Colorectal cancer (CRC) is the second most common cancer in Slovenia. The 5-year survival of patients depends on the clinical stage at presentation. More than 70% of patients with CRC are diagnosed ...as being in stage III or IV, with a 5-year survival rate of 52.7%. To improve the detection rate of CRC and to detect CRC in its early and more curable stage, a national screening programme is needed. In the year 2008, we started a pilot phase of the National CRC screening programme. We invited 9091 Slovene residents aged 64–68 years from Ljubljana, Kranj, and Celje regions, of whom 3807 responded to our invitation (41.9%). Two kits of the faecal immune test were sent to 3117 participants who met the inclusion criteria, and 2829 (90.7%) tests were returned. The compliance rate in our pilot programme was 32.9%. Among the patients who responded positively, 7.5% were positive. Until February 2009, 193 colonoscopies had been performed at DC Bled, DC Lipa and AM DC Rogaška. Intubation to the caecum was carried out in 99.4% of colonoscopies. Histology specimens were taken from 135 patients (70%). The adenoma detection rate was 53.8% (59.8% for men and 47.9% for women; P<0.05). We detected 1–17 adenomas per patient (2.4 on average). Advanced adenomas were detected in 60 patients (31%; 35.1% of men and 27.1% of women; P<0.05). Invasive carcinoma was detected in 15 patients (7.7%; 12.4% of men and 3.1% of women; P<0.05). Ten of them (73.3%) were in clinical stage I or II. In the pilot phase of the CRC screening programme the majority of CRCs were detected at early clinical stages. Invasive cancers were detected in 7.7% of patients. In almost all patients adenomas were resected at screening colonoscopy, thus reducing the possibility of later development of CRC in those patients.
Microsatellite instability (MSI) is present in more than 90% of colorectal cancers of patients with Lynch syndrome, and is therefore a feasible marker for the disease. Mutations in MLH1, MSH2, MSH6 ...and PMS2, which are one of the main causes of deficient mismatch repair and subsequent MSI, have been linked to the disease. In order to establish the role of each of the 4 genes in Slovenian Lynch syndrome patients, we performed MSI analysis on 593 unselected CRC patients and subsequently searched for the presence of point mutations, larger genomic rearrangements and MLH1 promoter hypermethylation in patients with MSI-high tumours. We detected 43 (7.3%) patients with MSI-H tumours, of which 7 patients (1.3%) harboured germline defects: 2 in MLH1, 4 in MSH2, 1 in PMS2 and none in MSH6. Twenty-nine germline sequence variations of unknown significance and 17 deleterious somatic mutations were found. MLH1 promoter methylation was detected in 56% of patients without detected germline defects and in 1 (14%) suspected Lynch syndrome. Due to the minor role of germline MSH6 mutations, we adapted the Lynch syndrome detection strategy for the Slovenian population of CRC patients, whereby germline alterations should be first sought in MLH1 and MSH2 followed by a search for larger genomic rearrangements in these two genes. When no germline mutations are found tumors should be further tested for the presence of germline defects in PMS2 and MSH6. The choice about which gene should be tested first can be guided more accurately by the immunohistochemical analysis. Our study demonstrates that the incidence of MMR mutations in a population should be known prior to the application of one of several suggested strategies for detection of Lynch syndrome.
ABSTRACT
In 43 MSI-H colorectal cancers we searched for new targets of promoter methylation, inspected the nature of methylation process, and the influence of methylation at specific CpG site on gene ...expression. CpG methylation was detected in 12 tumor suppressor genes. Our findings suggest a potential role of IGSF4 gene in the development of colorectal tumors. According to the detected methylation pattern, two groups of tumors, significantly differing in age, exist in MSI-H colorectal cancers. Our study also suggests that methylation at a specific CpG island in the promoter could be the representative for gene silencing and therefore serve as a biomarker.
The use of tissue microarray (TMA) technology may substantially reduce the costs of routine testing of breast carcinomas for human epidermal growth factor receptor 2 (HER2) status. After a ...preliminary pilot study comparing the TMA results with those obtained on whole section, which showed an excellent agreement (with kappa values >0.90) for both immunohistochemical and fluorescent in situ hybridization (FISH) method, we introduced the TMA technique in our routine work. A total of 1158 invasive breast carcinomas were submitted for the determination of HER2 status, which was assessed in 74 weekly runs. One hundred twenty-five of 1084 surgical specimens (11.5%) were judged as unsuitable for inclusion into TMAs. In 32 of 959 tumors included in TMAs (3.3%), the respective cores were uninformative, and HER2 status was determined on whole sections. Thus, HER2 status was finally determined on TMA in 927 cases (81.1%). A typical weekly run comprised 1 TMA (consisting, on average, of 13 tumors), 2 whole sections of surgical specimens and 1 whole section of core needle biopsy, and the number of processed slides for each method decreased from 16 to 4 per week. In all, 14.7% of tumors were HER2 positive by FISH. In both TMAs and whole sections, immunohistochemical results were in good agreement with FISH for cases scored as 0/1+ (98% and 97%) and for those scored as 3+ (96% and 87%), whereas concordance was poor in cases scored as 2+ (30% and 13%, respectively).
Electrochemotherapy treats tumors by combining specific chemotherapeutic drugs with an intracellular target and electric pulses, which increases drug uptake into the tumor cells. Electrochemotherapy ...has been successfully used for treatment of easily accessible superficial tumor nodules. In this paper, we present the first case of deep-seated tumor electrochemotherapy based on numerical treatment planning.
The aim of our study was to treat a melanoma metastasis in the thigh of a patient. Treatment planning for electrode positioning and electrical pulse parameters was performed for two different electrode configurations: one with four and another with five long needle electrodes. During the procedure, the four electrode treatment plan was adopted and the patient was treated accordingly by electrochemotherapy with bleomycin. The response to treatment was clinically and radiographically evaluated. Due to a partial response of the treated tumor, the metastasis was surgically removed after 2 months and pathological analysis was performed.
A partial response of the tumor to electrochemotherapy was obtained. Histologically, the metastasis showed partial necrosis due to electrochemotherapy, estimated to represent 40-50% of the tumor. Based on the data obtained, we re-evaluated the electrical treatment parameters in order to correlate the treatment plan with the clinical response. Electrode positions in the numerical model were updated according to the actual positions during treatment. We compared the maximum value of the measured electric current with the current predicted by the model and good agreement was obtained. Finally, tumor coverage with an electric field above the reversible threshold was recalculated and determined to be approximately 94%. Therefore, according to the calculations, a small volume of tumor cells remained viable after electrochemotherapy, and these were sufficient for tumor regrowth.
In this, the first reported clinical case, deep-seated melanoma metastasis in the thigh of the patient was treated by electrochemotherapy, according to a treatment plan obtained by numerical modeling and optimization. Although only a partial response was obtained, the presented work demonstrates that treatment of deep-seated tumor nodules by electrochemotherapy is feasible and sets the ground for numerical treatment planning-based electrochemotherapy.
EudraCT:2008-008290-54.
To assess the axillary recurrence rate in operable breast cancer patients with clinically negative axilla after negative sentinel lymph node in whom axillary lymph node dissection had not been ...performed.
Fifty consecutive female operable breast cancer patients with negative sentinel lymph node biopsy in whom axillary lymph node dissection had not been performed were included in the study and prospectively followed, with median follow-up time of 32 months (range 10-50 months). Sentinel lymph node biopsy was performed by the triple method.
The sentinel node identification rate was 100%. In only one of 50 patients with negative sentinel lymph node, axillary recurrence developed 26 months after surgery. This was the sole patient with sentinel lymph node biopsy after previous surgical biopsy. After treatment, all patients were alive and with no evidence of disease.
Omitting axillary node dissection after negative sentinel node biopsy in operable breast cancer patients proved to be safe. Patients with previous open surgical biopsy should be given special attention in the follow-up.
Preoperative capecitabine-based chemoradiation is a standard treatment for locally advanced rectal cancer (LARC). Here, we explored the safety and efficacy of the addition of bevacizumab to ...capecitabine and concurrent radiotherapy for LARC.
Patients with MRI-confirmed stage II/III rectal cancer received bevacizumab 5 mg/kg i.v. 2 weeks prior to neoadjuvant chemoradiotherapy followed by bevacizumab 5 mg/kg on Days 1, 15 and 29, capecitabine 825 mg/m2 twice daily on Days 1-38, and concurrent radiotherapy 50.4 Gy (1.8 Gy/day, 5 days/week for 5 weeks + three 1.8 Gy/day), starting on Day 1. Total mesorectal excision was scheduled 6-8 weeks after completion of chemoradiotherapy. Tumour regression grades (TRG) were evaluated on surgical specimens according to Dworak. The primary endpoint was pathological complete response (pCR).
61 patients were enrolled (median age 60 years range 31-80, 64% male). Twelve patients (19.7%) had T3N0 tumours, 1 patient T2N1, 19 patients (31.1%) T3N1, 2 patients (3.3%) T2N2, 22 patients (36.1%) T3N2 and 5 patients (8.2%) T4N2. Median tumour distance from the anal verge was 6 cm (range 0-11). Grade 3 adverse events included dermatitis (n = 6, 9.8%), proteinuria (n = 4, 6.5%) and leucocytopenia (n = 3, 4.9%). Radical resection was achieved in 57 patients (95%), and 42 patients (70%) underwent sphincter-preserving surgery. TRG 4 (pCR) was recorded in 8 patients (13.3%) and TRG 3 in 9 patients (15.0%). T-, N- and overall downstaging rates were 45.2%, 73.8%, and 73.8%, respectively.
This study demonstrates the feasibility of preoperative chemoradiotherapy with bevacizumab and capecitabine. The observed adverse events of neoadjuvant treatment are comparable with those previously reported, but the pCR rate was lower.
Alterations of cell cycle proteins contribute to the development and biological behaviour of malignant tumours. We evaluated the distribution and prognostic significance of immunohistochemically ...detected proteins p53, p21, Rb, and cyclin D1 in 101 laryngeal and hypopharyngeal squamous cell carcinomas (SCC) and adjacent epithelial hyperplastic lesions (EHL). Protein expression was correlated with tumour grade and stage. Varying patterns of protein expression were found in SCC. A significant correlation (p<0.05) was found between Rb expression and tumour grade. Different grades of EHL exhibited randomly distributed p53 and cyclin D1 positive cell clusters with no association to the pattern of their expression in SCC. Our study demonstrated derailment of cell cycle regulation in almost all cases of SCC of the larynx and hypopharynx. However, only cyclin D1 expression had an independent prognostic value for cancer-specific survival. The results also suggest that Rb gene inactivation, although rare, might be more important in the development of SCC than previously thought.
Colorectal cancer (CRC) is one of the most common malignancies in the western world.
We aimed to assess the first round of fecal immunochemical test (FIT)-based National CRC screening program (NCSP).
...In the NCSP conducted in Slovenia, a FIT and colonoscopy for those tested positive was used. The NCSP central unit sent 536,709 invitations to Slovenian residents age 50 to 69 years old between 2009 and 2011. The adherence rate was 56.9% (303,343 participants). FIT was positive in 6.2% (15,310) of the participants (men, 7.8%; women, 5.0%; P<0.01). A total of 13,919 unsedated colonoscopies were performed with the cecal intubation rate of 97.8%.
The overall adenoma detection rate was 51.3% 95% confidence interval (CI), 50.5%-52.1% of which 61.0% (95% CI, 59.9%-62.1%) was in men, and 39.1% (95% CI, 37.8%-40.3%) in women (P<0.01). The mean number of adenoma per positive colonoscopy was 1.94 (95% CI, 1.90-1.97). Adenoma, advanced adenoma, or cancer were found in 7732 (55.5%) colonoscopies. A total of 862 (6.2%) CRC cases were found. Only 161 (18.7%) carcinomas were situated in the right colon. A total of 597 (70.2%) patients with cancer were in the early clinical stages (N, negative; 194 22.8%) of all cancers were cured with only endoscopic resection.
In the NCSP, CRC was found in 6.2% of those participants attending colonoscopy, with 81.3% of carcinomas found in the left colon. A localized clinical stage was found in 70.2% participants. In 22.8% of CRC patients, cancer was cured with endoscopic resection only.
Skeletal pain and the resulting skeletal complications are common in Gaucher disease. The patients therefore usually receive symptomatic treatment and only rarely undergo additional diagnostic ...procedures. The paper describes the case of a patient with Gaucher disease who had advancing pain in the right knee and femur, which was first attributed to the basic disease. After a pathological fracture of the painful part of the leg, it became evident that the patient suffered from primary bone angiosarcoma. From this case, we learnt that not every skeletal pain in Gaucher disease represents a skeletal manifestation of this disease. Further surgical treatment was made difficult by the thrombocyte dysfunction discovered in the patient.
PDF
