Evaluation and Predictive Factors of Complete Response in Rectal Cancer after Neoadjuvant Chemoradiation Therapy.

The response to neoadjuvant chemoradiation therapy is an important prognostic factor for locally advanced rectal cancer. Although the majority of the patients after neoadjuvant therapy are referred to following surgery, the clinical data show that complete clinical or pathological response is found in a significant proportion of the patients. Diagnostic accuracy of confirming the complete response has a crucial role in further management of a rectal cancer patient. As the rate of clinical complete response, unfortunately, is not always consistent with pathological complete response, accurate diagnostic parameters and predictive markers of tumor response may help to guide more personalized treatment strategies and identify potential candidates for nonoperative management more safely. The management of complete response demands interdisciplinary collaboration including oncologists, radiotherapists, radiologists, pathologists, endoscopists and surgeons, because the absence of a multidisciplinary approach may compromise the oncological outcome. Prediction and improvement of rectal cancer response to neoadjuvant therapy is still an active and challenging field of further research. This literature review is summarizing the main, currently known clinical information about the complete response that could be useful in case if encountering such condition in rectal cancer patients after neoadjuvant chemoradiation therapy, using as a source PubMed publications from 2010-2021 matching the search terms "rectal cancer", "neoadjuvant therapy" and "response".

Pathogenic APC Variants in Latvian Familial Adenomatous Polyposis Patients.

Background and objectives: Familial adenomatous polyposis is one of the APC-associated polyposis conditions described as genetically predetermined colorectal polyposis syndrome with a variety of symptoms. The purpose of this study was to determine sequence variants of the APC gene in patients with familial adenomatous polyposis (FAP) phenotype and positive or negative family history. Materials and Methods: Eight families with defined criteria of adenomatous polyposis underwent molecular genetic testing. Coding regions and flanking intron regions of the APC gene were analyzed by Sanger sequencing. Results: Eight allelic variants of the APC gene coding sequence were detected. All allelic variants of the APC gene were predicted to be pathogenic based on criteria according to the "Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology" (2015), four of them c.1586_1587insAT, c.2336delT, c.3066_3067insGA, and c.4303_4304insC, were considered novel. Conclusions: The timely molecular genetic analysis of APC germline variants and standardized interpretation of the pathogenicity of novel allelic variants has a high impact on choice for treatment, cancer prevention, and family genetic counseling.

BRCA1/2 mutation screening in high-risk breast/ovarian cancer families and sporadic cancer patient surveilling for hidden high-risk families.

BACKGROUND: The estimated ratio of hereditary breast/ovarian cancer (HBOC) based on family history is 1.5% in Latvia. This is significantly lower than the European average of 5-10%. Molecular markers like mutations and SNPs can help distinguish HBOC patients in the sporadic breast and ovarian cancer group. METHODS: 50 patients diagnosed with HBOC in the Latvian Cancer Registry from January 2005 to December 2008 were screened for BRCA1 founder mutation-negatives and subjected to targeted resequencing of BRCA1 and BRCA2 genes. The newly found mutations were screened for in the breast and ovarian cancer group of 1075 patients by Real Time-PCR/HRM analysis and RFLP. RESULTS: Four BRCA2 mutations including three novel BRCA2 frameshift mutations and one previously known BRCA2 frameshift mutation and one BRCA1 splicing mutation were identified. Two of the BRCA2 mutations were found in a group of consecutive breast cancer patients with a frequency of 0.51% and 0.38%. CONCLUSIONS: Molecular screening of sequential cancer patients is an important tool to identify HBOC families.

Evaluation of Clinical Manifestations of Hemorrhoidal Disease, Carried Out Surgeries and Prolapsed Anorectal Tissues: Associations with ABO Blood Groups of Patients.

Hemorrhoidal disease (HD) is a chronic multifactorial disease. Increased abdominal pressure, along with hyperperfusion, neovascularization, overexpression of inflammatory mediators, and dysbiosis, contributes to the development of HD. The deterioration of the anchoring connective tissue with reduced collagen content and altered collagen ratios, dilatation of blood vessels and thrombosis, muscle injury, and inflammation gradually lead to clinically manifesting prolapse and bleeding from hemorrhoids. The associations of the ABO blood types with a disease have been investigated for the upper gastrointestinal tract only. This study aimed to evaluate HD clinical manifestations, surgeries carried out, and the status of prolapsed anorectal tissues by exploring the associations with the patients' ABO blood groups. Clinical and various morphological methods, combined with extensive bioinformatics, were used. The blood type 0, grade III and IV HD individuals constituted the largest group in a moderately-sized cohort of equally represented males and females studied and submitted to surgical treatment of hemorrhoids. There were significantly more complaints reported by HD females compared to males (p = 0.0094). The Longo technique appeared mostly used, and there were proportionally more surgeries performed below the dentate line for HD individuals with blood type 0 compared to other blood type patients (24% vs. 11%). HD males were found to present with significantly more often inflamed rectal mucosa (p < 0.05). Loosening and weakening of collagenous components of the rectal wall combined with vascular dilation and hemorrhage was found to differ in 0 blood type HD individuals compared to other types. HD males were demonstrated to develop the ruptures of vascular beds significantly more often when compared to HD females (p = 0.0165). Furthermore, 0 blood type HD males were significantly more often affected by a disease manifested with tissue hemorrhage compared to the 0 blood type HD females (p = 0.0081). Collectively, the local status of chronically injured anorectal tissue should be considered when applying surgical techniques. Future studies could include patients with HD grades I and II to gain a comprehensive understanding of the disease progression, allowing for a comparison of tissue changes at different disease stages.

The first evidence of hereditary and familial gastric cancer in Latvia: implications for prevention.

BACKGROUND AND OBJECTIVE: Gastric cancer is a frequent cause of cancer mortality. The prognosis of established tumor is unfavorable due to the propensity to spread and limited treatment efficiency. Therefore, prevention has a high significance. We tested a population screening approach in order to identify families with an increased gastric cancer load for further surveillance. MATERIAL AND METHODS: Population screening was performed by questionnaire reaching 76.6% of the population. Hereditary gastric cancer (HGC) syndrome was diagnosed if 3 mutually first-degree relatives with gastric cancer were reported in the kindred. Additional group (HGC2) of families with 2 first-degree relatives affected by gastric cancer was identified. RESULTS: The HGC syndrome was diagnosed in 0.11%, but HGC2 syndrome, in 0.4% probands. The gastric cancer frequency among blood relatives was 25.2% (95% CI, 20.6%-30.4%) in HGC, but 16.0% (95% CI, 13.8%-18.5%) in HGC2 families. The mean age at diagnosis of cancer was 56.9 years (95% CI, 53.4-60.3) in HGC and 62.5 years (95% CI, 60.1-64.8) in HGC2. The mean survival was 2.6 years (95% CI, 1.2-4.0). CONCLUSIONS: Population screening identifies reasonable number of families with a high frequency of gastric cancer. The frequency of gastric cancer and an unfavorable course characterized by low survival justify surveillance in families with 2 or 3 first-degree relatives affected by gastric cancer. Population screening provides the age characteristics of the respective tumors in order to adjust the surveillance schedule.

Genotype-phenotype correlations among BRCA1 4153delA and 5382insC mutation carriers from Latvia.

BACKGROUND: Mutations in the high penetrance breast and ovarian cancer susceptibility gene BRCA1 account for a significant percentage of hereditary breast and ovarian cancer cases. Genotype-phenotype correlations of BRCA1 mutations located in different parts of the BRCA1 gene have been described previously; however, phenotypic differences of specific BRCA1 mutations have not yet been fully investigated. In our study, based on the analysis of a population-based series of unselected breast and ovarian cancer cases in Latvia, we show some aspects of the genotype-phenotype correlation among the BRCA1 c.4034delA (4153delA) and c.5266dupC (5382insC) founder mutation carriers. METHODS: We investigated the prevalence of the BRCA1 founder mutations c.4034delA and c.5266dupC in a population-based series of unselected breast (n = 2546) and ovarian (n = 795) cancer cases. Among the BRCA1 mutation carriers identified in this analysis we compared the overall survival, age at diagnosis and family histories of breast and ovarian cancers. RESULTS: We have found that the prevalence of breast and ovarian cancer cases (breast: ovarian cancer ratio) differs significantly among the carriers of the c.5266dupC and c.4034delA founder mutations (OR = 2.98, 95%CI = 1.58 to 5.62, P < 0.001). We have also found a difference in the prevalence of breast and ovarian cancer cases among the 1st and 2nd degree relatives of the c.4034delA and c.5266dupC mutation carriers. In addition, among the breast cancer cases the c.4034delA mutation has been associated with a later age of onset and worse clinical outcomes in comparison with the c.5266dupC mutation. CONCLUSIONS: Our data suggest that the carriers of the c.4034delA and c.5266dupC founder mutations have different risks of breast and ovarian cancer development, different age of onset and prognosis of breast cancer.

Initial results of colorectal polyposis research in Latvia.

AIM: Patients suffering from colorectal polyps are more likely to develop a malignant condition with poor prognosis. The aim of the study is to investigate clinical and molecular features of colorectal polyposis syndromes in Latvia in order to offer and provide predictive genetic testing for the affected families, as well as to evaluate the frequency of familial adenomatous polyposis (FAP) in Latvia. PATIENTS AND METHODS: Six polyposis patients along with three of their relatives were included in this study. Two patients were selected from the colorectal cancer database (from a total of 2,552), and four patients not affected with colorectal cancer (CRC) were referred from the endoscopic facility of our hospital. All the patients were examined during the period from January 1st, 2000 until June 30th, 2007. Clinical data, histological examinations and family cancer histories of the respective patients were evaluated. Screening for germline APC mutations was performed in five patients and their relatives. In addition, all patients underwent genetic counseling. RESULTS: Two patients out of 2,552 from the CRC Hereditary Cancer Institute database fulfilled the clinical criteria for FAP. Thus, the frequency of FAP is 0.08% (2/2,552) of all CRC cases, and comprises approximately 0.0003% of the population of Latvia (7/22 million inhabitants). Unknown polyposis was identified in two cases. Pathogenic APC gene mutations were detected in five out of seven examined patients and their relatives. Two of the mutations (c.3942delG:p.Arg1314SerfsX7 and c.3286C > T;p.Gln1096X) are novel. CONCLUSION: In this study, we report the first four APC mutation-positive FAP cases in Latvia. The present frequency of FAP is lower than that reported in Finland, Lithuania, and other neighbouring countries, but the numbers might increase if a more systematic identification approach is used. Initial molecular examinations reveal partially unique spectrum of APC gene mutations.

Nationwide study of clinical and molecular features of hereditary non-polyposis colorectal cancer (HNPCC) in Latvia.

BACKGROUND: The mutational spectrum of mismatch repair (MMR) genes in the Baltic States has been reported to be quite similar to that in Poland; however during a country-wide study considerable differences in the population of Latvia were discovered. This study was undertaken to investigate the clinical and molecular features of HNPCC in Latvia. MATERIALS AND METHODS: Family cancer histories were collected, from January 2000 until October 2003, for 702 consecutive hospital based colorectal cancer (CRC) cases. In families suspected of having a history consistent with hereditary non-polyposis colorectal cancer (HNPCC), DNA testing for MLH1, MSH2 and MSH6 genes was performed. Immunohistochemical examination of the normal and the cancer tissue from large bowel tumors was undertaken for MSH2 and MSH6 protein expression in 182 out of 702 (26%) of the cases. RESULTS: Among the 702 CRC patients only 1 (0.14%) fulfilled the Amsterdam criteria. Thirteen (1.9%) cases matched the criteria for suspected HNPCC and 10 (1.4%) cases matched the late onset HNPCC criteria. Altogether in 7 out of 702 (1%) cases MMR gene mutations were detected: 2 in MLH1, 3 in MSH2 and 2 in MSH6 gene. Only one out of the seven mutations was registered in the Human Genome Mutation Database and the ICG (International Collaborational Group)-HNPCC mutation data base. Negative MSH2 and MSH6 protein expression was detected in 4 (2.2%) and 18 out of 182 (9.9%) cases respectively. CONCLUSION: The role of the classical Amsterdam criteria in diagnosing HNPCC in CRC patients from Latvia is very limited and diagnostic criteria for suspected HNPCC are the most effective. The frequency of constitutional mutations within the MMR genes is 1% of all newly diagnosed CRC cases and the spectrum of mutations is potentially characteristic.

Underestimated survival predictions of the prognostic tools Adjuvant! Online and PREDICT in BRCA1-associated breast cancer patients.

BRCA1-associated breast cancer is considered an unique clinical entity with its own specific histopathological characteristics. Several recently published large studies have shown that overall survival of BRCA1 mutation carriers having breast cancer is similar to sporadic breast cancer patients. It was also suggested that better response to chemotherapy is one of the most important factors that improves the clinical outcome of breast cancers with unfavorable histopathological subtypes in BRCA1 mutation carriers. Adjuvant! Online and PREDICT are web-based prognostic tools that estimate the survival benefit of adjuvant chemotherapy in primary breast cancer patients. These tools have been extensively validated in different populations; however, the accuracy of the predictions made by Adjuvant! Online and PREDICT among BRCA1 mutation carriers has not yet been investigated. In this study we have found, that predictions of overall and breast cancer-specific survival obtained from Adjuvant! Online and PREDICT were significantly lower than the observed survival percentages in the study population [predicted--observed difference for 10-year overall survival: -9.75%, P < 0.0001 (Adjuvant! Online); -10.21%, P < 0.0001 (PREDICT)]. Thus this study suggests that Adjuvant! Online and PREDICT should be used with caution in this group of patients. Further updating of adjuvant therapy benefit calculation tools by inclusion of the information about inherited genetic alterations should be considered to improve the performance of the prognostic programs among hereditary breast cancer patients.

Challenges in the management of a patient with Cowden syndrome: case report and literature review.

We would like to present a patient with a classical phenotype of a rare disorder - Cowden syndrome, its diagnostics and management challenges. A breast surgeon has to be aware of this rare condition when treating a patient with breast manifestations of Cowden syndrome and has to refer the patient to a clinical geneticist for further evaluation. Sequencing of the PTEN gene showed the Asp24Gly mutation. According to the latest literature data, the lifetime risk of breast cancer for Cowden syndrome patients is 81% and surgery is a justified option to reduce the risk of breast cancer. Bilateral risk-reducing mastectomy with immediate reconstruction was performed to eliminate further risk of breast cancer. 3 years after the risk-reducing breast surgery the patient is satisfied with the outcome. This is to our best knowledge the first reported Cowden syndrome case with follow-up data after risk-reducing measures have been taken.

Population screening for hereditary and familial cancer syndromes in Valka district of Latvia.

BACKGROUND: The growing possibilities of cancer prevention and treatment as well as the increasing knowledge about hereditary cancers require proper identification of the persons at risk. The aim of this study was to test the outcome of population screening in the scientific and practical evaluation of hereditary cancer. METHODS: Population screening for hereditary cancer was carried out retrospectively in a geographic area of Latvia. Family cancer histories were collected from 18642 adults representing 76.6% of the population of this area. Hereditary cancer syndromes were diagnosed clinically. Molecular testing for BRCA1 founder mutations 300 T/G, 4153delA and 5382insC was conducted in 588 persons who reported at least one case of breast or ovary cancer among blood relatives. RESULTS: Clinically, 74 (0.40%; 95% confidence interval (CI): 0.32 - 0.50%) high-risk and 548 (2.94%, 95% CI: 2.71 - 3.19) moderate-risk hereditary cancer syndromes were detected covering wide cancer spectrum. All syndromes were characterised by high cancer frequency among blood relatives ranging 8.6 - 46.2% in contrast to spouse correlation of 2.5 - 3.6%. The mean age of cancer onset ranged 38.0 - 72.0 years in different syndromes. The BRCA1 gene mutations were identified in 10 (1.7%; 95% CI: 0.9 - 3.1%) probands. Families with established BRCA1 gene founder mutations were identified with the frequency 1:2663 clinically screened persons. CONCLUSIONS: Population screening is a useful practical tool for the identification of persons belonging to families with high frequency of malignant tumours. The whole hereditary and familial cancer spectrum along with the age structure was identified adjusting follow-up guidelines. Another benefit of the population screening is the possibility to identify oncologically healthy persons belonging to hereditary and familial cancer families so that appropriate surveillance can be offered. Clinical diagnostics is appropriate for population screening purposes; molecular investigation provides additional information. In collaboration with family doctors, the screening is technically manageable as characterised by high compliance.

Pilot study on low penetrance breast and colorectal cancer predisposition markers in latvia.

INTRODUCTION: It has not been established whether CHEK2 and NOD2 variants are present in Latvia and whether inherited variation in these genes influences cancer risk in this population. AIM OF THE STUDY: To evaluate the role of CHEK2 and NOD2 mutations in breast and colorectal cancers in the population of Latvia. MATERIALS AND METHODS: Peripheral venous blood samples were collected from 185 breast cancer and 235 colorectal cancer consecutive hospital-based cases from 11/2003 to 06/2005. The population control group included blood samples from the clamped distal part of the umbilical cord from 978 consecutive anonymous newborns born between 03/2005 and 08/2005. All cases and controls were tested for the presence of NOD2 3020insC mutation and CHEK2 I157T mutation. RESULTS: NOD2 3020insC was present in 7.7% (18/235) of CRC cancers, in 9.2% (17/185) of breast cancers and in 7.7% (75/974) of controls. CHEK2 I157T variant was found in 7.6% (14/185) of breast cancer cases, 10.2% (24/235) of colon cancer cases and in 6.4% (63/978) of population controls. NOD2 3020insC variant was associated with increased risk of breast cancer (OR = 2.5, p < 0.05) for cases diagnosed at age between 51 and 60 years. CHEK2 I157T variant was associated with increased risk of colorectal cancer (OR = 1.7, p < 0.05) with the highest OR = 2.0 for cases diagnosed at age >70 yrs. CONCLUSIONS: NOD2 3020insC, CHEK2 I157T variants may be associated with increased risk of colorectal and breast cancers in Latvia.

Clinical, molecular and geographical features of hereditary breast/ovarian cancer in latvia.

INTRODUCTION: The aim of the study is to evaluate the incidence and phenotype-genotype characteristics of hereditary breast and ovarian cancer syndromes in Latvia in order to develop the basis of clinical management for patients and their relatives affected by this syndrome. MATERIALS AND METHODS: In 2002-2004 in two Latvian oncology hospitals (Liepãja Oncology Hospital and Daugavpils Oncology Hospital) cancer family histories were collected from 287 consecutive patients with breast and ovarian cancer. In all cases, when it was possible to obtain the blood sample, DNA testing for founder mutations in the BRCA1 gene was performed. RESULTS: Among 287 family cancer histories analysed in 8 (2.8%) cases criteria of hereditary breast cancer (HBC) were fulfilled and in 5 (1.7%) cases hereditary breast and ovarian cancer (HBOC) was diagnosed. In 50 (17.4%) cases we have suspicion of hereditary breast cancer (HBC susp.) and in 8 (2.8%) cases - suspicion of hereditary breast and ovarian cancer (HBOC susp.). We have one (0.3%) case with hereditary ovarian cancer (HOC). DNA testing of founder mutations in the BRCA1 gene (exon 20 (5382 insC) exon 5 (300T/G), exon 11, 17 (4153delA)) for 178/287 (62%) patients was performed. In 9/287 (4.9%) cases we found a mutation in the BRCA1 gene. 4 mutations were detected in exon 11, 17 (4153delA) and 4 mutations in exon 20 (5382 insC) and 1 in exon 5. CONCLUSIONS: Existing pedigree/clinical data suggest that in Latvia the clinical frequency of hereditary breast and ovarian cancer is around 5% of consecutive breast and ovarian cancer patients and suspicion of the syndrome is observed in another 20% of cases. Frequency of BRCA1 founder mutations is 5% of all consecutive breast and ovarian cancers. Considerable geographical differences in the clinical and molecular frequency of hereditary breast ovarian cancer have been observed in Latvia.