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R B Jenkins

Publications and source records attributed to R B Jenkins.

At least 91 records · Page 5Linked to original sources
PubMed1996

Absence of mutations in DNA mismatch repair genes in sporadic endometrial tumors with microsatellite instability.

DNA mismatch repair genes have been reported to play a role in the pathogenesis of hereditary nonpolyposis colorectal cancer (HNPCC). Mutations of DNA mismatch repair genes have accounted for 90% of HNPCC-related colon and endometrial tumors. These mutations have been associated with microsatellite instability (MIN). Because endometrial cancer (EC) is the most common extracolonic malignancy associated with HNPCC, we hypothesized that similar molecular alterations may occur in sporadic endometrial tumors exhibiting MIN. Mutational analysis of the MSH2 and MLH1 genes was undertaken in sporadic EC that demonstrate MIN to determine the role of these genes in the pathogenesis of sporadic ECs. Established microsatellite markers were used to determine the incidence of MIN from 28 patients with sporadic EC. MIN was observed in 32% (9 of 28) of the tumor specimens analyzed. Mutational analysis of MSH2 and MLH1 genes was performed by immunohistochemical analysis and direct sequencing of tumor specimens that exhibited MIN. All 28 tumor specimens exhibited strong nuclear staining with both MSH2 and MLH1 antibodies, suggesting the absence of mutations. Sequencing of all exons of both the MSH2 and MLH1 genes in the nine MIN-positive tumor specimens demonstrated no mutations. We conclude that the MSH2 and MLH1 genes do not play a role in the pathogenesis of sporadic endometrial cancer.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Chromosome-specific aneusomy in carcinoma of the breast.

Fluorescence in situ hybridization was performed on touch preparations from 55 primary infiltrating ductal carcinomas of the breast to determine numeric chromosome abnormalities. The frequency of aneusomy, measured by both nondisomy and chromosomal gain, was determined for chromosomes X, 4, 6-12, 17, and 18 with the use of chromosome-specific, alpha-satellite DNA probes. The presence of chromosome-specific numeric abnormalities was correlated with established clinicopathological parameters, including tumor size, lymph node involvement, tumor grade, estrogen receptor level, and menopause status. In addition, a case-control study was performed to explore a possible association between chromosome-specific aneusomy and recurrence in lymph-node-negative patients. Although chromosomes 8 and 6 were most frequently aneusomic, numeric abnormalities of chromosomes 4 and 11 were most strongly associated with established prognostic factors. For chromosomes 4 and 11, strong associations were found with tumor involvement of lymph nodes and increased tumor size, along with a weaker association with tumor grade. In addition, numeric abnormalities of the following chromosomes were associated with the corresponding prognostic factors: chromosomes X, 7, and 12 with lymph node status; chromosomes 10, 17, and 6 with tumor size; and chromosomes 7, 12, 17, and X with tumor grade. No correlations were observed with estrogen receptor level or menopause status. In the case-control study performed on isolated nuclei of paraffin-embedded tissue from lymph node-negative breast cancer patients (19 cases and 19 controls), the gain of chromosome 4 was correlated with disease progression. These findings suggest that chromosome-specific aneusomy is associated with certain established prognostic factors and may be associated with disease progression.

Adult↗
PubMed1995

Chromosomal anomalies in prostatic intraepithelial neoplasia and carcinoma detected by fluorescence in situ hybridization.

The pathogenetic relationship between high-grade prostatic intraepithelial neoplasia (PIN), prostatic carcinoma, and metastases is poorly understood. We used fluorescence in situ hybridization (FISH) with centromere-specific probes for chromosomes 7, 8, 10, 12, and Y to evaluate numeric chromosomal anomalies in PIN (68 foci), localized prostatic carcinoma (78 foci), and lymph node metastases (8 foci) in 40 whole-mount radical prostatectomy and pelvic lymphadenectomy specimens. Chromosomal anomalies were found in 50, 51, and 100% of the foci of PIN, carcinoma, and metastases, respectively. The mean numbers of abnormal chromosomes per focus were 0.66 in PIN, 1.09 in carcinoma, and 3.75 in metastases. The most frequent anomaly in PIN was a gain of chromosome 8 (32% of foci), followed by gains of chromosomes 10 (13%), 7 (10%), 12 (4%), and Y (4%). The most frequent anomalies in foci of carcinoma were gains of chromosomes 7 and 8 (28% and 30% of foci, respectively), followed by gains of chromosomes 10 (23%), 12 (9%), and Y (9%). There was a positive correlation of the gain of chromosome 8 with the pathological stage and Gleason score (both P < 0.05). Usually, carcinoma foci contained more anomalies than paired PIN foci, but five prostates contained one or more foci of PIN with more anomalies than carcinoma. Among the cases with metastases, usually one or more foci of the primary tumor shared chromosomal anomalies with the matched metastases. Our results indicate that PIN and prostatic carcinoma foci have similar proportions of chromosomal anomalies, but foci of carcinoma usually have more alterations. This observation supports the hypothesis that PIN is often a precursor of carcinoma, although there are some carcinoma foci that have few or no apparent chromosomal alterations, whereas concurrent PIN foci have multiple alterations. A gain of chromosome 8 was the most common numerical alteration and was associated with increasing cancer stage and grade, suggesting that it may play a role in the initiation and progression of prostatic carcinoma. Usually, one or more foci of the primary tumor shared chromosomal anomalies with associated lymph node metastases, suggesting that, often, just a single focus of carcinoma gives rise to metastases.

Aged↗
PubMed1995

Frequent loss of heterozygosity at 7q31.1 in primary prostate cancer is associated with tumor aggressiveness and progression.

Cytogenetic analyses have demonstrated that chromosome region 7q22-32 is commonly altered in prostate adenocarcinomas. In addition, in recent fluorescence in situ hybridization studies, we have observed that aneusomy of chromosome 7 is frequent in prostate cancer and is associated with higher tumor grade, advanced pathological stage, and early prostate cancer death. These findings suggest that genetic alterations of chromosome 7 play a significant role in the development of prostate cancer. To better define the chromosome 7 alterations, PCR analysis of 21 microsatellite loci was performed on 54 paired prostate cancer and control DNAs. Overall, chromosome 7 allelic imbalance was identified in 16 of 54 cases (30%). Allelic imbalances of loci mapped to 7q were observed in 15 of the 16 cases. The allelic imbalances were classified as losses in 15 tumors (28%) and as gains in 1 (2%) by comparative multiplex PCR analysis. The most common site of allelic loss included loci D7S523 and D7S486 at 7q31.1. A comparison with clinicopathological features of the tested tumors revealed that the allelic loss of 7q31.1 correlated with higher tumor grade (P = 0.012) and lymph node metastasis (P = 0.017). These results indicate that 7q31 may be the site of a putative suppressor gene(s) important for the pathogenesis of prostate carcinoma, and that the genetic alterations at 7q31.1 may participate in tumor progression and metastasis.

Alleles↗
PubMed1995

Uniparental disomy in congenital disorders: a prospective study.

Whole chromosome uniparental disomy (UPD) for several different chromosomes has been described in individuals with phenotypes that encompass a broad range of abnormalities. We prospectively searched for UPD in 25 cytogenetically normal individuals who had one or more of the following features: nonsyndromic multiple congenital anomalies, short stature, mental retardation, or dysmorphic findings. Using highly polymorphic microsatellite repeats, biparental inheritance of at least one locus on every chromosome was found in every individual and uniparental inheritance was not detected at any locus. If UPD does exist in this clinical setting, its frequency is less than 13.7% (95% confidence interval). Our data indicate that additional studies will be required to determine the true incidence of UPD in this population.

Abnormalities, Multiple↗
PubMed1995

A translocated erythropoietin receptor gene in a human erythroleukemia cell line (TF-1) expresses an abnormal transcript and a truncated protein.

We previously identified a translocation breakpoint in exon 8 of the erythropoietin receptor (EpoR) gene in TF-1 cells, a cell line derived from a human erythroleukemia. To investigate the potential pathogenetic significance of this abnormality, we more precisely mapped the breakpoint within exon 8 and studied the expression of the translocated gene by S1 nuclease mapping of EpoR transcripts and chemical crosslinking of labeled erythropoietin (Epo) to TF-1 cell surface receptors. Transcripts from the abnormal gene were found to be highly expressed in relation to normal EpoR transcripts in TF-1 cells. The breakpoint predicted by S1 mapping of abnormal EpoR transcripts agreed closely with that determined by Southern analysis. Chemical cross-linking of 125I-Epo to TF-1 cells showed an abnormal, low-molecular-weight cross-linked species directly recognized by anti-EpoR antibodies and present in considerable excess over the normal EpoR. Karyotype analysis showed that each of 10 TF-1 cell metaphases had, in addition to multiple other alterations, one chromosome 19 with additional chromosomal material translocated onto the short arm at 19p13.3, the location of the EpoR gene. We conclude that the structurally abnormal EpoR gene in TF-1 cells is highly expressed and produces an abnormal protein. We speculate that the chromosomal material brought into the EpoR locus by translocation is responsible for the high level of expression. We hypothesize that this translocation participated in the evolution of the erythroleukemia from which TF-1 cells were derived.

Base Sequence↗
PubMed1995

Region-specific loss of heterozygosity on chromosome 19 is related to the morphologic type of human glioma.

Allelic mutation on chromosome 19 has previously been reported as a frequent genetic event in human glial tumors. In an effort to localize specific regions of importance on this chromosome better, 13 highly polymorphic genetic markers distributed along the length of chromosome 19 were used for evaluation of loss of heterozygosity (LOH) and microsatellite instability in a total of 100 brain tumors, including 75 astrocytomas (55 grade 4; 7 grade 3; 5 grade 2; 6 grade 1; and 2 other), 17 oligodendrogliomas (1 grade 4; 5 grade 3; 10 grade 2; and 1 grade 1), and 8 mixed oligoastrocytomas (MOA) (3 grade 4; 2 grade 3; and 3 grade 2). No microsatellite expansion was observed in these glial tumors for any of the chromosome 19 loci examined. LOH for loci on chromosome 19 was detected in 23/74 informative astrocytomas (31%), 11/17 oligodendrogliomas (65%), and 3/8 MOA (38%). Partial deletion of chromosome 19 occurred more frequently (31/37 cases) than did loss of one whole copy of the chromosome, and a morphology-specific pattern of LOH was observed. In 12/14 (86%) instances of chromosome 19 deletion in oligodendrogliomas and MOA, the 19q arm showed LOH, whereas the 19p arm showed no loss for all informative loci. Conversely, in 17/23 (74%) instances of chromosome 19 deletion in astrocytomas, the 19p arm showed LOH, whereas the 19q arm showed no loss for one or more loci. Thus, loss of 19q and retention of 19p are strongly associated with oligodendroglioma and MOA, whereas loss of 19p and retention of distal 19q is associated with astrocytoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Chromosomal anomalies in atypical adenomatous hyperplasia and carcinoma of the prostate using fluorescence in situ hybridization.

OBJECTIVES: The genetic alterations of atypical adenomatous hyperplasia (AAH) of the prostate, a possible precursor of prostate adenocarcinoma, have not been previously investigated. METHODS: We used fluorescence in situ hybridization with centromere-specific probes for chromosomes 7, 8, 10, 12, and Y to evaluate chromosomal anomalies in atypical adenomatous hyperplasia (23 foci) and adenocarcinoma (31 foci) in 19 whole-mount radical prostatectomy specimens. RESULTS: Chromosomal anomalies were found in 2 foci (9%) of AAH and 17 foci (55%) of carcinoma. There was no relationship between the chromosomal anomalies in AAH and matched foci of carcinoma. CONCLUSIONS: These findings indicate that AAH is not obviously linked genetically to prostate cancer, although it occasionally contains chromosomal anomalies.

Adenocarcinoma↗
PubMed1995

Intraneural perineurioma. A clonal neoplasm associated with abnormalities of chromosome 22.

The nature of perineurioma, variably termed "localized hypertrophic neuropathy," "intraneural neurofibroma," and "hypertrophic interstitial neuritis" has long been an issue of contention. Most authors consider it a neoplasm, but some a reactive process. Eight clinically and morphologically typical perineuriomas were studied by histologic, immunohistochemical and ultrastructural methods. One perineurioma was subject to tissue culture and cytogenetic study and another to fluorescence in situ hybridization (FISH) analysis. The patients, 3 males and 5 females, ranged in age from 11 to 38 years. All tumors were intraneural, and involved extremities (2 sciatic, 1 median, 1 femoral, 1 peroneal, 1 brachial plexus, 1 ulnar, and 1 radial). Neurologic symptoms, motor in all cases and sensory in 4, were present from 1 month to 7 years (mean 1.2 years). Fusiform, segmental nerve enlargement was clinically apparent in only two patients, but was evident on MRI in five of eight patients. Lesion length ranged from 3.5 to 30 cm, the largest involving the sciatic nerve from the obturator foramen to the knee. One lesion involved two nerve roots, but no association with a phakomatosis was noted. Treatment consisted of biopsy in six cases and resection in two cases. Histologically, pseudo-onion bulbs composed of epithelial membrane antigen-reactive, S-100 protein-negative perineurial cells surrounded myelinated or nonmyelinated nerve fibers. Many were accompanied by their S-100 protein-positive Schwann sheaths. Some whorls lacked a central axon. A single mitosis was noted in one case. The MIB-1 antigen labelling index ranged from 4% to 17%. Staining for p53 antigen in six cases showed no (2 of 6), rare (2 of 6), or scattered (2 of 6) immunoreactive nuclei. Cytogenetic analysis in one case demonstrated a chromosomally abnormal clone. Each of 16 metaphases was abnormal; the tumor cells appeared to be homozygously deficient for the region 22q11.2qter. In another case, 53% of interphase nuclei showed three FISH signals with a chromosome 14/22 probe, thus suggesting either monosomy for the centromere of chromosome 14 or that of chromosome 22.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1995

Use of fluorescence in situ hybridization to detect loss of chromosome 10 in astrocytomas.

Models describing progression in the genetic derangement of glial tumors have shown loss of chromosome 10 to occur most frequently in high-grade lesions, suggesting that identification of this loss may be prognostically significant. Fluorescence in situ hybridization (FISH) analysis may be a valuable adjunct to histological grading if it can accurately detect this loss. In this paper, the authors correlate results obtained from FISH, cytogenetic, molecular genetic, and flow cytometric analyses of a series of 39 brain specimens, including seven normal, two gliotic, and 30 neoplastic (one Grade II, one Grade III, and 28 Grade IV astrocytoma) specimens. Contiguous section of freshly resected surgical tissue were submitted for tissue culturing (karyotype) and touch preparation (FISH), snap-frozen (molecular genetic), or paraffin-embedded (histology and flow cytometry). Centromere-specific probes for chromosomes 10 and 12 were used for FISH analysis, and 19 restriction fragment length polymorphisms (two p-arm and 17 q-arm) and four microsatellite sequence polymorphisms (three p-arm and one q-arm) were used for molecular genetic analysis of chromosome 10. Findings showed FISH and loss of heterozygosity (LOH) analyses to be concordant in 33 of 38 specimens (sensitivity 94%, specificity 81%), with one specimen indeterminate on LOH analysis. Both FISH and LOH analyses were more sensitive at detecting chromosome 10 loss than conventional cytogenetic (karyotype) analysis. The authors conclude that FISH is a sensitive test for detecting chromosome 10 loss and ploidy in astrocytic tumors.

Adolescent↗
PubMed1994

Prognostic factors in gliomas. A multivariate analysis of clinical, pathologic, flow cytometric, cytogenetic, and molecular markers.

BACKGROUND: The ability to divide subsets of patients with glial neoplasms into prognostic groups currently is limited because only a few clinical and pathologic variables are available. The goal of this investigation was to identify biologic factors of potential prognostic value in patients with cerebral gliomas. METHODS: This prospective investigation used clinical, pathologic, flow cytometric, cytogenetic, and molecular genetic variables as potential prognostic factors in 207 patients with newly diagnosed gliomas (153 astrocytic tumors of the fibrillary type, 31 oligodendrogliomas, and 23 pilocytic astrocytomas). Classification and regression tree (CART) analysis was performed as part of the multivariate statistical analysis. RESULTS: The age of the patient and the grade of the tumor were confirmed as strong prognostic factors. Cytogenetic or molecular genetic abnormalities of chromosomes 7 and 10 were associated with poor survival in univariate analysis (P < 0.0001). CART multivariate analysis identified several subsets of patients with different prognoses. In the subset of patients younger than 66.5 years with Grade 4 tumors, the survival time was longer for those with aneuploid tumors than for those with nonaneuploid tumors. In the subset of patients with Grades 1-3 tumors, the survival time was longer for those whose tumors had a %G2M of less than 6.9 than for those whose tumors had a %G2M of 6.9 or greater. CONCLUSION: This investigation provides further evidence that flow cytometry, cytogenetic, and molecular genetic factors that may have prognostic value in patients with gliomas can be identified.

Adult↗
PubMed1994

Aneuploidy and aneusomy of chromosome 7 detected by fluorescence in situ hybridization are markers of poor prognosis in prostate cancer.

Fluorescence in situ hybridization is a new methodology which can be used to detect cytogenetic anomalies within interphase tumor cells. We used this technique to identify nonrandom numeric chromosomal alterations in tumor specimens from the poorest prognosis patients with pathological stages T2N0M0 and T3N0M0 prostate carcinomas. Among 1368 patients treated by radical prostatectomy, 25 study patients were ascertained who died most quickly from progressive prostate carcinoma within 3 years of diagnosis and surgery. Tumors from 25 control patients who survival for more than 5 years and who were matched for age, tumor histological grade, and pathological stage also were evaluated. The tumors from all 25 (100%) poor prognosis patients and from 11 of 25 (44%) control patients were found to be aneuploid by fluorescence in situ hybridization (P < 0.0001). Alterations of chromosome 7 were observed in 24 of the tumors (96%) from the poor prognosis patients versus 3 tumors (12%) from the control group (P < 0.0001). Moreover, a characteristic aneuploidy pattern with multiple abnormal chromosomes and a hypertetrasomic population was generally found in tumors from the poor prognosis patients. This preliminary study suggests that fluorescence in situ hybridization studies of prostate cancer specimens may help to identify those patients at highest risk for early cancer death.

Aged↗
PubMed1994

Potential markers of prostate cancer aggressiveness detected by fluorescence in situ hybridization in needle biopsies.

Fluorescence in situ hybridization (FISH) with centromere-specific probes for chromosomes 7, 8, 11, and 12 was used to evaluate multiple 18-gauge needle biopsy cores from 50 randomly selected radical prostatectomy specimens. FISH analysis detected 26 diploid (52%), 7 tetraploid (14%), and 17 aneuploid tumors (34%). The FISH results were concordant with flow cytometric (FCM) DNA content measurements of the corresponding prostatectomy specimens for 31 tumors. For the 19 FISH/FCM discordant tumors, FISH was more sensitive than FCM for detecting ploidy anomalies. Common numerical chromosome alterations were gains of chromosomes 7 and 8, which were found in 13 (76%) and 10 (59%) aneuploid tumors, respectively. Gain of chromosome 7 was strongly associated with higher Gleason score (> or = 8) (P < 0.0001) and with advanced tumor pathological stages (stages T3 + T4; P < 0.01). Gain of chromosome 8 also correlated with higher Gleason score (P < 0.01). FISH showed intratumoral ploidy heterogeneity in 3 of 41 (7%) studied tumors. Among 17 noncancerous adjacent tissue specimens, chromosome alterations were observed in one, which contained high-grade prostatic intraepithelial neoplasia. Combined FISH and fluorescent leukocyte common antigen staining showed that infiltrating leukocytes do not contribute to the observed gains of chromosomes 7 and 8 in prostate cancer tissue. These results demonstrate that (a) FISH analysis of prostate needle biopsy-sized specimens can be a practical, sensitive method for determination of nuclear ploidy and numerical chromosome alterations; and (b) gains of chromosomes 7 and 8 are common numerical alterations of prostate cancer cells and may be potential markers of tumor behavior and patient prognosis.

Biopsy, Needle↗
PubMed1994

Evidence of functional RB protein in epithelial ovarian carcinomas despite loss of heterozygosity at the RB locus.

The presence of retinoblastoma (RB) protein was evaluated by immunohistochemical staining and correlated with loss of heterozygosity (LOH) at the RB locus in 52 primary epithelial ovarian carcinomas. Forty-eight tumors were informative at the RB locus by molecular genetic analysis. Twenty-five tumors (52%) showed loss of heterozygosity at the RB locus. RB protein expression was found in 23 of these tumors. The remaining two tumors were negative for RB protein product by immunohistochemical staining. All 23 tumors showing no LOH at the RB locus had a normal RB protein pattern. All but three tumors revealed either no LOH with any marker or, if LOH was found for one chromosome 13 marker, all other informative markers also showed LOH. The three recombinant tumors included two which retained alleles at one or more loci distal and one which retained alleles proximal to the RB locus. LOH at the RB locus was significantly more common in invasive high-grade (grades 3 and 4) tumors as compared to invasive low-grade (grades 1 and 2) tumors (P < 0.001). Our data suggest that while molecular genetic studies reveal frequent LOH at the RB locus, particularly in high-grade tumors, normal RB protein expression is present in the majority (96%) of these tumors. This implies that another, unidentified, gene or genes located on chromosome 13 may be important in the progression of most epithelial ovarian carcinomas. Additionally, it is likely that the specific chromosome 13 alteration(s) associated with sporadic ovarian neoplasms will be extremely difficult to identify using allelic loss and deletion mapping studies.

Epithelium↗
PubMed1994

Comparative genomic hybridization, allelic imbalance, and fluorescence in situ hybridization on chromosome 8 in prostate cancer.

Due to problems with primary tumor cell culture, conventional cytogenetics has yielded little insightful information on chromosomal alterations in prostate cancer. The primary aim of this study was to define the ability of comparative genomic hybridization (CGH) to detect and map genetic deletions in prostate tumors. A secondary aim was to apply multiple assays to individual tumors as a means of deciphering the mechanisms of genetic alterations in prostate cancer. CGH results were compared with allelic imbalance measurements at 29 distinct loci on chromosome 8 in 18 specimens (17 malignant and 1 benign). CGH detected no changes in cases where all informative PCR/RFLP loci were retained and detected all p arm deletions consisting of at least two loci. We estimate that in this study, the smallest deletions detected by CGH were approximately 20-30 cM. Physical mapping of subchromosomal arm deletions by CGH correlated well with allelic imbalance mapping by PCR/RFLP: The data agreed at 88% of loci on 8p and 92% of loci on 8q. Fluorescence in situ hybridization (FISH) with multiple centromere probes and DNA content flow cytometry (FCM) also was performed on selected specimens. FISH revealed two cases of chromosome 8 aneusomy. In these two cases and three others, CGH showed simultaneous p arm deletion and q arm gain, suggesting isochromosome 8q formation. Together, these data suggested that, simple chromosomal aberrations were responsible for allelic losses on 8p and allelic gains on 8q in a significant number of prostate tumors. We also used CGH to examine relative DNA sequence copy number throughout the genome. Changes frequently associated with 8p loss include gains of 8q and losses of 13q, 16p, 16q, 17p, 17q, 20q, and Y. Cases with 8p loss exhibited five times the number of alterations as did cases without 8p loss.

Alleles↗
PubMed1994

Comparison of fluorescence in situ hybridization with flow cytometry and static image analysis in ploidy analysis of paraffin-embedded prostate adenocarcinoma.

Nuclear DNA ploidy has been shown to have an important prognostic association for patients with adenocarcinoma of the prostate. Flow cytometry and static image analysis are ploidy methods that have been used in prostate carcinoma. Fluorescence in situ hybridization (FISH) using chromosome-specific probes can be used to evaluate the ploidy of interphase nuclei. In this study FISH was compared with flow cytometry and static image analysis in determining ploidy in paraffin-embedded tissue from 34 prostatic adenocarcinomas. Ploidy status using FISH was determined by enumerating centromeres of two chromosomes (8 and 12) by use of directly-labeled alpha-satellite DNA probes in isolated whole nuclei obtained by the Hedley technique. All three methods identified 11 of 34 cases as diploid and 17 of 34 cases as nondiploid (82% concordance). Six cases were discordant; two cases had discrepant results by each method. Ploidy classification as determined by FISH had an 88% concordance with ploidy classification by either flow cytometry or static image analysis. In conclusion, FISH was found to be a sensitive method of ploidy analysis in isolated paraffin-embedded nuclei from prostate adenocarcinomas. When the chromosomes commonly involved in aneuploidy have been identified in prostate adenocarcinoma, FISH has the potential to provide greater sensitivity for aneuploidy detection compared with currently available methods.

Adenocarcinoma↗