicin, did not undergo oxidation by the horseradish peroxidase-hydrogen peroxide system.

Interaction of the peroxidase-derived metabolite of mitoxantrone with nucleic acids. Evidence for covalent binding of 14C-labeled drug.

The antitumor agent mitoxantrone undergoes horseradish peroxidase-catalyzed oxidation by hydrogen peroxide to an identifiable cyclic metabolite which is a substituted hexahydronaphtho[2,3-f]-quinoxaline-7,12-dione. Binding of mitoxantrone to DNA inhibited enzymatic oxidation of the drug. The metabolite of mitoxantrone, derived from the action of the HRP/H2O2 system on the drug, bound non-covalently to DNA oligomers. Spectrophotometric analyses of such complexes showed formation of a new, blue-shifted, metachromatic absorption band which was observed when the DNA base pair to drug ratio was close to 1. Measurements of DNA unwinding angles suggest that the metabolite, in contrast to mitoxantrone, did not intercalate but rather bound externally to DNA. Experiments with 14C-labeled mitoxantrone confirmed that peroxidase-activated drug binds covalently to DNA.

The relationship between gastric cancer cells circulating in the blood and microsatellite instability positive gastric carcinomas.

BACKGROUND: Cancers characterized by microsatellite instability may be biologically different from their counterparts with stable microsatellite sequences. Circulating cancers cell present in blood prior to surgery may constitute an adverse prognostic finding. AIM: To correlate these two phenomena with morphological features and survival in advanced gastric cancer. METHODS: We examined 76 cases of resected sporadic, advanced gastric cancer by means of routine morphology and a panel of microsatellite markers. Sixty-six cases were screened for presence of cancer cells circulating in blood prior to the surgery using combined morphological and immunocytochemical approach. RESULTS: Twenty-one (27.6%) cases demonstrated microsatellite instability in at least one locus. Among them 11 (14.5%) showed microsatellite instability in more than 30% (4/12) examined loci, and they were therefore designated as replication error positive (RER+). Circulating cancer cells were detected in 2/19 microsatellite instability and in 11/47 remaining cases (difference not significant). The survival of the microsatellite instability cases was significantly better. The presence of circulating cancer cells did not correlate with survival. CONCLUSION: It is possible that the microsatellite instability status, but not circulating cancer cells, constitutes a prognostic predictive factor in advanced gastric carcinoma. Confirmation of this hypothesis requires continuation of patient follow-up.

The structure of amphotericin A. I. Mass spectrometric analysis of dodecahydroamphotericin A.

Amphotericin A had been transformed into dodecahydroamphotericin A by hydrogenation. Subsequently, the product obtained was reduced with metal borohydrides or borodeuterides and derivatized to volatile compounds which were analyzed by mass spectrometry.