Jung S. Kim

Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients.

The genotypic consequences of numerous single-nucleotide variants in human mismatch repair genes are mostly undetermined. We examined 27 reported single-nucleotide variants, rarely or ambiguously verified in a population-based study, to identify single-nucleotide polymorphisms (SNPs), haplotypes, and the genotype–phenotype association in Korean populations of 330 healthy individuals, 107 sporadic colorectal cancer patients, and 107 of their first-degree relatives. Real-time PCR 5′-nuclease assays (TaqMan® MGB assay) were used to determine 24 single-nucleotide variants, and restriction fragment length polymorphism (RFLP) assays were used to determine 3 variants. Of these 27 variants, 4 (hMSH2 gIVS12-6, hMLH1 655, hMLH1 1151, and hMSH2 1168, in descending order) were identified as SNPs occurring in 4.5 to 53.1% of healthy individuals, with polymorphism levels of 0.023–0.3 (mean, 0.092). East Asian populations had an ethnic predilection for the hMLH1 1151 SNP. The genotype distribution for all four SNPs showed no association with sporadic colorectal cancer. Twenty-three variants were not identified in the Korean population, suggesting that fifteen of these variants are colorectal cancer-related mutations and eight are SNPs. Two haplotype patterns existed exclusively, but with rare frequency, in sporadic colorectal cancer patients. The hMLH1 655 allele was closely correlated with hMLH1 protein expression (P= 0.02), but none of the four SNPs was associated with clinicopathologic variables. Among the 27 single nucleotide variants of mismatch repair genes, 12 were suggestive of nonfunctional SNPs and 15 may be colorectal cancer-related mutations. Further verification in other ethnic groups may provide the genotypic and phenotypic significance of single nucleotide variants found in mismatch repair genes.

Selective soft-tissue release for recurrent or residual deformity after conservative treatment of idiopathic clubfoot

We reviewed the results of a selective à la carte soft-tissue release operation for recurrent or residual deformity after initial conservative treatment for idiopathic clubfoot by the Ponseti method. Recurrent or residual deformity occurred in 13 (19 feet) of 33 patients (48 feet; 40%). The mean age at surgery was 2.3 years (1.3 to 4) and the mean follow-up was 3.6 years (2 to 5.3). The mean Pirani score had improved from 2.8 to 1.1 points, and the clinical and radiological results were satisfactory in all patients. However, six of the 13 patients (9 of 19 feet) had required further surgery in the form of tibial derotation osteotomy, split anterior tibialis tendon transfer, split posterior tibialis transfer or a combination of these for recurrent deformity. We concluded that selective soft-tissue release can provide satisfactory early results after failure of initial treatment of clubfoot by the Ponseti method, but long-term follow-up to skeletal maturity will be necessary.

Genetic and epigenetic changes in the APC gene in sporadic colorectal carcinoma with synchronous adenoma.

Abstract Background and aims. Somatic APC mutation, frequently associated with colorectal tumors, is implicated in the early stage of tumorigenesis. This study was performed to identify APC-related colorectal tumorigenesis in sporadic colorectal carcinomas with synchronous adenoma. Materials and methods. We screened the entire coding region of APC and also assessed 5q LOH, 5q MSI, and promoter hypermethylation in fresh colorectal tissue and the lymphocytes of 31 patients with synchronous colorectal adenoma and carcinoma. Results. The APC mutation prevalence was greater in carcinomas (70%) than in adenomas (45%). The 5q LOH and MSI were identified in 7 and in 5 of 31 carcinomas and in 6 each of 43 adenomas, respectively. The APC promoter methylation was identified in 3 cases each of both carcinomas and adenomas. Mutations in cases with 5q LOH were identified exclusively from codons 959 to the 3′ end of exon 15. Otherwise mutations identified between exons 1 and 14 showed additional mutation on exon 15 and no additional mutation in two cases. All carcinomas with 5q LOH, 5q MSI, or methylation included at least one APC mutation, whereas 5 carcinomas and 6 adenomas showed solely an APC mutation. Both alleles were disrupted in 1 of 31 normal mucosa (3.2%), 12 of 40 adenomas (30%), and 18 of 33 carcinomas (54.5%). Conclusion. Genetic and epigenetic events encompassing APC occur variously among patients and tissues in sporadic colorectal cancer patients with synchronous colorectal adenoma. Moreover, these changes sometimes appear to be accumulated in all of the stages of colorectal tumorigenesis.

3′-Deoxy-3′-18F-Fluorothymidine PET for the Early Prediction of Response to Leucovorin, 5-Fluorouracil, and Oxaliplatin Therapy in Patients with Metastatic Colorectal Cancer

The aim of this study was to evaluate 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) PET for early prediction of the standard anatomic response and survival outcomes in patients with metastatic colorectal cancer (mCRC) receiving leucovorin, 5-fluorouracil (5-FU), and oxaliplatin (FOLFOX). Methods: The main eligibility criteria included histologically confirmed mCRC, ≥1 extrahepatic measurable lesions, and no prior chemotherapy in a metastatic setting. Chemotherapy consisted of leucovorin on day 1, followed by the continuous infusion of 5-FU on days 1 and 2, and oxaliplatin on day 3. In the second and subsequent cycles of chemotherapy, oxaliplatin was administered simultaneously with leucovorin on day 1. 18F-FLT PET scans were obtained 3 times during the first cycle of chemotherapy: before chemotherapy, 24 h after infusion of 5-FU (day 2), and 48 h after completion of chemotherapy (day 5). The maximum standardized uptake value (SUVMAX) of 18F-FLT was measured. Treatment responses were assessed by CT after 3 cycles of FOLFOX. Results: Eighteen patients were included in the study. The response rate after 3 cycles of FOLFOX was 27.8% (5/18). The SUVMAX was increased in responders (P = 0.043) and nonresponders (P < 0.001) on day 2 and was decreased, compared with baseline values, on day 5 in responders only (P = 0.043). Receiver-operating-characteristic curve analysis indicated that the use of a threshold of an SUVMAX increase on day 2 of ≤45.8% resulted in a sensitivity of 100%, specificity of 69.2%, and relative risk of 2.250 (P = 0.029) for the diagnosis of responders. Use of a threshold of an SUVMAX decrease on day 5 of ≥10.6% resulted in a sensitivity of 100%, specificity of 76.9%, and relative risk of 2.667 (P = 0.007). Patients with low 18F-FLT flare tended to have longer survivals than patients with high flare (2-y overall survival rate, 77.8% vs. 44.4%; P = 0.051). Conclusion: The 18F-FLT flare observed during 5-FU infusion was associated with poor treatment response in patients with mCRC. The degree of 18F-FLT flare might be used to predict the outcome of patients who receive infusional 5-FU–based chemotherapy.

Characterization of mutator phenotype in Familial colorectal cancer patients not fulfilling Amsterdam criteria

Purpose: Although the mutator phenotype, including genetic and epigenetic alterations of the mismatch repair (MMR) system, seems to be pronounced in familial colorectal cancer, there have been few integrative studies comprising the entire mutator pathway. This study was done to identify the entire mutator pathway determining risk factors in patients with familial colorectal cancer not fulfilling the Amsterdam criteria. Experimental Design: We consecutively recruited 134 colorectal cancer patients with a family history of accompanying cancers. Patients with hereditary nonpolyposis colorectal cancer meeting the Amsterdam criteria, familial adenomatous polyposis, or those receiving preoperative radiotherapy were excluded. Mutator phenotype was assessed by assaying microsatellite instability (MSI) at 24 markers, hMLH1-promoter methylation, mutations at MMR genes (hMLH1, hMSH2, hMSH6, and hPMS2), and immune staining of MMR proteins (hMLH1, hMSH2, hMSH6, hPMS1, and hPMS2). Results: Of the 208 cancers in first-degree and/or second-degree relatives of patients, colorectal and gastric cancers (81%) were most common. Of the 134 proband colorectal cancers, 23 (17%) were MSI in high level, and 32 (24%) were MSI in low level. MMR alterations, including known polymorphism and splicing substitution, were identified in eight patients (6%). Twenty-eight tumors with mutator phenotype were further identified by hMLH1-promoter methylation and/or loss of MMR protein expression. In 51 tumors (38%), mutator phenotype was associated with right-sided colon cancer (P < 0.001) and younger age at onset (P = 0.032), but the number of patients with a mutator phenotype did not differ with respect to inheritance patterns of accompanying cancers, either successive or horizontal transmission (P = 0.815). Familial impact value, which differentially associated the degree of relatives with all accompanying cancers, effectively discriminated MSI in high level from microsatellite stable/MSI in low level tumors. Conclusion: Familial colorectal cancer may be associated with multiple occurrences of colorectal or accompanying cancers inherited by dominant or recessive transmission. MMR gene mutations, however, are less associated with mutator phenotype in familial colorectal cancer.

Non-tuberculous mycobacterial infection of the musculoskeletal system: pattern of infection and efficacy of combined surgical/antimicrobial treatment

Non-tuberculous mycobacterial (NTM) infection of the musculoskeletal tissue is a rare disease. An early and accurate diagnosis is often difficult because of the indolent clinical course and difficulty of isolating pathogens. Our goal was to determine the clinical features of musculoskeletal NTM infection and to present the treatment outcomes. A total of 29 patients (nine females, 20 males between 34 and 85 years old, mean age 61.7 years; 34 to 85) with NTM infection of the musculoskeletal system between 1998 to 2011 were identified and their treatment retrospectively analysed. Microbiological studies demonstrated NTM in 29 patients: the isolates were Mycobacterium intracellulare in six patients, M. fortuitum in three, M. abscessus in two and M. marinum in one. In the remaining patients we failed to identify the species. The involved sites were the hand/wrist in nine patients the knee in five patients, spine in four patients, foot in two patients, elbow in two patients, shoulder in one, ankle in two patients, leg in three patients and multiple in one patient. The mean interval between the appearance of symptoms and diagnosis was 20.8 months (1.5 to 180). All patients underwent surgical treatment and antimicrobial medication according to our protocol for chronic musculoskeletal infection: 20 patients had NTM-specific medication and nine had conventional antimicrobial therapy. At the final follow-up 22 patients were cured, three failed to respond to treatment and four were lost to follow-up. Identifying these diseases due the initial non-specific presentation can be difficult. Treatment consists of surgical intervention and adequate antimicrobial therapy, which can result in satisfactory outcomes.

Clinical implications of mucinous components correlated with microsatellite instability in patients with colorectal cancer

Colorectal cancer (CRC) with microsatellite instability (MSI) is characterized by frequent poor differentiation or mucinous histology. The purpose of this study was to evaluate the association of MSI with clinicopathological features and the oncological outcome in patients with a mucinous component.

Geno- and pheno-typic characterization in ten patients with double-primary gastric and colorectal adenocarcinomas

AbstractBackground and aimsAlthough a number of double-primary gastric and colorectal cancers have been known to correlate with the mutator pathway, a possible association with known hereditary cancers regarding geno-pathogenesis has rarely been investigated. This study was intended to identify a possible association of hereditary cancers and the implications of the mutator or tumor-suppressor pathway in double-primary gastric and colorectal cancers.Materials and methodsFresh colorectal tissues and lymphocytes from ten patients with double-primary gastric and colorectal cancers were obtained consecutively. The mutator pathway was evaluated by detecting hMSH2 and hMLH1 mutations, microsatellite instability (MSI) using 12 microsatellite markers, and hMLH1 promoter region methylation. Protein expressions of hMSH2, hMLH1, APC, E-cadherin, and β-catenin were identified by immune staining.ResultsThere was no pathogenic mutation in any introns or exons of hMSH2, hMLH1 or CDH1, and in exons 3, 5, 6, and 15 of CTNNB1. Either MSI or methylator phenotype was found in five gastric cancers and in four colorectal cancers. No patients met the Amsterdam criteria of hereditary nonpolyposis colorectal cancer (HNPCC) or its equivalent of hereditary gastric cancer. Two patients with gastric cancers among their first-degree relatives showed no E-cadherin expression. The two of the three patients with rectal cancers among their first-degree relatives showed mutator phenotype either in the gastric or in the colorectal cancer. A subset of double-primary gastric and colorectal cancers may thereby be categorized as variant forms of hereditary gastric or colorectal cancer. Both cytoplasmic and nuclear β-catenins were expressed in all gastric and colorectal cancers. Among the gastric and colorectal cancers with either MSI or methylator phenotype, four of five gastric cancers showed both APC and E-cadherin expression, whereas one of four colorectal cancers showed them.ConclusionThis may suggest that the mutator pathway and the aberrant tumor suppressor pathway of the APC-E-cadherin may be cooperative or separately activated in the geno-pathogenesis of double-primary gastric and colorectal cancers.

Utility of quantitative 18F-fluorodeoxyglucose uptake measurement to identify occult tonsillar carcinoma in patients with cervical metastasis of unknown primary tumours: a retrospective case–control study

Due to relatively high 18F‐fluorodeoxyglucose accumulation in the tonsillar region, the detection of occult tonsillar cancers by 18F‐fluorodeoxyglucose positron emission tomography/computerised tomography remains controversial. Therefore, we assessed the usefulness of quantitative tonsil 18F‐fluorodeoxyglucose uptake in identifying occult tonsillar squamous cell carcinoma.

Non-tuberculous mycobacterial infection of the musculoskeletal system

Non-tuberculous mycobacterial (NTM) infection of the musculoskeletal tissue is a rare disease. An early and accurate diagnosis is often difficult because of the indolent clinical course and difficulty of isolating pathogens. Our goal was to determine the clinical features of musculoskeletal NTM infection and to present the treatment outcomes. A total of 29 patients (nine females, 20 males between 34 and 85 years old, mean age 61.7 years; 34 to 85) with NTM infection of the musculoskeletal system between 1998 to 2011 were identified and their treatment retrospectively analysed. Microbiological studies demonstrated NTM in 29 patients: the isolates were Mycobacterium intracellulare in six patients, M. fortuitum in three, M. abscessus in two and M. marinum in one. In the remaining patients we failed to identify the species. The involved sites were the hand/wrist in nine patients the knee in five patients, spine in four patients, foot in two patients, elbow in two patients, shoulder in one, ankle in two patients, leg in three patients and multiple in one patient. The mean interval between the appearance of symptoms and diagnosis was 20.8 months (1.5 to 180). All patients underwent surgical treatment and antimicrobial medication according to our protocol for chronic musculoskeletal infection: 20 patients had NTM-specific medication and nine had conventional antimicrobial therapy. At the final follow-up 22 patients were cured, three failed to respond to treatment and four were lost to follow-up. Identifying these diseases due the initial non-specific presentation can be difficult. Treatment consists of surgical intervention and adequate antimicrobial therapy, which can result in satisfactory outcomes.