Long-course preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study.

BACKGROUND: This trial evaluated whether preoperative short-course radiotherapy and consolidation chemotherapy (CCT) were superior to chemoradiation in rectal cancers with clinical (c)T4 or fixed cT3. Previously, we reported early results showing no differences in the radical surgery rate (primary end point). In the short-course/CCT group, we observed lower acute toxicity of preoperative treatment and better overall survival (OS). We updated results to determine whether the benefit in OS was sustained and to evaluate late complications. PATIENTS AND METHODS: Patients with cT4 or fixed cT3 rectal cancer were randomized either to preoperative 5 × 5 Gy and three cycles of FOLFOX4 or to chemoradiation (50.4 Gy with bolus 5-Fu, leucovorin and oxaliplatin). RESULTS: Patients (N = 515) were eligible for analysis, 261 in the short-course/CCT group and 254 in the chemoradiation group. The median follow-up was 7.0 years. The difference in OS was insignificant [hazard ratio (HR) 0.90; 95% confidence interval (CI) 0.70-1.15; P = 0.38). However, the difference in early OS favouring short-course/CCT previously reported was observed again, being 9% at 3 years (95% CI 0.5% to 17%). This difference disappeared later; at 8 years OS was 49% in both groups. There was no difference in disease-free survival (HR 0.95; 95% CI 0.75-1.19; P = 0.65) at 8 years 43% versus 41% in the short-course/CCT group versus the chemoradiation group, respectively. The corresponding values for cumulative incidences of local failure and distant metastases did not differ and were HR = 1.08, 95% CI 0.70-1.23, P = 0.60, 35% versus 32% and HR = 1.10, 95% CI 0.68-1.23, P = 0.54, 36% versus 34%, respectively. The rate of late complications was similar (P = 0.66), grade 3+ being 11% versus 9% in the short-course/CCT group versus the chemoradiation group, respectively. CONCLUSION: The superiority of preoperative short-course/CCT over chemoradiation was not demonstrated. CLINICAL TRIAL NUMBER: The trial is registered as ClinicalTrials.gov number NCT00833131.

Serum selenium levels predict survival after breast cancer.

BACKGROUND: Studies have reported an inverse relationship between serum selenium levels and cancer incidence, but the impact of low serum selenium status on survival after a diagnosis of breast cancer has not been established. METHODS: We obtained a blood sample from 546 women diagnosed with a first primary invasive breast cancer between 2008 and 2015 in the region of Szczecin, Poland. Blood was collected after diagnosis, but prior to treatment. Serum selenium was quantified by mass spectroscopy and each patient was assigned to one of four categories (quartiles) based on the distribution in the entire cohort. Patients were followed from diagnosis to death over a mean follow-up of 3.8 years. Vital status was obtained by linkage to the Polish National Death Registry. RESULTS: The 5-year overall actuarial survival was 68.1% for women in the lowest (< 64.4 µg/L) and 82.5% for those in the highest (> 81.0 µg/L) quartile of serum selenium. In an adjusted analysis, the hazard ratio for death was 2.49 (95%CI 1.53-4.04; P = 0.0002) for patients in the lowest quartile of serum selenium, compared to those in all other quartiles. The effect of low selenium on breast cancer-specific mortality was stronger for women who were past smokers (HR 6.03; 95%CI 1.96-18.6; P = 0.0002). CONCLUSIONS: This study suggests that a selenium level in excess of 64.4 µg//L might be beneficial for women undergoing treatment for breast cancer and that selenium supplementation to achieve this level may favorably impact the outcome. Further studies are needed to confirm this association and to evaluate the impact of selenium supplementation on breast cancer survival among women with low post-diagnostic selenium levels.

Vitamin D receptor variants and breast cancer risk in the Polish population.

The aim of the study was to determine whether four VDR gene single nucleotide polymorphisms (SNPs: rs1544410, rs731236, rs10735810 and rs4516035) are associated with breast cancer risk in Polish population. Two independent series of female patients were employed: 960 consecutive breast cancer cases, and 800 unselected early onset cases diagnosed under the age of 51. The control group for the consecutive breast cancer cases consisted of 960 healthy, age-matched women with a negative cancer family history. 550 healthy women, aged 51 or less, with negative cancer family history were selected as the independent controls for the early onset breast cancer cases. The frequencies of the VDR polymorphisms in the unselected cases when compared to the respective control population failed to reveal any association between the individual SNPs and disease. Examination of the group of early-onset patients, revealed an association between rs10735810 and increased breast cancer risk. Heterozygous carriers for the change had an OR = 1.73 (95% CI 1.33-2.26, P < 0.0001) and homozygous carriers OR = 2.34 (95% CI 1.71-3.21, P < 0.0001). The remaining three examined SNPs failed to show any association with disease risk. In summary, this study has identified an association between the VDR gene and early onset breast cancer risk in the Polish population.

Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients.

BACKGROUND: Ten patients with breast cancer and a breast cancer susceptibility gene 1 (BRCA1) mutation, who presented with stages I to III breast cancer between December 2006 and 2007, were treated with four cycles of neoadjuvant cisplatin, followed by mastectomy and conventional chemotherapy. METHODS: The excised breast tissue and lymph nodes were examined for the presence of residual disease. RESULTS: Pathologic complete response was observed in nine patients (90%). CONCLUSIONS: Platinum-based chemotherapy appears to be effective in a high proportion of patients with BRCA1-associated breast cancers. Clinical trials are now warranted to determine the optimum treatment for this subgroup of breast cancer patients.

Common variants of DNA repair genes and malignant melanoma.

In the current study, we evaluated the possible associations of seven common variants of the DNA repair and cell cycle control genes BRCA2 and CHEK2 with malignant melanoma (MM). We genotyped 630 unselected MM patients and over 3700 controls (newborns, age- and sex-matched healthy adults with negative cancer family histories, and the adults selected at random by family doctors) for the prevalence of three common variants of the BRCA2 (T1915M, N991D and N372H) and four common variants of the CHEK2 (1100delC, VS2+1G --> A, I157T and del5395). Our study strongly suggests that the common variant of the BRCA2 gene -- the N991D variant is associated with malignant melanoma risk (OR=1.8, p=0.002 after Bonferroni correction). Patients homozygote for the N991D variant were present in 0.32% of cases and only 0.13% of controls. The other variants studied were not over-represented among MM patients when compared to the general population. In conclusion, we report an increased melanoma risk among carriers of the N991D change of the BRCA2 and no association of the CHEK2 changes with malignant melanoma.

Cryptosporidiosis in patients with colorectal cancer.

Parasitological examination of feces was carried out for 55 patients with diagnosed colorectal cancer before chemotherapy. Except for Cryptosporidium sp., no other intestinal parasites were found in the specimens; moreover, only the patients with watery diarrhea were Cryptosporidium sp.-positive by enzyme immunoassay. Prevalence of infection in the group of patients with diarrhea (23 persons) was 43.5%, whereas it was 18% for the entire group of patients under study. Coproantigens of this parasite were detected primarily in the patients with tumors located on the left side (in the sigmoid and descending colon).

Optimization of experimental conditions for RNA-based sequencing of MLH1 and MSH2 genes.

The most sensitive technique for the detection of germline mutations is exon by exon sequencing of the gene under investigation using genomic DNA as a template for analysis. This approach, however, has cost and sensitivity limitations that can, at least in part, be overcome by RNA-based analysis. Germline mutations of MLH1 and MSH2 are the most frequent cause of the inherited susceptibility to colorectal and other epithelial cancers known as hereditary non-polyposis colorectal cancer (HNPCC). We compared the analysis of the MLH1 and MSH2 genes using mRNA and genomic DNA as starting material from 21 HNPCC patients. All samples were investigated by RT-PCR, sequencing of cDNA and simultaneous sequencing of genomic DNA. The cDNA was generated using specific primers complementary to the ends of MLH1 and MSH2 genes, respectively. Mutations in MLH1 and MSH2 were detected in 11 out of 21 unrelated patients. In 10 out of 11 cases, mutations were detected independently of the type of primers used for reverse transcription (RT). One novel missense mutation (K751R) in MLH1 was detected using this method. One nonsense mutation (E205X) in MSH2 was only detectable when RT was performed using MSH2 gene-specific primers. Shorter PCR products indicative of alternatively spliced transcripts were not observed when MLH1 or MSH2 specific cDNA RT primers were employed to generate template, except in one case where exon skipping was observed for exons 9 and 10. In this report we demonstrate that primers specific for RT of MLH1 and MSH2 are crucial for increasing the sensitivity of cDNA analysis. DNA sequencing using RNA as a basis for template construction may be a valuable and economical alternative to genomic DNA sequencing.

Value of pedigree/clinical data, immunohistochemistry and microsatellite instability analyses in reducing the cost of determining hMLH1 and hMSH2 gene mutations in patients with colorectal cancer.

The aim of this study was to evaluate the significance of pedigree/clinical data, immunohistochemistry (IHC) and microsatellite instability (MI) analyses in the reduction of costs of constitutional hMLH1 and hMSH2 gene mutation diagnosis in patients with colorectal cancers (CRC). Pedigree/clinical data were evaluated on a series of 168 patients with CRC, including 43 consecutive sporadic late-onset and 25 consecutive, definitive or suspected hereditary non-polyposis colorectal cancer (HNPCC) cases, examined by IHC and MI analyses. In the latter group, 6/25 (24%) constitutional mutations were found. We detected no germline mutations in the sporadic late-onset patients. The lowest costs (880 Euro/mutation detected) were achieved by performing pedigree/clinical data (for exclusion of late-onset sporadic CRC) in conjuction with IHC only. In this model 1/6 (17%) mutations was missed. Additional preselection by IHC and MI analyses before sequencing was required to detect all mutations. In this approach, which seems to be the most effective in the search for hMLH1 and hMSH2 gene mutation, the cost was 1767 euro/mutation detected.

Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy.

BACKGROUND AND PURPOSE: The aim was to verify whether preoperative conventionally fractionated chemoradiation offers an advantage in sphincter preservation in comparison with preoperative short-term irradiation. PATIENTS AND METHODS: Patients with resectable T3-4 rectal carcinoma without sphincters' infiltration and with a lesion accessible to digital rectal examination were randomised into: preoperative 5x5Gy short-term irradiation with subsequent total mesorectal excision (TME) performed within 7 days or chemoradiation to a total dose of 50.4Gy (1.8Gy per fraction) concomitantly with two courses of bolus 5-fluorouracil and leucovorin followed by TME after 4-6 weeks. Surgeons were obliged to base the type of operation on the tumour status at the time of surgery. RESULTS: Between 1999 and 2002, 316 patients from 19 institutions were enrolled. The sphincter preservation rate was 61% in the 5x5Gy arm and 58% in the radiochemotherapy arm, P = 0.57. The tumour was on average 1.9 cm smaller (P < 0.001) among patients treated with chemoradiation compared with short-term schedule. For patients who underwent sphincter-preserving procedure, the surgeons generally followed the rule of tailoring the resection according to tumour downsizing; the median distal bowel margin was identical (2 cm) for both randomised groups. However, in the chemoradiation group, five patients underwent abdominoperineal resection despite clinical complete response. CONCLUSIONS: Despite significant downsizing, chemoradiation did not result in increased sphincter preservation rate in comparison with short-term preoperative radiotherapy. The surgeons' decisions were subjective and based on pre-treatment tumour volume at least in clinical complete responders.

Comparison of Alu-PCR, microsatelite instability, and immunohistochemical analyses in finding features characteristic for hereditary nonpolyposis colorectal cancer.

PURPOSE: To evaluate and compare alterations detected by Alu-PCR, microsatellite instability (MI), and absence of hMLH1 and hMSH2 protein expression measured by immunohistochemical (IHC) analyses as features characteristic of hereditary nonpolyposis colorectal cancer (HNPCC). METHODS: Alu-PCR, MI, and IHC analyses were performed in two groups of patients: (A) HNPCC diagnosed definitively or with high probability (11 patients); (B) sporadic late-onset colorectal cancers (15 patients). RESULTS: Quantitative alterations recorded by Alu-PCR were not characteristic for Lynch syndrome, occurring more frequently in sporadic late-onset CRC (73% in group B vs 45% in group A). Qualitative changes (occurrence of additional peaks or shifts) have been found to be associated with HNPCC with odds ratio (OR) 2.4, specificity approximately 70% and sensitivity approximately 55%. Findings in MI and IHC analyses have been recognized as features more characteristic of HNPCC suggesting Lynch syndrome with OR 4.8, specificity approximately 80%, sensitivity approximately 55% (MI) and OR 8.0, specificity approximately 93%, sensitivity approximately 36% (IHC). CONCLUSION: Molecular techniques allowing identification of patients with a high probability of having HNPCC include IHC and MI analyses. Our results suggest that their replacement by Alu-PCR analysis in diagnosis of HNPCC is not justified.

Increased risk of breast cancer in relatives of malignant melanoma patients from families with strong cancer familial aggregation.

The aim of this study was to evaluate the risk of occurrence of malignancies of different site of origin in patients with malignant melanoma (MM) of the skin and their first-degree relatives from families with cancer familial aggregations with unknown pathogenetic background (CFA). We analysed tumour spectrum and age at diagnosis of malignancies in 51 families with MM/CFA. In addition, we evaluated observed frequency (OF); expected frequency (EF); and relative risk (RR) of occurrence of malignancies in these families. In all cases peripheral blood examination of common Polish founder BRCA1 mutations was performed. In 25 families, we analysed loss of heterozygosity of BRCA1 and BRCA2 genes. We identified two subgroups of cases: 22 MM/CFA families with MM diagnosed before 55 years (< or =55 MM/CFA) and 29 MM/CFA families with MM diagnosed after 55 (>55 MM/CFA). In these families we observed increased proportion of breast cancers: 17.52% in the first subgroup (mean age of diagnosis 48.5) and 12.15% in the second subgroup. The odds ratio for breast tumours occurring before 50 in < or =55 MM/CFA families was 3.71. We also observed increased numbers of liver cancers, CSU and leukaemias. OF and EF analyses revealed increased risk of occurrence of cancers of breast (OF 10.4%, EF 4.5%) and liver (OF 1.9%, EF 0.8%) in women from MM/CFA families, RR for breast tumours was approximately 3.3 in < or =55 MM/CFA families. Molecular examination of MM/CFA families revealed no alterations within the BRCA2 gene and one germline mutation of the BRCA1 gene. In conclusion, it seems to be justified to consider systematic breast surveillance beginning at the age around 35-40 years as an option in women from < or =55 MM/CFA families.

Age at diagnosis of cancer as predictor of mutation occurrence in families suspected of HNPCC.

Analysis of significance of age at cancer diagnosis as a factor allowing identification of a subgroup of patients with a high frequency of hMSH2 and hMLH1 mutations among families that fulfil suspected HNPCC criteria was performed. DNA from thirty-one unrelated patients affected by colorectal cancer from families matching the above criteria were studied by direct sequencing for occurrence of hMSH2 and hMLH1 gene mutations. Seven unequivocal constitutional mutations were detected: five in the hMLH1 gene and two in the hMSH2 gene. Additionally, one hMLH1 alteration of unknown significance was found. All seven mutations were found in a subgroup of 19 patients with cancer diagnosed before the age of 50 years. In a subgroup of 12 patients with cancer diagnosed at an older age only one case with hMLH1 alteration of unknown significance was detected. Our results indicate that early age at cancer diagnosis seems to be a crucial pedigree factor in discrimination of patients with hMSH2 or hMLH1 mutations among families suspected of HNPCC and matching criteria I of ICG-HNPCC.

Luminescence investigations of redox cycling of adriamycin.

The light emission from the adriamycin + Co2+ + H2O2 system has been studied. Chemiluminescence, fluorescence and absorption spectra were measured. The fluorescence spectra were time-dependent exhibiting maxima at 555, 590 and 645 nm. The chemiluminescence spectra consist of four bands with maxima at around 460-500, 550-580, 640 and 700 nm. Free radical reaction inhibitors, (1)O2-quenchers and catalase inhibited the light emission indicating that hydroxyl radical, superoxide anion radical and singlet oxygen are generated during the redox cycling of adriamycin. Chemiluminescence studies revealed that adriamycin undergoes chemiexcitation under our experimental conditions.

Polymorphism of GSTM1 gene in patients with colorectal cancer and colonic polyps.

The frequency of the GSTM1 gene in patients with nonpolyposis colorectal cancer (CRC) (n = 70) and in subjects with colonic polyps (n = 27) was evaluated and compared with healthy individuals (n = 145). Patients with CRC were divided into the three groups: patients coming from the families with hereditary nonpolyposis colorectal cancer (HNPCC) (n = 17); patients with a high risk of HNPCC who were referred to as suspected of HNPCC (n = 25); patients with sporadic colorectal cancer without clinical features of hereditary tumours (n = 28). A simple polymerase chain reaction (PCR) - based assay to identify GSTM1 nulled and positive (non-nulled) genotype was used. No significant differences in frequency of nulled individuals were observed in both patients with HNPCC and patients suspected of HNPCC as well as in subjects with colonic polyps. The most interesting observation was made in the group of patients with sporadic CRC. Twenty individuals (71.4 %) of the group were GSTM 1 deficient which was significantly different from the control population (p < 0.04). The above data indicate that the absence of the GSTM1 gene is associated with a greater risk of sporadic colorectal cancer. There is an increase in the overall risk of approximately 2.5 as compared with the control population.

Clinico-pathological characteristics of colorectal cancer and serum anti-p53 antibodies.

The purpose of this study was to correlate the presence of p53 antibodies in sera of patients with colorectal adenocarcinoma with size, site and stage of the tumour, age and sex of a patient and the level of carcinoembryonic antigen (CEA) in the serum. p53 antibodies were detected using enzyme-linked immunoabsorbent assay (ELISA). Serum p53 antibodies were detected in 30 of 145 patients (21%), mostly in Astler-Coller stage B1 (28% of patients). No association was found between p53 antibody status in stage A+B1+B2 vs stages C1+C2+D (22% vs 19%) i.e. between patients without and with metastases to regional lymph nodes and/or distant metastases. Serum p53 antibodies were detected in 9 of 34 patients (26%) with tumour localised in the right part vs 21 of 109 patients (19%) with tumours in the left part of the colon and in 18 of 96 (19%) of patients with tumours localised in rectosigmoideum vs 12 of 47 (26%) with tumours in the remaining colon. There was no significant correlation between serum anti p53 antibody and CEA statuses. Increased level of serum CEA was seen in 46/145 (32%) patients. Patients with C1+C2+D stage cancers had high serum CEA level more frequently than did patients with A+B1+B2 stage tumours (44% vs 19% respectively, p < 0.001). Of 102 cases with normal CEA level, 19 (19%) were positive for anti p53 antibodies. These results together with the literature data [11, 20] indicate that approximately 27% CEA negative patients may have serum p53 antibodies. Therefore simultaneous assessment of serum p53 antibodies and CEA seems to be useful for monitoring high risk patients and for postoperative patient monitoring.

[Self-assessment of health status among welders]. / Uwarunkowania samooceny zdrowia spawaczy.

The study covered 371 males (including 206 arc welders) at the productive age. A significant diversify of health self-assessment was found in the examined groups. The relationship between the assessment of health and age, period of employment, social status, education, age at which the employment began, body structure, was statistically significant. There was stronger relationship with the period of employment than with the age. Positive assessment of health was more frequent among those who started their employment at the age over 24 years than among those who joined their job below 20 years of age. Negative assessment of health was observed more often among males suffering from chronic diseases than among those enjoying good health.

[A patient with abdominal actinomycosis--diagnostic problems]. / Chora z promienica brzuszna--problemy diagnostyczne.

The difficulties in diagnosis of abdominal actinomycosis are presented. Clinical manifestations and colonoscopy suggested malignancy. Final diagnosis was made on the basis of pathological assessment of resected sigmoid. Authors underline that in case of "negative" pathomorphological results of material obtained during endoscopy from lesions suspected, benign disease should be consider including anctinomycosis and intraoperative pathomorphological examination should be performed.

[The Peutz-Jeghers syndrome]. / Zespól Peutz-Jeghersa.

A case is described of the Peutz-Jeghers syndrome in a 28-year-old female patient. The patient was treated surgically for intussusception of small intestine caused by polyp.

[Results of treating inflammatory aneurysms of the abdominal aorta]. / Wyniki leczenia tetniaków zapalnych aorty brzusznej.

The authors present the results of treatment of six inflammatory aneurysms in the material of 53 aneurysms treated surgically in the years 1987-1992. Direct results of surgical treatment, hospitalization period, and peri-operational complications are the subject of analysis. Peri-operational mortality of the patients with inflammatory aneurysm was higher than that of patients with non-inflammatory aneurysm, undergoing elective surgery. Higher incidence of peri-operational complications indicates higher operational risk of inflammatory aneurysm.