Geeta Lal

Accuracy of preoperative localization studies and intraoperative parathyroid hormone assay in patients with primary hyperparathyroidism and double adenoma

BACKGROUND The purpose of this retrospective investigation was to evaluate the results of preoperative localization studies and intraoperative parathyroid hormone (IOPTH) assay in patients with primary hyperparathyroidism and double adenomas. STUDY DESIGN Twenty-one of 287 consecutive patients with primary hyperparathyroidism who had double adenomas identified during first-time parathyroid exploration between July 1999 and September 2002 were analyzed. Individual and combined accuracy of preoperative localization studies, and IOPTH assay and their influence on surgical strategy, were compared. RESULTS Seven percent of these 287 patients had double adenomas. Fifteen of the patients were female and six were male with a mean age of 59 years (range 17 to 76 years). The accuracy of ultrasonography (US) and technetium 99m sestamibi ((99m)TC-sestamibi) was 40% and 30%, respectively, in this select group. Combined accuracy of both tests reached 60% and guided the surgeon to select a bilateral approach. After removal of the first gland, IOPTH failed to decrease by 50% relative to the highest baseline value in 43% of the cases, indicating other hyperfunctioning parathyroid glands. These results prompted the surgeon to explore further after an initially planned focused approach. When the combination of three tests was analyzed, at least one test accurately suggested a double adenoma in 80% of the patients; in 15% of the patients, no test was suggestive of a double adenoma and in 5% the sestamibi scan was false positive. CONCLUSIONS This retrospective investigation documents that neither preoperative localization tests nor IOPTH assay accurately document double adenomas in patients with primary hyperparathyroidism. The combined accuracy of US, sestamibi, and IOPTH assay predicted a double adenoma in 80% of the patients.

Inherited colorectal polyposis and cancer risk of the APC I1307K polymorphism.

Germ-line and somatic truncating mutations of the APC gene are thought to initiate colorectal tumor formation in familial adenomatous polyposis syndrome and sporadic colorectal carcinogenesis, respectively. Recently, an isoleucine-->lysine polymorphism at codon 1307 (I1307K) of the APC gene has been identified in 6%-7% of the Ashkenazi Jewish population. To assess the risk of this common APC allelic variant in colorectal carcinogenesis, we have analyzed a large cohort of unselected Ashkenazi Jewish subjects with adenomatous polyps and.or colorectal cancer, for the APC I1307K polymorphism. The APC I1307K allele was identified in 48 (10.1%) of 476 patients. Compared with the frequency in two separate population control groups, the APC I1307K allele is associated with an estimated relative risk of 1.5-1.7 for colorectal neoplasia (both P=.01). Furthermore, compared with noncarriers, APC I1307K carriers had increased numbers of adenomas and colorectal cancers per patient (P=.03), as well as a younger age at diagnosis. We conclude that the APC I1307K variant leads to increased adenoma formation and directly contributes to 3%-4% of all Ashkenazi Jewish colorectal cancer. The estimated relative risk for carriers may justify specific clinical screening for the 360,000 Americans expected to harbor this allele, and genetic testing in the setting of long-term-outcome studies may impact significantly on colorectal cancer prevention in this population.

Laparoscopic adrenalectomy--indications and technique.

Laparoscopic adrenalectomy has become the procedure of choice for the surgical management of most adrenal tumors, including functional and non-functional lesions. The role of laparoscopic adrenalectomy in the management of malignant adrenal tumors is controversial and most adrenocortical cancers are generally treated by open adrenalectomy. Laparoscopic adrenalectomy can be performed by both the anterior or lateral trans-abdominal approach and by the lateral or posterior retro-peritoneal approach, with each method being suitable for specific indications. Although there are no randomized trials comparing laparoscopic with open adrenalectomy, the laparoscopic approach is associated with shorter hospital stay, reduced pain and improved cosmesis. This review discusses the indications and contraindications, technique and outcomes for laparoscopic adrenalectomy.

Risk of pancreatic cancer among individuals with a family history of cancer of the pancreas

In a hospital based case‐control study of pancreatic cancer in Ontario and Quebec, a total of 174 incident pancreatic cancer cases and 136 healthy controls were compared for their family history of cancer. Information regarding the ages and sites of cancer was taken for 966 first‐degree relatives of the cancer cases and for 903 first‐degree relatives of the controls. A total of 150 cancer cases were reported among the relatives of the cases, compared to 122 cases among the relatives of the controls (relative risk 1.15; p = 0.23). Pancreatic cancer was the only site statistically in excess in the case relatives, compared to the control relatives (relative risk = 5.0; p = 0.01). The lifetime risk of pancreatic cancer was 4.7% for the first‐degree relatives of the pancreatic cancer cases. The risk was 7.2% for relatives of cases diagnosed before age 60, and was 12.3% for relatives of patients with multiple primary cancers (all ages). These individuals comprise a high‐risk group for pancreatic cancer and might benefit from enhanced surveillance or chemoprevention. Familial site‐specific pancreatic cancer appears to be a distinct genetic entity, but contributes only modestly to the total burden of pancreatic cancer.

Familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is a dominantly inherited familial cancer syndrome characterized by an increased predisposition to colorectal cancer and other benign and malignant extra-colonic lesions. FAP has been linked to germline mutations of the adenomatous polyposis coli (APC) gene that encodes a protein with 2,843 amino acids that has important functions in the regulation of cell growth. A genotype-phenotype correlation has also been observed between mutations in the APC gene and polyp phenotype. We review the clinical and genetic features of this disorder and provide information on the diagnostic approaches and treatment options available for this disease.

Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations.

Germline mutations of the CDKN2A tumor suppressor gene have been identified in melanoma kindreds linked to 9p21, and pancreatic adenocarcinoma is the second most common malignancy in some of these families. We hypothesized that unselected patients with both primary cancers, i.e., pancreatic cancer and malignant melanoma, have a genetic predisposition to tumor development, and that this susceptibility may be due to germline CDKN2A mutations. Fourteen patients, with both pathologically verified pancreatic adenocarcinoma and melanoma, were assessed for germline CDKN2A mutations by polymerase chain reaction amplification and sequencing of six overlapping fragments encompassing exons 1α and 2. A yeast two‐hybrid assay was used to assess the functional consequences of CDKN2A variants. Germline CDKN2A mutations were identified in 2/14 patients: I49S, a novel substitution in exon 1α, and M53I, a previously reported missense mutation in exon 2. Both variants lead to compromised CDKN2A function. We conclude that the occurrence of both pancreatic cancer and melanoma, in the same patient, signals an inherited susceptibility to cancer, and that this predisposition is, in some cases, due to germline CDKN2A mutations. This finding has important implications not only for the proband, but also for other family members. Genes Chromosomes Cancer 27:358–361, 2000.

Determinants of survival in patients with calciphylaxis: a multivariate analysis.

BACKGROUND Our study aims to assess the factors affecting survival in patients with calciphylaxis. METHODS We identified 26 patients with biopsy-proven calciphylaxis treated between 1995 and 2007. Clinical and follow-up data were obtained from medical records. Cox proportional hazards models were used to assess the factors affecting survival. RESULTS The study group consisted of 23 women and 3 men with a mean age of 56.4 +/- 12.9 years. All patients had multiple comorbidities/risk factors including coronary artery disease (58%), diabetes mellitus (58%), and peripheral vascular disease (23%). Mean laboratory values were: calcium, 9.0 mg/dL (range, 6.8-11.6); albumin, 2.8 mg/dL; phosphate, 4.5 mg/dL (range, 2.5-7.5); Ca *phosphate, 35.9; and parathyroid hormone, 320.9 pg/mL (range, 4.6-2,419). Parathyroidectomy was performed in 9 of 26 patients (35%). Of our patients, 19% underwent revascularization procedures and 58% underwent debridement. In multivariate analyses, factors associated with poor survival were female gender ( P = .01), increased weight ( P = .01), and need for vascular procedures ( P = .06). Improved survival was associated with operative debridement ( P = .01). Parathyroidectomy alone did not emerge as a determinant of patient survival, although there was a trend to improved survival when debridement and parathyroidectomy were combined ( P = .09). CONCLUSION Rather than a single intervention such as parathyroidectomy, a multidisciplinary approach involving early diagnosis, aggressive medical management, operative debridement, and parathyroidectomy may improve survival in calciphylaxis.

ENG mutations in MADH4/BMPR1A mutation negative patients with juvenile polyposis

To the Editor: Juvenile polyposis (JP, OMIM 174900) is an autosomal dominant syndrome in which affected individuals may develop colonic hamartomatous polyps, upper gastrointestinal (GI) polyps, and a pre-disposition to GI cancer (1–3). Two predisposing genes for JP have been identified thus far, with MADH4 and BMPR1A each accounting for approximately 20% of cases (4–6). Some patients with JP also have hereditary hemorrhagic telangiectasia (HHT) (7, 8). The genes pre-disposing to HHT are ENG (HHT1, OMIM 131195) (9) and ACVR1 (HHT2, OMIM 601284) (10, 11). Both genes are members of the transforming growth factor beta (TGF-b) superfamily, like MADH4 and BMPR1A. Gallione et al. foundMADH4 germline mutations in seven families with both JP and HHT but no mutations of ENG or ACVR1 (12). We previously found no ACVR1 mutations in 32 patients with JP without HHT,MADH4mutation, or BMPR1A mutation (6). Sweet recently reported that 2 of 14 patients with JP had germline ENG mutations and suggested a role for this gene in the causation of JP (13). The objective of this study was to examine the prevalence of ENG mutations in patients meeting the diagnostic criteria for JP who did not have germline mutations ofMADH4 or BMPR1A. All exons and intron–exon boundaries of MADH4 and BMPR1A were sequenced in probands with JP and sporadic cases (6), and in 31 mutation-negative cases, all exons and intron– exon boundaries of ENG were amplified and sequenced. When sequence variants were found, these exons were amplified from a panel of 132 randomly selected individuals and subjected to restriction enzyme digestion, allowing detection of the mutant or wild-type sequence. The results of ENG sequencing are shown in Table 1. One patient with multiple juvenile polyps diagnosed at age of 8 was homozygous for a 14C.T (T5M) substitution. Markers D9S934 and D9S1825 were both heterozygous ( 9 and 3 Mb centromeric to ENG, respectively) and D9S2157 was homozygous in this patient ( 5 Mb telomeric to ENG). A second patient with multiple juvenile polyps diagnosed at the age of 5 was heterozygous for the 14C.T (T5M) mutation. Three of 132 controls digested with SphI also manifested this change. A third patient with multiple juvenile polyps diagnosed at age 9 had a 1096G.C mutation (D366H), which was not found in control samples digested with HgaI. The patients with JP with ENG mutations did not have clinical manifestations, a family history of HHT, or upper GI polyps and had a mean age of 7.4 years (vs 14.4 years for those without ENG mutations). The 14C.T(T5M) substitution has been described in patients with HHT and is believed to be a polymorphism rather than a diseasecausing mutation (14, 15), with an approximately 2% incidence in controls (16, 17). The 1096G.C(D366H) substitution has also been described as a polymorphism in families with HHT (18, 19), with an allele frequency of 0.3–1% of controls (16, 17). Sweet et al. found two ENG mutations in 14 patients with JP found to be negative for MADH4, BMPR1A and PTEN mutations (13). Both patients had an early onset of disease (at ages 3 and 5 years) and no stigmata of HHT. One patient with JP had the change 1538A.G (K531R) and the other 1711C.T (R571C), which were not found in 105 controls, and have not been described in patients with HHT (15). Sweet et al. concluded that these children had a new, genetically defined form of JP. Gallione et al. found that seven probands with both JP and HHT had germline MADH4 mutations, while none had ENG or ACVR1 mutations and suggested that the overlap of JP and HHT phenotypes could be because of the varied effects of perturbing the TGF-b pathway in different cell types (20). The findings of the current study do not confirm the suggestion that ENG is

RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma

Allelotype studies have suggested that chromosome 1p is frequently lost in thyroid cancers, thus suggesting that there is an important tumor suppressor at this location. RIZ1 (PRDM2), located on 1p36, is a recently described tumor suppressor gene and is a member of the protein methyltransferase superfamily. RIZ1 expression is lost in a variety of tumors, primarily by means of epigenetic mechanisms that involve promoter hypermethylation.

Polymorphisms in GSTM1, GSTT1 and CYP1A1 and risk of pancreatic adenocarcinoma

A prospective study of 149 unselected incident cases of pancreatic adenocarcinoma and 146 ethnically-matched controls found no associations between GSTM1 (adjusted odds ratio (AOR) 1.14), GSTT1 (AOR: 1.19) and CYP1A1 (AOR: 1.08) polymorphisms and pancreatic cancer susceptibility. Smoking and drinking status did not affect results. These polymorphisms do not appear to be important gene modifiers in pancreatic cancer.