The use of an early ACTH test to identify hypoadrenalism-related hypotension in low birth weight infants.

OBJECTIVE: To investigate if in preterm newborns, an early adrenocorticotropin hormone (ACTH) test can identify possible transient adrenal insufficiency (TAI), using significant hypotension as a clinical marker. STUDY DESIGN: We studied 40 premature newborns born 24 to 29 weeks gestational age (GA) before 8 h of life. Serum cortisol levels were obtained before and 40 min after administration of 1.0 mcg kg(-1) cosyntropin. Inotropes were used to treat hypotension based on clinical assessment following no response to fluid boluses. Functional echocardiogram was used to support the clinical diagnosis of hypotension. The accuracy of the ACTH test was evaluated using receiver operating characteristic (ROC) curve. RESULT: Study patients had mean GA of 26.6 weeks and birth weight of 876 g. In all, 30% required inotropes. The area under the ROC curve for the ACTH test was 87%. Using a cutoff of an increase in cortisol below 12% from baseline had 75% sensitivity and 93% specificity for detecting hypotension. This cutoff was associated with bronchopulmonary dysplasia (8/12 vs 7/28, 95% CI: 0.1 to 0.72), but not with other morbidities or death. CONCLUSION: An early ACTH test using the above cutoff has high specificity for detecting hypotension, and thus, can serve as a marker for potential TAI in preterm newborns. Future studies should focus on identifying those newborns for which steroid supplementation would be most beneficial.

Long-term outcome after neonatal intraparenchymal echodensities with porencephaly.

OBJECTIVE: To compare long-term neurodevelopmental and functional outcomes of neonatal intensive care unit (NICU) survivors with neonatal intraparenchymal echodensities (IPE) with porencephaly on cranial ultrasonography with matched controls. To compare the developmental trajectories of these infants over the childhood years with those of matched controls. DESIGN: Cohort study. SETTING: Tertiary level NICU and the Neonatal Follow-Up Programme (NFUP) in Vancouver, Canada. PATIENTS: NICU survivors with birth weights <1250 g, born between 1983 and 1985. METHODS: Cranial ultrasound scans of NICU subjects with grade 4 intraventricular haemorrhage (IVH) were reviewed by a neuroradiologist and cases were defined, using stringent criteria, as IVH with IPE with porencephaly. Controls with normal cranial ultrasound findings were selected case-matched for birth weight and sex. Prospective sequential multidisciplinary assessments were performed up to 17 years in the NFUP. Mann-Whitney U test was used to compare outcomes between cases and controls. RESULTS: Of 385 eligible patients, 14 met IPE and porencephaly criteria and 10 survived to discharge. All cases with IPE and porencephaly had one or more impairments, significantly different from preterm controls (p<0.001). At all ages assessed, rates of motor, cognitive and overall impairment were significantly higher in the cases (p< or =0.002 for all tests). Most cases at adolescence were ambulatory, required learning assistance in school and had social challenges. CONCLUSIONS: Children with neonatal IPE and porencephaly have a much worse long-term neurodevelopmental outcome than children with normal cranial ultrasound findings.

Are twitches, startles, and body movements pain indicators in extremely low birth weight infants?

OBJECTIVE: The goal of this study was to examine whether body activity such as postural, trunk, and limb movements may be potential pain cues in preterm infants. DESIGN: Convenience sample. SETTING: Level III neonatal intensive care unit (NICU). PATIENTS: Extremely low birth weight (< or = 1,000 g) preterm infants (n = 64) undergoing routine NICU medical care. OUTCOME MEASURES: Procedures likely to differ in evoking distress (i.e., endotracheal suctioning, chest physical therapy, diaper change, or nasogastric feed) were observed. Behaviors were recorded at bedside using the Neonatal Individualized Developmental Care and Assessment Program system. RESULTS: Changes in heart rate and sleep/waking state were related to the procedures, supporting the assumption of differing relative disruption to the infant. Arching, squirming, startles, and twitching were not observed significantly more during procedures than at baseline. After controlling for background variables, finger splay and leg extension were significantly related to ongoing procedures. Facial brow raising was a function of the number of invasive procedures in the past 24 hours; thus, it may be a useful cue of sensitization. CONCLUSIONS: Some extensor movements seemed to be distress signals, whereas tremors, startles, and twitches were not related to discomfort during the observation period. These behaviors may differ qualitatively during longer lasting tissue invasive events. The results of this study indicate the need for more in-depth study of patterns of motor activity in preterm infants over longer observation periods to evaluate potential signs of stress and pain in babies undergoing NICU medical care.

Upper extremity performance and self-care skill changes in children with spastic cerebral palsy following selective posterior rhizotomy.

Changes in upper extremity and self-care performance following selective posterior rhizotomy (SPR) are reported frequently, but rarely quantified. In this study, 36 children with spastic cerebral palsy were assessed preoperatively and 1 year following SPR using the Quality of Upper Extremity Skills Test (QUEST). Twenty-six children were assessed at similar intervals using the Functional Independence Measure for Children (WeeFIM) as a measure of self-care performance. Wilcoxon matched-pair signed-rank tests were used to compare the QUEST total scores and the WeeFIM motor, cognitive, and total scores before and after SPR. One year after SPR, the total QUEST scores were significantly better (median improvement = 3.2%, p < 0.0001), as were the WeeFIM motor (median improvement = 9.5, p < 0. 0001), cognitive (median improvement = 1.0, p < 0.008), and total (median improvement = 11.0, p < 0.0001) scores. The results indicate quantifiable improvements in upper extremity function, and motor and cognitive self-care skills in children 1 year after SPR.

Biweekly dose escalation in curative accelerated hyperfractionation for advanced head and neck cancer: a feasibility study.

PURPOSE: To study the feasibility of a dose-escalated accelerated hyperfractionation schedule for patients with advanced head and neck cancer. MATERIALS AND METHODS: Twenty-nine previously untreated patients with advanced squamous cell carcinoma were treated with the following biweekly dose-escalated accelerated hyperfraction schedule: during the first 2 weeks 1.2 Gy twice a daily (bid) up to 24 Gy, thereafter during the next following 2 weeks 1.4 Gy bid to 28 Gy in 20 fractions, and thereafter 22.4 Gy in 1.6 Gy bid fractions during 1 1/2 weeks. Thus, the the total dose was 74.4 Gy in 54 fractions given in 5 1/2 weeks. RESULTS: The planned total dose was given within the planned time to 19 (66%) patients. For seven patients the treatment time was prolonged with 1 to 6 days because of department closure for holidays or machine-down days, and in three cases the treatment time was prolonged more than 8 weeks. When the tumor responses were evaluated at 3 months after given radiotherapy, 27 (93%) patients showed complete tumor clearance, 1 patient had a recidual focus, and 1 patient showed progressive disease. The ultimate 1-, 2-, and 3-year local control rates were: 87, 71, and 60%. Four patients had a salvage laryngectomy. The 1-, 2-, and 3-year survival rates for all patients were as follows: 96, 81, and 73%. All patients developed confluent mucositis, 15 patients were hospitalized for nutritional support, and 11 patients had moist desquamation. However, all acute reactions healed completely, and no serious late complications were observed. CONCLUSIONS: This is a safe and effective treatment schedule for patients with advanced head and neck cancer.

Altered fractionation of hemithorax irradiation for pleural mesothelioma and failure patterns after treatment.

Malignant pleural mesothelioma is a rare malignancy with a bleak prognosis. The role of radiotherapy has not yet been clarified. Our aim was to study the effect of altered fractionation on mesothelioma. We have treated 57 patients, 41 males and 16 females, with hemithorax irradiation with six different fractionation schedules. All the patients have been included in a combined modality program consisting of surgery followed by chemotherapy and finally by hemithorax irradiation. The radiotherapy schedules used were: I. Conventional fractionation of 20 Gy in 10 fractions over 12 days. II. Split-course radiotherapy 55 Gy in 25 fractions of 2.2 Gy over 7 weeks (a two weeks rest halfways) followed by a boost dose of 15 Gy over 8 days to the major tumour area. III. Hyperfractionation of 70 Gy over 7 weeks, 1.25 Gy BID with a 6-h interval and a 10-day rest halfways. IV. Combined hyperfractionation and hypofractionation, 35 Gy hyperfractionation in 28 fractions (1.25 Gy BID with a 6-h interval) over three weeks followed by 36 Gy hypofractionation 9 fractions of 4 Gy given every other day over 3 weeks to the major tumour areas only. V. Hypofractionation of 38.5 Gy over 15 days (9 x 3.5 Gy). VI. Combined conventional radiotherapy and hypofractionation with 20 Gy given conventionally in 10 fractions followed by 10 fractions of 3 Gy over two weeks, overall time 4 weeks. The 2-year survival rate of all patients was 21% and the 5-year survival rate 9%. Two patients are still alive more than 6 and 9 years after radiotherapy. Progression occurred after surgery in four patients, during and after chemotherapy in 22 patients and after completed radiotherapy in 29 patients. The pattern of progression was similar in each treatment group.

Extremely premature (< or = 800 g) schoolchildren: multiple areas of hidden disability.

AIM: To examine the functional abilities of extremely low birthweight (ELBW, < or = 800 g) children at school age compared with full term children. METHODS: ELBW children (n = 115) in a geographically defined regional cohort born between 1974 and mid-1985 (comprising 96% of 120 survivors of 400 ELBW infants admitted to the Provincial Tertiary neonatal intensive care unit), were compared with (n = 50) children of comparable age and sociodemographic status. Each child was categorised by the pattern and degree of disability, using a system derived from the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM IV). Psycho-educational, behavioural, and motor results for ELBW children free of severe/multiple neurosensory disabilities (n = 90; 91% return rate) were compared with the term children. RESULTS: Severe/multiple neurosensory disabilities were present in 16 ELBW children (14%), and 15 (13%) had borderline intelligence. ELBW children of global IQ > or = 85 scored significantly lower in standardised tests of fine and gross motor control, visuo-motor pencil output, visual memory, and academic achievement (reading, arithmetic, written language). ELBW survivors were three times more likely to have learning disorders (47% vs 18%) and 22 (41%) of the 54 ELBW children with learning disorders had multiple areas of learning difficulty. Of the ELBW group, 30 (26%) were not disabled compared with 41 (82%) of the term group. Only five (12%) of the ELBW boys were not disabled, compared with 25 (35%) of the ELBW girls. Finally, ELBW children had significantly worse scores on ratings of behaviour during testing by the psychologist and behaviour by parental report. CONCLUSION: The most likely outcome for ELBW survivors at school age is a learning disorder, often multiple, or borderline intellectual functioning, combined with behavioural and motor risk factors rather than severe/multiple disability. Mean scores on psycho-educational testing showed poorer performance of the ELBW children, but grossly understated the complex nature of the individual degree of educational difficulty faced by these children.

How radiation oncology emerged as a discipline in Finland.

The news about the discovery of Röntgen's new rays spread over Finland quite early, and the first Finnish writing about the rays appeared in February 1896. The first x-ray machine was installed in 1897. Proper training of radiologists began, however, at a comparatively late date. For a long time the position of radiologists remained a subordinate one. Radiology had the nature of a spare time hobby, because in most hospitals surgeons treated x-ray machines as a sideline. Because of this, scientific research work was delayed. The specialty of x-ray diagnosis and therapy was, however, established in 1921, and the Finnish Society of Radiology was founded in 1924. The first radiotherapy department with its own beds was opened in 1936 in Helsinki. In 1950, the first professor of medical radiology was appointed at the University of Helsinki. The Finnish Cancer Society played an important role in developing the radiotherapy net in the country by supplying cobalt devises and auxiliary hospital activities in the 1960s. In the early 1960s roentgen diagnosis and radiotherapy were separated into two distinct disciplines. There are now five medical faculties with chairs in radiation oncology. The country is divided into five regions for cancer care. The managing groups in each region are headed by the professor of radiotherapy and oncology. The radiation oncologists in Finland are involved in diagnosis and staging of cancer and are responsible for radiation therapy, chemotherapy and hormones. They are responsible for follow-up of treated patients, their own wards, and the general care of their patients.

Effect of overall treatment time on local control in radical radiotherapy for squamous cell carcinoma of esophagus.

PURPOSE: To analyze the effect of overall treatment time on local control in radical radiotherapy for squamous cell carcinoma of esophagus. METHODS AND MATERIALS: Three hundred and fifty-three patients with inoperable esophageal cancer (tumor length < or = 10 cm in all cases) treated during 1963-1988 by radical radiotherapy alone either as continuous or split-course therapy. The overall treatment time varied from 35 to 55 days and the total dosage from 50 to 71 Gy in the continuous therapy group (n = 138), and in the split-course group (n = 215) with a planned 3-week rest interval in the middle of the treatment from 56 to 70 days and from 55 to 70 Gy, respectively. The logit method of the linear-quadratic formula for local control at 1 year was used to examine the effect of treatment time on local control. All patients were pooled to obtain a wide range of overall treatment times. RESULTS: The 1-, 2-, and 5-year actuarial survival rates according to the T-stage in the continuous therapy group from the first day of the radiotherapy were: 57%, 32%, and 10% for the T1 tumors and 23%, 8%, and 5% for the T2 tumors. The corresponding figures for the split-course group were: 50%, 19%, and 4% for the T1 tumors and 17%, 6%, and 3% for the T2 tumors. The 1-year local control rate was 56% for the T1 tumors and 15% for the T2 tumors in the continuous therapy group and 48% for the T1 tumors and 10% for the T2 tumors in the split-course group. The results of the logit method did not fit well with the T1 tumors. For the T2 tumors, they showed Dprolif to be about 0.24 Gy/day for local control at 1 year. As a consequence, protraction of overall time by 1 week should be compensated by increasing the total dose by 1.8 Gy for 1 year local control. CONCLUSIONS: More attention should be focused on repopulation. Shortening of overall treatment time might be beneficial for the treatment of squamous cell carcinoma of esophagus.

Development of clinical radiotherapy since 1896.

From the discovery of x-rays in November 1895 and the first publication in December 1985 it did not take long for the first x-ray therapy of cancer in January 1896. The first 25 years in the history of radiotherapy was not a very flattering period for the discipline. During the following 25 years, however, important developments in clinical radiotherapy occurred and in some countries the speciality of radiotherapy was established in the 1930s. In the last 50 years gradual changes have taken place and now modern radiotherapy is an established curative method in the treatment of cancer. The scientific background of radiotherapy is solid, and the understanding of cancer biology and radiobiology has improved drastically. The radiotherapists of today are cancer specialists, oncologists. The technical development has been enormous. The future of radiation oncology looks very promising, with local cancer treatment being shown to be most effective.

Effect of split-course radiotherapy on survival and local control in advanced localized prostatic carcinoma.

PURPOSE: to analyze the effect of overall treatment time of radiotherapy on survival and local control in locally advanced prostatic cancer in a split-course treatment setting. METHODS AND MATERIALS: 168 patients with Stage C prostatic cancer treated during 1979-1989 by the split-course method where the overall treatment time is protracted. Treatment consisted of whole pelvis irradiation of 40 Gy in 4 weeks, followed by a planned 3-week interruption and an additional 26 Gy by the reduced field technique to a total dose of 66 Gy in 9 weeks and 30-33 fractions. The overall treatment time varied from 55 to 100 days. Thirty-eight percent (63) of the patients were treated primarily with radiotherapy, while the rest (105) had received androgen ablative therapy during 2 to 4.5 years before radiotherapy. To examine the effect of treatment time on local control, the patients were divided into three groups ( < or = 63 days, 64-70 days, and > 70 days) by treatment time. RESULTS: the 5-year actuarial survival rates, calculated from the date of diagnosis, were 91% for the hormonally manipulated patients and 69% for the patients treated with radiotherapy alone. The 5-year actuarial local control rates, counted from the start of radiotherapy, were 84% for radiotherapy and 80% for the hormonally manipulated group. Overall, no significant effect of treatment time could be seen, either for radiotherapy alone or for the hormonally manipulated group. The results were similar when the material was further divided by T category and histologic grade. CONCLUSIONS: no significant effect of overall treatment time (55 to 100 days) on survival or local control was found in either group. The survival time from diagnosis was longer in the hormonally pretreated group. Apparently, with adequate doses ( > or = 65 Gy) the overall treatment time becomes less important for local control of advanced prostatic cancer, even in a split-course treatment setting.

Radical surgery and postoperative split-course radiotherapy in squamous cell carcinoma of the head and neck--factors influencing local control and survival.

During the period 1970-1989, 256 patients with squamous cell carcinoma of the head and neck were treated with radical surgery and postoperative split-course radiotherapy. The 3-week rest period was compensated by a 10% increase in the total radiation dose to 66 Gy. The 5-year actuarial local control rate was 66% in tonsillar, 60% in mobile tongue, 64% in floor of the mouth, 51% in lower gingiva, 63% in laryngeal, and 35% in hypopharyngeal cancer. Failures were observed in 102 patients (40%) and 51 (20%) died of intercurrent diseases. Except in mobile tongue cancer, the results in the logistic regression analyses showed that T- and N-category and pretreatment Karnofsky index had the strongest association with local control, whereas in Cox's proportional hazard's regression analyses T-category and pretreatment Karnofsky had the strongest association with survival. In mobile tongue cancer, the histologic grade and the time interval between surgery and radiotherapy had the strongest association with local control and survival respectively. However, the lengthening of the time interval was often caused by factors or events which could have influenced the prognosis. On the basis of both univariate and multivariate analyses, when the tumour resection margins were free, a time interval of less than 3 months, the overall treatment time and the duration of the split of radiotherapy, became less important for local control and survival when doses of 65 Gy were given by fraction of 2 Gy or greater.

N-acetylcysteine in combination with radiotherapy in the treatment of non-small cell lung cancer: a feasibility study.

N-Acetylcysteine (NAC) is a free radical scavenger and could therefore act as a radioprotector. To test the feasibility of administering NAC in combination with radiotherapy, we studied 10 patients with inoperable non-small cell lung cancer who were receiving hyperfractionated radiotherapy (RT) of 1.25 Gy B.I.D. (6-h interval) up to a total dose of 60 Gy/48 fractions/32 days. They were given NAC concomitantly with RT: 100 mg/kg i.v. 30 min before the first RT session followed by 30 mg/kg as an i.v. infusion over 7 h; and 600 mg inhaled 30 min before and after each RT session. The patients were assessed by serial CT scans and lung function studies during a 1-year follow-up period. The treatment regime was feasible, but expensive in time and resources. Normal tissue reactions and tumour responses were similar to those in a control group.

Diagnosis and prognostic factors in malignant pleural mesothelioma: a retrospective analysis of sixty-five patients.

This report is an analysis of the medical records of 83 patients registered between 1960 and 1980 at Helsinki University Central Hospital as having malignant pleural mesothelioma. 65 of 83 patients had histologically confirmed malignant mesothelioma, and are the focus of this analysis. The remaining 18 (22%) patients were excluded because malignant mesothelioma was only confirmed cytologically, or because the primary tumor was not a mesothelioma. The ratio of men to women was 2:1.30 of 65 (46%) patients were not known or not likely to have been exposed to asbestos. The main symptoms at presentation were dyspnea, cough, chest pain, fatigue and weight loss. The median survival from diagnosis was 12 months, and from the onset of symptoms 18 months. Clinical stage and performance status were significant prognostic factors. Hematogenous metastases were present at autopsy in most cases. Disease and performance status therefore need to be well established and documented in clinical trials involving mesothelioma.

Disease stabilization by leukocyte alpha interferon and survival of patients with metastatic melanoma.

Thirty-one patients, 13 males and 18 females, with metastatic malignant melanoma were treated with human leukocyte interferon (IFN) alpha. The dose was 3 x 10(6) IU daily s.c. for 6 weeks followed by 6 x 10(6) IU/day 3 times a week. Only 1 patient (3%) achieved a partial response (PR) while 14 patients (45%) had disease stabilization for 2-8 months. Three patients experienced mixed responses, where some of the metastases responded, while the others were only stabilized. Interestingly, 1 patient showed regression of lung and disappearance of liver metastases after termination of IFN treatment. Two female patients are still alive without evidence of disease. After IFN they were treated with radiotherapy or surgery. The median survival for all the patients was 48 weeks. Our conclusion is that in IFN therapy long-term follow-up is indicated even in the absence of objective responses. In spite of poor response rate IFN may contribute beneficially to survival in a proportion of patients.

Multimodality treatment programs for malignant pleural mesothelioma using high-dose hemithorax irradiation.

The characteristic of malignant pleural mesothelioma is a tumor that grows by plate-like extension over the pleura, and invades adjacent tissues and organs. Radical surgical removal of the tumor is generally not possible, and most treatment regimens involve combined chemotherapy and radiotherapy, as well as debulking surgery. We have prospectively evaluated five locally-aggressive multi-modality treatment programs, using different hemithorax irradiation schedules and chemotherapy regimens. One hundred patients with confirmed malignant pleural mesothelioma entered the study between 1977 and 1989. The treatment programs, which can consecutively, were: I, 20 Gy (10 x 2 Gy) to the hemithorax + CYVADIC (cyclophosphamide 500 mg/m2 d 1, vincristine 1 mg/m2 d 1 and 5, adriamycin 40 mg/m2 d 1 and dacarbazine 200 mg/m2 d 1 and 5, several cycles before and after irradiation); II, 55 Gy (25 x 2.2 Gy) to the hemithorax + 15 Gy (6 x 2.5 Gy) to the tumor + CYVADIC (2 cycles before, 1 cycle during, and 2 cycles after irradiation); III, Mitoxantrone (14 mg/m2 q 28 d, < or = 6 cycles) followed by 70 Gy (56 x 1.25 Gy, twice a day); IV, 4-Epirubicin (110-130 mg/m2 q 28 d, < or = 6 cycles) followed by 35 Gy (28 x 1.25 Gy twice a day) to the hemithorax + 36 Gy (9 x 4 Gy every 2 days) to the tumor; V, Etoposide (150 mg/m2 1, 3, 5 q 28 d) followed by 38.5 Gy (11 x 3.5 Gy) to the hemithorax. A new system for evaluating tumor response in pleural mesothelioma was applied. None of the combined treatment programs prevented local invasive growth or the spread of mesothelioma outside the hemithorax. The median survival time was slightly increased from 8 to 12 months for those patients who completed the protocol treatments, but progressive disease was the invariable outcome. Radiation pneumonitis and fibrosis were severe and compatible with results of total loss of lung function on the irradiated side. We conclude that data relating to therapeutic responses and treatment programs in malignant mesothelioma should be better correlated internationally, if the problems associated with the evaluation of treatment and the management of patients with mesothelioma are to be improved.

Natural interferon alfa as maintenance therapy for small cell lung cancer.

We performed a 3-armed phase III study between 1982 and 1990 to evaluate low dose natural interferon alfa (nIFN-alpha) as a maintenance therapy in small cell lung cancer (SCLC) following induction chemotherapy (CT) and consolidation radiotherapy (RT). All patients received four cycles of CT (cyclophosphamide, vincristine, etoposide), followed by split-course RT (55 Gy in 20 fractions over 7 weeks). 410 patients entered the study. 237 patients who completed induction CT + RT and were classified as responders (complete response + partial response) were randomly assigned to arm 1: low dose nIFN-alpha (91 patients); arm 2: maintenance CT, six cycles of CAP (cyclophosphamide, doxorubicin, cisplatin) (59 patients); or arm 3: control arm (no maintenance treatment) (87 patients). Halfway through the study the CAP arm was discontinued. There was no difference in median survival between the groups (IFN: 11 months, CAP: 11 months, control: 10 months), but a clear difference in long-term survival and in survival in the limited disease group, favouring nIFN-alpha maintenance therapy. Proportional hazards regression analysis also showed a significant effect of IFN treatment on survival. Our results suggest a role for nIFN-alpha in maintaining a clinically disease-free status achieved with other treatment modalities.