Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines.

BACKGROUND: Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA-binding enzyme activated by DNA breaks and involved in DNA repair and other cellular processes. Poly(ADP-ribose) polymerase activity can be higher in cancer than in adjacent normal tissue, but cancer predisposition is reported to be greater in individuals with a single-nucleotide polymorphism (SNP) V762A (T2444C) in the catalytic domain that reduces PARP-1 activity. METHODS: To resolve these divergent observations, we determined PARP-1 polymorphisms, PARP-1 protein expression and activity in a panel of 19 solid and haematological, adult and paediatric human cancer cell lines. RESULTS: There was a wide variation in PARP activity in the cell line panel (coefficient of variation, CV=103%), with the lowest and the highest activity being 2460 pmol PAR/10(6) (HS-5 cells) and 85 750 pmol PAR/10(6) (NGP cells). Lower variation (CV=32%) was observed in PARP-1 protein expression with the lowest expression being 2.0 ng microg(-1) (HS-5 cells) and the highest being 7.1 ng microg(-1) (ML-1 cells). The mean activity in the cancer cells was 45-fold higher than the mean activity in normal human lymphocytes and the PARP-1 protein levels were 23-fold higher. CONCLUSIONS: Surprisingly, there was no significant correlation between PARP activity and PARP-1 protein level or the investigated polymorphisms, T2444C and CA.

Amplification in human breast cancer of a gene encoding a c-myc mRNA-binding protein.

The coding region determinant-binding protein (CRD-BP) binds in vitro to c-myc mRNA and is thought to stabilize the mRNA and increase c-Myc protein abundance. The CRD-BP gene has 15 exons and 14 introns, is single-copy, and is located on chromosome 11 in mice and 17 in humans, close to HER-2/neu. The CRD-BP gene is moderately amplified in 12 of 40 human breast cancers; it is highly amplified in 2 others (14.4 and 20 copies). Despite their proximity, CRD-BP and HER-2/neu genes can be amplified independently. Amplification of a gene that might up-regulate c-Myc abundance could accelerate breast cancer.

Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting.

This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

Molecular analysis of transient cytogenetic relapse after allogeneic bone marrow transplantation for chronic myeloid leukaemia.

Serial quantification of residual disease in CML patients after allogeneic BMT is useful for early detection of relapse. However, the fact that some cytogenetic relapses appear to be transient may complicate protocols for early therapeutic intervention based on molecular analysis and could result in the unnecessary treatment of some patients. To determine the frequency and significance of transient cytogenetic relapse, we have studied serial samples from 98 CML patients after allogeneic BMT by conventional cytogenetics and competitive RT-PCR for BCR-ABL mRNA. During the period of study, 26 patients had cytogenetic or haematologic evidence or relapse. In four cases (15% of those who relapsed; 4% of all patients) relapse appeared to be transient; i.e., subsequent marrow samples were completely Ph chromosome-negative despite the fact that there had been no change in treatment, including the level of immunosuppression. BCR-ABL mRNA levels broadly paralleled the cytogenetic findings. Of these four patients, two subsequently progressed to frank haematologic relapse and two remained strongly positive for BCR-ABL transcripts and are therefore presumably still at risk of relapse. Analysis of B cell-enriched, T cell-enriched and lymphoid-depleted fractions for three patients demonstrated that transient relapse was not due to the proliferations of BCR-ABL-positive lymphoid cells. In contrast, BCR-ABL-positive myeloid precursor cells were detected in two of three patients tested. We conclude that transient cytogenetic relapse followed by sustained remission is a relatively infrequent occurrence after current allogeneic transplant regimens.

Sclerosing cervicitis: homologue of sclerosing retroperitonitis and mediastinitis.

The first known case of an invasive, sclerosing fibrosis of the deep soft tissue of the neck is presented. The morbidity, clinical course, and, most importantly, pathological identity with sclerosing retroperitonitis and sclerosing mediastinitis led us to consider this lesion as the cervical homologue of these lesions, ie, sclerosing cervicitis.

Digital subtraction angiography: applications in otolaryngology--head and neck surgery.

Digital electronic technology has made its most notable contribution to radiology in the form of the CT scanners which have so greatly benefited medical practice. Experience with intravenous angiography using a digital fluoroscopy unit developed at the University of Arizona gives promise of a further major benefit in the area of angiography. The majority of examinations are conducted on an outpatient basis with a risk level comparable to that of an intravenous pyelogram. The authors review their experience with this unit, including it's diagnostic and therapeutic applications to congenital and acquired vascular diseases, neoplasms, and vascular trauma of the head and neck.

Infectious facial and nasal cutaneous necrosis: evaluation and diagnosis.

A review of the literature reveals that pyogenic gangrenosum (ecthyma gangrenosum) is fatal to most patients, especially infants. In this article, the authors review the differential diagnosis of facial necrosis, present two cases of infants who succumbed to the systemic manifestations of the disorder, and a third case of survival in an adult with concomitant systemic lupus erythematosus and pyogenic gangrenosum. Finally, a brief discussion of Pseudomonas gastroenteritis, Pseudomonas septicemia, and pseudomembranous enterocolitis is presented.

The growth of cartilage from a free perichondrial graft in the larynx.

An attempt was made to promote the growth of new cartilage from a frlage. Three dogs had the perichondrial grafting alone, while two had both the perichondrial grafting and a full thickness buccal mucosal graft. In all these dogs new cartilage was found as early as four weeks postoperative.

Mucosal melanoma of the head and neck.

Nine cases of primary malignant melanoma of the upper respiratory tract treated at the University Hospital over the past 10 years are presented. Of the 9 cases, 6 had primary lesions located in the nasal cavity with the remaining 3 presenting in the nasopharynx, hard palate, and larynx, respectively. The authors review presenting symptoms, diagnostic evaluation, current therapeutic modalities, and clinical course in these cases. Specific cases are discussed to emphasize items of clinical or therapeutic importance.

Retropharyngeal abscess--a ten-year experience.

The authors present an extensive review of current literature as well as their ten-year experience in management of patients with retropharyngeal abscesses. Emphasis is placed upon age, sex, type and duration of symptoms, bacteriology, methods of diagnosis, therapy, and complications. The authors' series reveals that retropharyngeal abscesses are found in adults, there is a wide spectrum of bacteriological organisms represented, and with appropriate antibiotic and surgical management the majority of patients survive without major residual sequelae.

Radiation therapy for paragangliomas of the temporal bone.

Treatment of paragangliomas of the temporal bone (glomus jugulare and glomus tympanicum tumors) is controversial, with both surgery and radiation therapy having their advocates. This paper discusses the experience at the University of Arizona Health Sciences Center in treating 10 cases of this uncommon tumor between 1971 and 1988. Seven of 10 cases were initially treated using irradiation and achieved complete tumor control for a mean of 67 months (range = 23-107 months). Two patients, one treated surgically and the other by embolization, had recurrences and were salvaged by radiation, and neither has recurred. The final patient is disease-free 9 months after embolization and surgery. There have been no serious sequelae of treatment. We conclude that moderate-dose irradiation can safely control most temporal bone paragangliomas.

Laryngeal involvement in disseminated coccidioidomycosis.

Coccidioidomycosis is a pulmonary fungal infection endemic to the desert southwest of the United States and northern Mexico. Rarely (0.5% of cases), the fungus disseminates widely, causing life-threatening complications. Seven percent of these cases will involve the head and neck. We report a case of disseminated coccidioidomycosis that involved the larynx and cervical lymph nodes in a 40-year-old white woman who presented with hoarseness and unsuspected airway compromise. Review of the 12 reported cases of laryngeal coccidioidomycosis showed a predominance of male and dark-skinned patients; seven were children, and nine presented with airway compromise. Other reported sites of head and neck involvement include the skin, mucosa, bones of the skull, and meninges, and there have been reports of abscesses of the soft tissues and fascial spaces of the neck.

Radiation therapy for squamous cell carcinoma of the supraglottic larynx.

Sixty-five patients with invasive squamous cell carcinoma of the supraglottic larynx received irradiation with curative intent between 1975 and 1984, with a 5-year actuarial survival of 48% and a local control rate of 70%. Five-year survivals for clinical Stages I, II, and III + IV were 60, 53, and 52%, respectively; local control rates were 88, 76, and 63%, respectively. These patients included one treated with preoperative irradiation, 35 treated with surgery followed by postoperative irradiation, and 29 treated with radiation therapy alone. In the surgery plus irradiation group, 5-year local control was 93% for clinical Stages I + II (14 patients), and 61% for clinical Stages III + IV (21 patients). Three patients had pathologic Stage II disease, with the remainder demonstrating a higher pathologic than clinical stage. Multiple positive nodes predisposed to local/regional recurrence, while no relationship could be established between recurrence and extracapsular nodal spread, positive margins, emergency tracheostomy, total versus less-than-total laryngectomy, radiation field size, radiation dose, or delay until radiation therapy, probably because of patient numbers. Six patients, five with positive nodes, developed distant metastases, and three developed second primary tumors outside the head and neck region. In the radiation therapy alone group, 5-year local control rates were 86, 59, and 53% for clinical Stages I (7 patients), II (11 patients), and III + IV (11 patients), respectively. However, three of four Stage II local/regional failures were surgically salvaged for periods greater than 30 months, for an ultimate Stage II local control of 89%. No relationship could be established between local control and radiation dose or field size, again probably because of small patient numbers. Three patients developed distant metastases, and eight developed second malignancies, one within the irradiated volume. Fifteen patients developed acute toxicity during irradiation, and there were eight chronic complications, five requiring surgery; toxicity was more common in the group treated with radiation alone. Radiation therapy alone with surgical salvage is an effective, function-preserving treatment for clinical Stages I and II carcinoma of the supraglottic larynx, and appears to yield local control and survival comparable with that of combined irradiation and surgery in more advanced disease.

Low-dose radiation therapy for benign salivary disorders.

Two patients, one with a persistent salivary fistula after surgery for a skin tumor overlying the parotid region, and the other with a ranula recurrent after surgery, were treated with low-dose irradiation. Both problems resolved after a total dose of less than 30 Gy, and neither patient experienced xerostomia. In selected patients, low-dose radiation therapy offers a solution to persistent salivary flow refractory to surgical management.

The use of denaturing high-pressure liquid chromatography for the detection of mutations in thiopurine methyltransferase.

The level of expression of the enzyme thiopurine methyltransferase (TPMT) is an important determinant of the metabolism of drugs used both in the treatment of acute leukaemia (6-mercaptopurine and 6-thioguanine) and as an immunosuppressant in patients with autoimmune diseases or following organ transplantation (azathioprine). Studies of enzyme activity in red blood cells have shown that TPMT expression displays genetic polymorphism with 11% of individuals having intermediate and one in 300 undetectable levels. Patients with biallelic mutations and undetectable enzyme activity suffer life-threatening myelosuppression when treated with conventional doses of these drugs. Patients with intermediate activity have an increased risk of drug-associated toxicity. In the Caucasian populations studied to date, intermediate activity is associated with mutations at two sites of the TPMT gene, G460A and A719G (designated TPMT*3A), in 80% of cases. Detection of these mutations has, to date, been based on the analysis of restriction digests of PCR products. In order to simplify this process we have investigated the ability of denaturing high pressure liquid chromatography (DHPLC) to detect the A719G mutation. DHPLC of PCR products from 15 known heterozygotes (TPMT*3A/TPMT*1) and 18 known homozygotes (TPMT*1/TPMT*1) gave a clear pattern difference between the groups and 100% concordance with the results of restriction digests. These results suggest DHPLC represents a valuable technique for accurate and rapid detection of pharmacologically important mutations in the TPMT gene.

Sleep apnea syndrome associated with a neck mass.

Sleep apnea is an entity that is becoming more commonly diagnosed as the signs and symptoms are becoming better understood. In this report, the first known case of sleep apnea secondary to a lipoma of the submandibular area of the neck is presented. A brief discussion of the types of sleep apnea, along with the most common signs and symptoms of the entity, are reported. The diagnostic workup, operative findings, and postoperative results in this patient are discussed.

Complications of carotid artery replacement in head and neck neoplasms.

Carotid artery involvement by neoplastic disease has grave prognostic implications. However, with the advent of postoperative radiation therapy and chemotherapy, carotid artery sacrifice and replacement is more widely performed. In this report the authors discuss their experience with preoperative and intraoperative evaluation of cerebral blood flow and complications of carotid artery replacement.

Metastatic disease of the parotid gland.

Metastatic lesions of the parotid gland represent the spread of a neoplasm from the primary site to parotid paraglandular, intraglandular, or parenchymal locations. These lesions are frequently difficult to differentiate from primary parotid gland neoplasms. The most common histologic type of neoplasm that metastasizes to the parotid gland is the melanoma. The melanoma is generally found superficial in its metastatic spread. Squamous cell carcinoma is also frequently found, but is usually intraglandular in its metastatic pattern. Although the melanoma and squamous cell carcinoma represent 80 per cent of the metastatic lesions involved in the parotid gland, a variety of other histologic types have been reported. The surgeon must be ready to deal with this complex problem when he enters into an exploratory operation. Even though vigorous treatment is carried out, the histologic types of neoplasms and the anatomic complexities of the area contribute to survival rates between 10 and 15 per cent over a five year period.

Sialadenitis in children.

Sialadenitis in children has been discussed. A literature review highlighting salient points in sialadenitis is presented. Classification of sialadenitis is discussed using the categories of several authors. An unusual case involving acute suppurative parotitis in a child is presented. The development of contralateral disease while treatment was in progress was unusual. In this case, association with mumps parotitis was strongly suspected despite previous immunization. Progression of disease with abscess formation is also unusual. Mumps virus parotitis has been rarely reported in association with acute suppurative parotitis. Immunization affords protection, but a definite failure rate exists. Based upon histologic examination, mumps parotitis would seem to be a predisposing factor for bacterial infection.

The clinical impact of thiopurine methyltransferase polymorphisms on thiopurine treatment.

Acute lymphoblastic leukaemia (ALL) is the most common malignancy of childhood. Although current treatment results in long term survival in over 70% of cases there is evidence that as many as 50% could have been cured using a less complex regimen with a lower incidence of long term side effects. In previous studies it has been found that thiopurines given as part of continuing therapy are key agents in preventing relapse. However, optimal administration during continuing therapy is often not achieved. Variation in the level of thiopurine methyltransferase (TPMT) activity appears to be a major molecular determinant of the extent of thiopurine metabolism. TPMT activity shows a trimodal distribution pattern. A lack of activity is found in approximately one in 300 Caucasians; approximately 11% have intermediate activity and the remaining 89% high activity. Congenital loss of activity is associated with grossly elevated levels of active drug and profound myelosuppression on exposure to thiopurines. This loss of activity has been attributed to single nucleotide polymorphisms (SNPs) within the TPMT gene. The frequency of SNPs is related to ethnicity, with the most common in Caucasians being TPMT*3A which is characterized by a G to A transition at position 460 with a substitution of alanine for tyrosine at amino acid 154 (A154Y) and a transition of A to G at nucleotide 719 resulting in a change of tyrosine to cysteine at position 240 (Y240C). Polymorphisms have also been identified within the 5' flanking promoter region of the TPMT gene due to a variable number of tandem repeats (VNTR*3-*8). An overview of the polymorphisms identified to date, their implication on the metabolism of the thiopurine drugs and therapeutic importance will be discussed.