Long-term survival with stage IV poorly differentiated pancreatic adenocarcinoma.

BACKGROUND: Metastatic poorly differentiated adenocarcinoma of the pancreas has a poor outcome despite the use of various chemotherapy regimes. CASE OUTLINE: A 57-year-old woman presented with a 3-month history of generalised abdominal pain associated with weight loss. Computed tomography (CT) showed a large tumour in the head and body of pancreas, and needle biopsy confirmed a poorly differentiated adenocarcinoma. Laparoscopy revealed liver metastases in both lobes, again histologically shown to be poorly differentiated adenocarcinoma. Six cycles of cisplatin, epirubicin and infusional 5-fluorouracil were given. Five years later the patient remains completely well. Repeat CT scans show a complete radiological response. DISCUSSION: Previous studies using numerous chemotherapy regimes have not significantly altered the outcome of pancreatic cancer. To the best of our knowledge this is the longest surviving case of a patient with advanced metastatic adenocarcinoma (stage IV) of the pancreas treated with chemotherapy.

Chlorambucil and acute intermittent porphyria.

A 54-year-old women with quiescent acute intermittent porphyria (AIP) developed low-grade non-Hodgkin's lymphoma. She was successfully treated with chlorambucil without any significant rise in urinary proto-porphyrins. The case is described and a review of chemotherapy use in AIP is presented.

DNA double-strand break induction and rejoining as determinants of human tumour cell radiosensitivity. A pulsed-field gel electrophoresis study.

Measurement of the surviving fraction after 2 Gy (SF2) may predict for local control of the tumour and patients cure, but clonogenic assays are unsuitable for wider clinical application. Promising results have been obtained using DNA damage assays such as pulsed-field gel electrophoresis, PFGE. In the current study, nine human tumour cell lines (SF2, range 0.08-0.62) were studied for DNA double-strand break (dsb) induction and six of these for dsb rejoining using PFGE. Differences in dsb induction, as the slope (+/- SEM) of DNA release per Gy, varied from 1.30 (0.05) to 2.42 (0.17). The dsb induction frequency varied from 3.55 (0.33) to 9.69 (2.18) dsb x 10(-9)/bp/Gy (21-56 dsb/Gy/cell). Variations in the half-time for fast phase (18-60 min) and slow phase (38-445 min) dsb rejoining were observed. Statistically significant correlations were found between SF2 and the slope of the DNA release curve (p = 0.003), DNA release after 10 Gy (p = 0.029) and 20 Gy (p = 0.011) and slow phase dsb rejoining (p = 0.012). While the underlying mechanisms of cell killing remain unclear, PFGF measurement of dsb induction and rejoining shows great potential as a predictive assay for intrinsic cellular radiosensitivity.

A comparison of methods for calculating DNA double-strand break induction frequency in mammalian cells by pulsed-field gel electrophoresis.

Pulsed-field electrophoresis (PFGE) has become one of the most widely used methods for the evaluation of radiation-induced DNA double-strand breaks (dsb). In most studies a simple quantification of DNA migration from the well in the gel has been used as the correlate with dsb formation. Here we have compared such a method, as calibrated with 125I-labelled UdR, with two methods which involved the analysis of the distribution of sizes of DNA fragments migrating in the gel. We conclude that the three methods produce similar absolute values for dsb induction frequency. It is not clear which is the single method of choice but the comparison of the analyses increases the information which can be derived from PFGE experiments.

Dose-rate effect for DNA damage induced by ionizing radiation in human tumor cells.

The effect of dose rate on clonogenic cell survival and DNA double-strand breaks (DSBs) has been examined in a human bladder carcinoma cell line, RT112, treated with ionizing radiation. Cell survival changed markedly over the range of dose rates used (0.01-1.28 Gy/min) with the curves becoming shallower and straighter as the dose rate was lowered. Similarly, the number of DSBs measured by pulsed-field gel electrophoresis (PFGE) immediately after irradiation varied with dose rate. Fewer DSBs were detectable after low-dose-rate irradiation. However, when a 4-h repair period was allowed after irradiation, cells treated at all dose rates exhibited approximately the same amount of damage. The final level of unrejoined DSBs, as detected by PFGE, therefore does not correlate with cell survival at different dose rates.

Pulsed-field gel electrophoresis in the measurement of DNA double-strand break repair in xrs-6 and CHO cell lines: DNA degradation under some conditions interferes with the assessment of double-strand break rejoining.

Pulsed-field gel electrophoresis (PFGE) is a sensitive assay for DNA double-strand breaks (DSBs). The application of PFGE to the measurement of DSB rejoining requires attention to conditions after irradiation. When cells are irradiated and incubated while encapsulated in agarose, DNA DSB rejoining appears incomplete or absent due to DNA degradation artifacts. Using PFGE we have measured the DSB rejoining defect in xrs-6 cells and shown how DNA degradation can affect the results.

A DNA repair defect in a radiation-sensitive clone of a human bladder carcinoma cell line.

DNA repair was measured in an ionising radiation-sensitive mutant of a human bladder carcinoma cell line. No difference in the rate or extent of double-strand break rejoining was found using the techniques of neutral filter elution and pulsed-field gel electrophoresis. In contrast, significant differences in repair fidelity, measured by plasmid reconstitution, were found. The parent line had a repair fidelity of 84.7% compared with 58.9% for S40b (P = 0.0003). It is suggested that repair fidelity can be an important determinant of radiosensitivity in human tumour cells.

Oxygen effect for DNA double-strand break induction determined by pulsed-field gel electrophoresis.

The induction of DNA double-strand breaks (dsb) following irradiation under oxygenated and hypoxic conditions with and without misonidazole was measured by pulsed-field gel electrophoresis (PFGE) in a human bladder carcinoma cell line. The dose-response curve for DNA dsb detection by PFGE was biphasic with an apparent reduction in rate of dsb induced with dose. Oxygen enhancement ratios (OER) for cell survival (at a surviving fraction of 0.1) and for DNA damage assessed by PFGE (at 80% retained) were 2.0 and 3.0 respectively. Dose-modifying factors for misonidazole (15 mM), of 1.9 (survival) and 2.4 (DNA damage) were found. Although the magnitude of the inter-experiment variations limit the precision with which cell survival and DNA electrophoresis can be compared, the data do support a simple correlation between these two measures of response. When DNA dsb induction frequency was assessed from the number average molecular weight, values of 2.7 (+/- 0.3), 0.7 (+/- 0.1) and 2.6 (+/- 0.5) x 10(-9) dsb/bp/Gy were found for irradiation under oxic, hypoxic alone and hypoxic + misonidazole conditions respectively. This gives an OER of 3.9 and a DMF of 3.7.

DNA damage by drugs and radiation: what is important and how is it measured?

DNA is the most important target for drug and radiation induced cell killing. The mode of cell killing by cytotoxic drugs and radiation has been derived by correlating the type and quantity of DNA damage induced with lethality. Cytotoxic drugs can be classified by their main mode of action, while ionising radiation causes a range of lesions with the DNA double-strand break (dsb) being the most significant. Strand-breaks are measured from the reduction in the size of DNA molecules following treatment. Molecule size can be derived from the rate that DNA fragments sediment when centrifuged, elute through filters or migrate under electrophoresis. The effect of strand-breaks on DNA loop supercoiling allow a sensitive assay of DNA damage. Specific assays for base damage and drug adducts include changes in chromatographic mobility or binding by specific antibodies. By comparing the levels of damage in the genome overall with damage in specific gene targets, regions susceptible to damage induction, and varying in repair efficiency, have been revealed.

Postoperative radiotherapy in the management of spinal cord ependymoma.

Fifty-eight patients with histologically verified spinal cord ependymomas were treated at the Royal Marsden Hospital and Atkinson Morley's Hospital between 1950 and 1987. The median age in this series was 40 years (range 1 to 79 years) and the male:female ratio was 1.8:1. Ten patients had tumors in the cervical cord and 10 in the thoracic cord; 14 tumors involved the conus medullaris and 24 the cauda equina. Forty ependymomas were grade I and 13 were grades II to IV (in five patients there was insufficient material for grading). Eleven patients underwent biopsy only, 33 had partial or subtotal resection, and 14 had complete resection. Forty-three patients received postoperative radiotherapy. The median follow-up period was 70 months (range 3 to 408 months). Cause-specific survival rates were 74% and 68% at 5 and 10 years, respectively. On univariate analysis, age, histological grade, postoperative neurological function, and era of treatment were significant prognostic factors for survival. The histological grade was the only significant independent prognostic factor. The relative risk of death from ependymoma was 9.0 for patients with tumor grades II to IV compared to grade I (p less than 0.005, 95% confidence interval 2.7 to 30). The survival rates of patients following complete excision were significantly better compared to those after incomplete surgery (p less than 0.025). The majority of completely resected neoplasms were low-grade cauda equina tumors. Despite incomplete surgery, 5- and 10-year progression-free survival rates following radical radiotherapy were both 59%, and cause-specific survival rates were 69% at 5 years and 62% at 10 years. This suggests that radiotherapy may achieve long-term tumor control in over half of those patients with residual spinal ependymoma.

Molecular assays of radiation-induced DNA damage.

There is a need for assays of DNA damage in many areas of laboratory research applied to radiation therapy, in order to understand the molecular processes involved in cell killing by ionising radiation and to predict in vivo response. Assays exist which measure many types of DNA damage following ionising radiation. From studies of the dose-response relationships for different types of damage, the double-strand break (dsb) has been shown to be the most significant lesion. Assays for DNA dsb have been of low sensitivity, such that supralethal doses of radiation had to be used in order to study dsb induction or repair. New assays, such as pulsed-field gel electrophoresis, are sensitive to dsb in a dose range relevant to cell survival. In addition, these assays can assess the distribution of dsb in different parts of the genome and determine heterogeneity of damage induction and repair. Assays which measure the effects of strand breaks on DNA complexed with nuclear matrix can reveal features of chromatin organisation and their influence on cellular radiosensitivity.

The value of cervical cytology in detecting recurrent squamous carcinoma of the cervix postradiotherapy.

Twenty-six patients with central recurrent squamous carcinoma of the cervix following radiotherapy were identified from hospital records, 22 of which had cervical smears available for review, and are described here. As a second part to this study the cervical cytology results for 1987 and 1988 were compared with the clinical findings and eventual outcome. From a total of 384 smears in 1987 and 1988 there were 11 correctly identifying recurrence. Two smears, however, were false positive and two false negative. The overall sensitivity was 85% with a specificity of 99.5%. In addition three microscopic, operable recurrences were identified by cytology. In experienced hands routine smear cytology postradiotherapy is a reliable and useful addition to surveillance.

Stage I-II pediatric Hodgkin's disease: long-term follow-up demonstrates equivalent survival rates following different management schemes.

The results of treatment of 171 children with stage I-II Hodgkin's disease from two institutions with differing approaches to management have been analyzed. At the Stanford University Medical Center/Children's Hospital at Stanford (SUMC/CHaS), pathologic staging followed by extended-field radiation alone or involved-field radiation plus combination chemotherapy have been cardinal to the management policy. At St Bartholomew's Hospital/The Hospital for Sick Children at Great Ormond Street (Barts/GOS), clinical staging only has been used over the last 10 years, and involved/regional-field radiotherapy used as the treatment of choice rather than extended-field radiotherapy. Some children at each institution received combined modality therapy as primary management. Relapse among children with stage I disease was a more frequent occurrence in the Barts/GOS series than in the SUMC/CHaS group. However, the survival rates from the two centers are identical, 91% at 10 years. The following scientific-philosophic question is asked: Should one maximally stage and treat all children to increase the likelihood of a high freedom from relapse (FFR; cure) rate, or is it acceptable to minimize the initial staging and treatment, realizing that a proportion of patients will fail and require salvage/rescue therapy? With the awareness of morbidity from pathologic staging and aggressive treatment, and the favorable survival data reported from specialized centers using differing approaches, treatment strategies should be directed toward the long-term goal of cure of disease with maximal quality of life. A multidisciplinary management philosophy undertaken at a center with extensive experience in pediatric Hodgkin's disease is important to achieving this goal.

The 'urn' portal; an alternative to the 'mantle' portal in the chemoradiotherapy management of paediatric Hodgkin's disease.

The experience of St Bartholomew's Hospital with a less than full mantle radiation field in the treatment of 31 children with clinically staged Hodgkin's disease is reported over a ten year period (1977-1987). The major indication for this portal was initial bulk, or residual disease after chemotherapy. Primary treatment consisted of radiotherapy alone (two children) or in combination with chemotherapy (29 children). An 'Urn' radiation portal has been used to encompass mediastinal and neck nodes, but with the aim of reducing radiation doses to lung, breast, axilla, lateral end of clavicle and humeral head. More recently, a further modification has employed partial heart shielding when anthracyclines have been part of the chemotherapy schedule. The majority have received 35 Gy in 20 fractions over 4 weeks with 4-6 Mv photons, and no child received in excess of 35 Gy to the mediastinum. An overall 5-year actuarial survival of 85% was achieved, and a 5-year relapse-free survival of 77%. Seven relapses and five deaths have been reported, all of which occurred in children who presented with nodular sclerosing histology. Six children relapsed within the radiation portals, and one with systemic disease alone. Only a single child relapsed in the unirradiated axilla, and this simultaneously with cervical, mediastinal and paraortic nodes. To date no second malignancies have been reported.

A pilot study of chemo-radiotherapy in advanced carcinoma of the vulva.

Advanced squamous cell carcinoma of the vulva (FIGO stages III and IV) has a poor cure rate even with exenterative surgery. We report a pilot study of combined pre-operative chemo-radiotherapy (CHT/RT) in all patients with advanced vulval carcinoma presenting to St Bartholomew's Hospital between July 1987 and March 1989. Twelve patients have been treated, of whom nine had primary lesions (four FIGO stage III and five stage IV) and three had recurrent disease after simple or radical vulvectomy. Seven patients were treated with an initial split course of CHT/RT: there was one treatment-related death and the others have all died following recurrence with a median disease-free survival of 5 months (range 3-12) and a median survival of 7 months (range 3-16). Five patients have received a continuous course of CHT/RT: one died before operation with pulmonary metastases, three patients are disease free at 6 to 9 months, and another patient has been treated with only palliative intent. Toxicity was acceptable in the continuous regimen and this treatment seems to have a promising role in the management of advanced carcinoma of the vulva. A review of the literature on combined therapy is presented.

Deaths of two hospital inpatients poisoned by pilocarpine.

Two inpatients of one hospital ward died. Pilocarpine poisoning was suspected and subsequently confirmed by analysis of urine. The circumstantial evidence strongly suggested that the food given to the patients in the ward had been adulterated. Police inquiries failed to elicit any further information, and open verdicts were returned at the inquest. Precautions taken subsequently to prevent a similar event--sealing food containers and trolleys--entailed a capital cost of 43,000 pounds. In addition, food stores were kept locked and tighter control kept on drugs stored in ward pharmacies.

Fluid balance and secretion of antidiuretic hormone following transsphenoidal pituitary surgery. A preliminary series.

Hyponatremia developing some days after transsphenoidal pituitary adenectomy is a treacherous complication of uncertain cause. Of 19 patients monitored in a pilot study at the Wessex Neurological Centre, plasma sodium fell below 125 mmol/liter in three patients at times ranging from 6 to 9 days postoperatively. One patient had evidence of inappropriate secretion of arginine vasopressin (AVP), and the other two probably had steroid insufficiency despite apparently adequate steroid cover. In a more detailed study, the fluid and sodium balance of a further 16 patients was monitored for 7 to 11 days following transsphenoidal surgery together with plasma cortisol, renin, and AVP concentrations. No patient became severely hyponatremic. Three developed partial diabetes insipidus. Two patients with Cushing's disease had evidence of postoperative corticosteroid insufficiency despite normal steroid protection. An inappropriately low plasma cortisol concentration was recorded in both. Plasma AVP concentrations did not show a delayed surge postoperatively. Delayed hyponatremia appears to occur most often in patients with hypoadrenalism, as glucocorticoid cover is decreased. It results from water retention combined with natriuresis, and is reversed by glucocorticoid treatment.

A syndrome of hepatogenous photosensitisation, resembling geeldikkop, in sheep grazing Tribulus terrestris.

Two outbreaks of photosensitivity disease occurred in weaner sheep in south western New South Wales during early autumn 1982. In each instance there was a history of access to the annual herb, Tribulus terrestris and both the clinical and pathological findings were consistent with geeldikkop, a major disease in the Republic of South Africa. The prevalence rates of clinical cases were 21 and 37%, while the case fatality rates approached 70%. Clinical signs were dominated by jaundice and photosensitisation. Ochre and khaki discolouration were present in the liver and kidneys, respectively. Histopathologically, the most characteristic lesion was the presence of acicular, cholesterol-like clefts in the lumens of bile ducts and in the cytoplasm of hepatocytes and Kupffer cells. Similar structures were also evident in the lumens of nephrons in association with segmental hyperplasia of the neighbouring tubular epithelium. The possible pathogenesis of the hepatogenous photosensitisation and its resemblance to geeldikkop are discussed.