Childhood Wilson Disease: Bangladesh Perspective.

Wilson's disease (WD) is an autosomal recessive disorder affecting copper metabolism causing copper induced damage to various organs. In children liver is commonly involved. Central nervous system, eyes, RBC, kidneys, brain and bones may also be affected. Aim of the study is to evaluate clinical & laboratory profile of Wilson's disease in children. This cross sectional descriptive study was conducted at the department of Paediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, from January 2011 to December, 2013. One hundred consecutive children of WD between 3 to 18 years of age were evaluated for clinical & biochemical profile. Mean age of studied children was 8.5±1.5 years. Male female ratio was 2:1. Ninety one percent patients were Muslim and nine percent Hindu. Consanguinity of marriage was found in 30% cases. Seven parents were first degree cousin. Family history of chronic liver disease was present in 15% of patients. Most (53%) cases of the hepatic WD presented between 5 to 10 years of age and most of the neurologic WD manifested in 10-15 years age group. Among 100 patients of WD, 69 children presented only with hepatic manifestations, 6 only with neurological manifestations, 14 with both hepatic & neurological manifestation, 10 children was asymptomatic and 1 patient presented with psychiatric features. WD presented as chronic liver disease (CLD) in 42%, CLD with portal hypertension in 34%, acute hepatitis in 20% and fulminant hepatic failure in 4% cases. Stigmata of chronic liver disease were found in 18% patients. Commonest stigmata was thenar and hypothenar wasting (n=8). Keiser- Fleischser ring (K-F ring) was found in 76% of the total patients. K-F ring was present in 84% ( 58 out of 69) of the hepatic only Wilsonian patients and in 90% (18 out of 20) of all neurologic Wilsonian patients. Asymptomatic and psychiatric patient had no K-F ring. About 26% of the WD patients had Coombs negative hemolytic anemia in PBF. Most of the WD patients had altered liver function. Elevated serum transaminase was found in 85% of all cases, prolonged prothrombin time in 59% cases & low serum albumin in 53% cases. Seventy three percent patients had low serum ceruloplasmin, basal urinary copper of >100µgm/day was found in 81% cases and urinary copper following penicillamine challenge of >1200µgm/day was found in 92% cases. In 28 cases with hepatic presentation esophageal varices were identified by upper gastrointestinal endoscopy. WD patient with hepatic presentations were given zinc sulphate along with penicillamine. All patients with neurological manifestation as well as asymptomatic cases were maintained on zinc therapy. WD is a treatable metabolic cause of liver disease. Majority of studied WD children presented with hepatic manifestation of which 76% presented with CLD. Any child presented with jaundice after the age of 3 years should be investigated for WD.

Associations between common intestinal parasites and bacteria in humans as revealed by qPCR.

Several studies have shown associations between groups of intestinal bacterial or specific ratios between bacterial groups and various disease traits. Meanwhile, little is known about interactions and associations between eukaryotic and prokaryotic microorganisms in the human gut. In this work, we set out to investigate potential associations between common single-celled parasites such as Blastocystis spp. and Dientamoeba fragilis and intestinal bacteria. Stool DNA from patients with intestinal symptoms were selected based on being Blastocystis spp.-positive (B+)/negative (B-) and D. fragilis-positive (D+)/negative (D-), and split into four groups of 21 samples (B+ D+, B+ D-, B- D+, and B- D-). Quantitative PCR targeting the six bacterial taxa Bacteroides, Prevotella, the butyrate-producing clostridial clusters IV and XIVa, the mucin-degrading Akkermansia muciniphila, and the indigenous group of Bifidobacterium was subsequently performed, and the relative abundance of these bacteria across the four groups was compared. The relative abundance of Bacteroides in B- D- samples was significantly higher compared with B+ D- and B+ D+ samples (P < 0.05 and P < 0.01, respectively), and this association was even more significant when comparing all parasite-positive samples with parasite-negative samples (P < 0.001). Additionally, our data revealed that a low abundance of Prevotella and a higher abundance of Clostridial cluster XIVa was associated with parasite-negative samples (P < 0.05 and P < 0.01, respectively). Our data support the theory that Blastocystis alone or combined with D. fragilis is associated with gut microbiota characterized by low relative abundances of Bacteroides and Clostridial cluster XIVa and high levels of Prevotella.

Aetiology and Outcome of Acute Liver Failure in Children: Experience at a Tertiary Care Hospital of Bangladesh.

Acute liver failure (ALF) is a rapidly progressive, potentially fatal syndrome resulting from rapid death or injury to a large proportion of hepatocytes, caused by a variety of insult, leaving insufficient hepatic paranchymal mass to sustain liver function. The aetiology of ALF varies according to the age of patient and development of the country. The outcome of ALF also varies according to aetiology: survival is better in paracetamol poisoning whereas it is poor in metabolic diseases. The present study was undertaken to observe the underlying aetiology and outcome of ALF in children under 18 years of age admitted at the department of Paediatric Gastroenterology & Nutrition, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh. It was a retrospective review of medical records from November 2011 through October 2014. During this period a total of 35 patients were diagnosed to have ALF. Aetiology was established in 25(71.4%) cases, whereas in 10(28.6%) cases, no identifiable cause was found. Viral hepatitis was the underlying cause in 12(34.3%) cases. After treatment 15(43%) ALF patients survived, 8(23%) left hospital with risk bond (DORB), and 12(34%) patients died. The study showed that among the 12 death patients, 5(41.7%) had viral hepatitis, 3(25%) Wilson's disease, and in 4(33.3%) no cause could be identified. Viral hepatitis and Wilson disease were found to be two common causes of ALF in this study. Future studies with larger sample size are required to know the actual causes of acute liver failure in Bangladeshi children.

Iodine and selenium: Dietary sources and nutritional status of the population of the Kurdistan Region in Northern Iraq.

AIM: The primary aim of this study was to determine the selenium (Se) and iodine (I) food concentrations and dietary intake of the population living in the Kurdish controlled region of northern Iraq. We also assessed the extent to which iodised salt contributes to dietary iodine intake. METHODOLOGY: Foods and samples of salt and drinking water were analysed, including 300 crops samples from 40 local farms. The results, supplemented by food composition data, were used to assess dietary Se and I intake for 410 volunteers using a semi-quantitative food questionnaire. To directly investigate the nutritional status of individuals, urine samples were also collected from participants. RESULTS: Selenium intake was mainly supplied by protein and cereal sources. Calculated median dietary intake of Se was 62.7 µg d-1 (mean = 66.3 µg d-1) with c. 72 % of participants meeting or exceeding dietary reference intake recommendations for age. Median dietary intake of I, excluding salt consumption, was 94.6 µg d-1 (mean 100.2 µg d-1), increasing to 607.2 µg d-1 when salt (of which >90 % was iodized) was included. Salt intake was estimated to be c.13.5 g d-1 (5400 mg Na d-1) which greatly exceeds WHO recommended intake (< 2000 mg d-1 of Na). Urine iodine concentrations indicated that 98 % of school aged children had excessive iodine intake (≥300 µg L-1) and 80-90 % of all study participants had above average or excessive iodine intake (≥200 µg L-1). CONCLUSIONS: Poultry and rice are the main sources of dietary Se to this population but around a third of children receive an inadequate Se intake. Fresh fruit and vegetables are the main sources of dietary I, but consumption of local foods cannot supply adequate I without iodised salt supplementation. Consumption of iodized salt well above recommended amounts is supplying this population with substantial iodine intake. Interventions to reduce salt intake would help to limit excessive iodine intake whilst also reducing cardio-vascular risks from Na consumption.

Safety and immunogenicity profile of human papillomavirus-16/18 AS04 adjuvant cervical cancer vaccine: a randomized controlled trial in healthy adolescent girls of Bangladesh.

AIM: Bangladesh has the highest level of incidence and mortality rates due to cervical cancer among women. The prevalence of cervical cancer in Bangladeshi women is 25-30/100,000. Human papillomavirus is an important cause of cervical cancer. The study was conducted to assess the immunogenicity and safety profile of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccines in healthy Bangladeshi girls aged 9-13 years. Procedure This was a randomized (3:1) controlled trial with two parallel groups, the vaccine and control groups, that included 67 participants in Bangladesh. Subjects were given GlaxoSmithKline human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine (and controls no vaccine) at the first day of vaccination (Day 0), at 1- and 6-month schedule and followed up until 7 months. Blood samples were taken for human papillomavirus antibody at enrollment and 1 month post-schedule at Month 7 from both subjects and controls. Safety data were gathered throughout the study period. RESULTS: Fifty subjects received vaccine at Day 0, 1 month and 6 months. All subjects were initially sero-negative in the vaccine group, and developed sero-conversion for human papillomavirus-16 and -18 antibodies except for one at Month 7. Seventeen controls did not receive vaccine. Clients were followed up for serious medically important events and blood samples were taken for human papillomavirus antibody detection at Day 0 and Month 7. Sero-conversion was found in 97.5% of subjects and no sero-conversion was found in the controls. Bivalent human papillomavirus vaccine was generally well tolerated, with no vaccine-related serious adverse experiences. CONCLUSIONS: The human papillomavirus-16/18 AS04-adjuvanted vaccine was generally well tolerated and highly immunogenic when administered to young adolescent females and could be a promising tool for the prevention and control of cervical cancer in Bangladesh.

Immunity after Primary Hepatitis B Vaccination in Children 7 Years or More Attending A Tertiary Care Hospital.

Hepatitis B virus is a serious public health problem. Effective hepatitis B vaccination gives protection in about 85-90% cases. Most follow-up studies in different countries showed a similar pattern of antibody decline with increasing age. Many authors observed a declined level of HBs-antibody over a period of 3-6 years. This study was aimed at to observe immune status in children 7 years or more after primary hepatitis B vaccination. This cross sectional descriptive study was conducted at the department of Pediatric Gastroenterology and Nutrition, BSMMU, Dhaka, Bangladesh from April 2015 to March 2016. For this study children of both sexes aged between 7 to 18 years, who had history of 2 or more doses of hepatitis B vaccine 7 or more years back were included in the study. All the serum samples were tested for anti HBs by chemiluminescence's technique. Total 120 children were studied among them male was 59.2% and male female ratio was 1.4:1 with a mean age of 8.6±1.7 years. Good immune response (66.7%) was observed against hepatitis B. Significantly higher geometric mean titer of anti HBs was found in the age group of 7-8 years (p=0.02). Waning of immunity including non seroprotectivity was significantly associated with increasing age (p=0.015). Majority (96.7%) of children received EPI vaccination than commercially available vaccine. Children with weight for age percentile (WAP), height for age percentile (HAP) and BMI for age lies below 5th percentile had comparatively lower non seroprotection rate than normal children, but this was not statistically significant. History of dental or surgical procedure, blood transfusion and family history of contact with known case of hepatitis B infection did not have any significant inference on anti- HBs response. The study detected a good immune response against hepatitis B. About 66.7% of children were seroprotective 7 years or more after primary hepatitis B vaccination. Waning of immunity including non seroprotectivity was significantly associated with increasing age. Further studies with larger sample size are needed about booster dose to come to a final conclusion.

Histopathological Evaluation of Endoscopic Duodenal Biopsies in Children with Coeliac Disease and its Correlation with Tissue Transglutaminase Level.

This cross sectional, descriptive study was conducted at Paediatrics department of BSMMU from July 2016 to June 2018 to find out histopathological pattern of Coeliac disease according to Modified Marsh criteria and to correlate it with tissue transglutaminase IgA level. A total of 62 children (age <18 years) attending the Paediatrics department of BSMMU with clinical suspicion of celiac disease were enrolled for the study. Mean age of studied children was 7.87±4.67 years. Ratio of the male and female was 2.27:1. Maximum (66.1%) children came from middle income class family. Out of 62 children, 35.5% (22) were positive for IgA anti-tTG of who female were 11.3% and male 24.2%. Mean duration of symptoms was 44.07±21.77 months in serology positive patients and 34.49±30.52 months in serology negative patients. The age group, 10-14 year showed the highest (50.0%) prevalence of positive anti-tTG. In the tTG positive group mean Hb was 9.6±1.14gm/dl and which is lower than that in tTG negative group (11.7±1.47gm/dl). Among 22 sero-positive patients, histological changes compatible with CD were found in 19 (86.3%) cases and normal in 3 cases. Histological changes were of 3a category of Marsh was found in 12(63.2%) cases, 3b in 4(21.1%) cases and 3c in 3(15.8%) cases. Strong correlation was observed between the serological level of tTGA and histological types of CD by Modified Marsh criteria. In conclusion, screening for celiac disease may be included in diagnostic tests to investigate clinically suspected children and serum tTGA level can be used to predict histopathological severity of coeliac disease.

Abdominal Tuberculosis in Children: Is It Really Uncommon?

Now a day's tuberculosis has become a global emergency especially in children and abdomen is the sixth commonest extra-pulmonary site of involvement. Diagnosis of abdominal tuberculosis (TB) in children is still challenging. Non specific constitutional symptoms and long lasting abdominal manifestations cause unnecessary delay in diagnosis in children. Abdominal TB can be of various types like peritoneal TB, gastrointestinal TB, tubercular lymphadenopathy and visceral TB. Diagnosis can be confirmed by histopathology, culture or PCR and imaging technique also play an important role in diagnosis. Morbidity and mortality can be reduced in significant number by early recognition and effective aggressive treatment. In TB endemic areas, it could be strongly considered in children with vague complaints like chronic abdominal pain, low grade fever and weight loss. Response to anti-tubercular therapy may indirectly help the physicians to come to a diagnosis.

Celiac Disease in Children with Chronic Diarrhoea Attending At Paediatric Gastroenterology and Nutrition Department of BSMMU.

This descriptive, cross sectional study was conducted at Bangabandhu Sheikh Mujib Medical University from July 2012 to July 2015 to see the occurrence of celiac disease in children with chronic diarrhea. A total of 62 children (age <18 years) attending the Paediatric Gastroenterology and Nutrition department of BSMMU with chronic diarrhoea were enrolled for the study. Mean age of studied children was 7.87±4.67 years. Ratio of the male and female was 2.27:1. Maximum (66.1%) children came from middle income class family. Out of 62 children with chronic diarrhea, 35.5% (22) were positive for IgA anti-tTG of whom female were 11.3% and male 24.2%. Mean duration of diarrhoea was 44.07±21.77 months in serology positive patients and 34.49±30.52 months in serology negative patients. The age group, 10-14 year showed the highest (50%) prevalence of positive anti-tTG. In the tTG positive group mean Hb was 9.6±1.14gm/dl and which is lower than that in tTG negative group (11.7±1.47gm/dl). Among 22 seropositive patients, histological changes compatible with CD were found in 19 (86.3%) cases and normal in 3 cases. Histological changes were of 3c category of Marsh was found in 3(15.8%) cases, 3b in 4(21.1%) cases and 3a in 12(63.2%) cases. In conclusion, Screening for celiac disease may be included in diagnostic tests for evaluating chronic diarrhoea in children.

Irritable Bowel Syndrome: Is it Rare in Children?

Irritable bowel syndrome (IBS) is one of the most common and best studied disorders among the group of functional gastrointestinal disorders. It is a functional bowel disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habit. Visceral hypersensitivity and increased GIT motility are the main patho-physiological mechanism for developing IBS. IBS present with diarrhea and constipation or both. Investigation is least needed for diagnosis of IBS rather done to exclude differential diagnosis. Diagnosis is done on the basis of Rome-III criteria. Proper counseling, dietary management, anti-spasmotic and antidepressant are the mainstay of treatment.

Role of Liver Biopsy in the Diagnosis of Neonatal Cholestasis due to Biliary Atresia.

Biliary atresia is the commonest cause of cholestatic jaundice. Early diagnosis & surgical correction helps long time survival & prevent development of cirrhosis. This study was conducted to find out the role of liver biopsy in the diagnosis of biliary atresia having positive hepatobiliary scintigraphy as there is chance of false positivity. This cross sectional study was carried out in Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh at Paediatric Gastroenterology & Nutrition Department from January 2014 to June 2015. All admitted patients with the diagnosis of neonatal cholestasis were evaluated clinically and by scintigraphy for biliary atresia. Having positive hepatobiliary scintigraphy but highly suggestive of biliary atresia were enrolled for this study. A total of 108 cases were initially selected. Among them 33 patients showed no excretion of tracer during hepatobiliary scintigraphy. Liver biopsy was done in these 33 cases. All cases (100%) had history of passage of pale or acholic stool. Fractionated serum bilirubin of >2mg/dl was found all of the cases. Histological scoring system reveals typical features of biliary atresia in 27(81.8%). Two had no conclusive histology of biliary atresia, four had features of neonatal hepatitis (12.1%). In this study, percutaneous liver biopsy with histological analysis by scoring system was found useful for the correct diagnosis of biliary atresia.

Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial.

BACKGROUND: Postoperative policies of "wait-and-see" and radiotherapy for low-grade glioma are poorly defined. A trial in the mid 1980s established the radiation dose. In 1986 the EORTC Radiotherapy and Brain Tumor Groups initiated a prospective trial to compare early radiotherapy with delayed radiotherapy. An interim analysis has been reported. We now present the long-term results. METHODS: After surgery, patients from 24 centres across Europe were randomly assigned to either early radiotherapy of 54 Gy in fractions of 1.8 Gy or deferred radiotherapy until the time of progression (control group). Patients with low-grade astrocytoma, oligodendroglioma, mixed oligoastrocytoma, and incompletely resected pilocytic astrocytoma, with a WHO performance status 0-2 were eligible. Analysis was by intention to treat, and primary endpoints were overall and progression-free survival. FINDINGS: 157 patients were assigned early radiotherapy, and 157 control. Median progression-free survival was 5.3 years in the early radiotherapy group and 3.4 years in the control group (hazard ratio 0.59, 95% CI 0.45-0.77; p<0.0001). However, overall survival was similar between groups: median survival in the radiotherapy group was 7.4 years compared with 7.2 years in the control group (hazard ratio 0.97, 95% CI 0.71-1.34; p=0.872). In the control group, 65% of patients received radiotherapy at progression. At 1 year, seizures were better controlled in the early radiotherapy group. INTERPRETATION: Early radiotherapy after surgery lengthens the period without progression but does not affect overall survival. Because quality of life was not studied, it is not known whether time to progression reflects clinical deterioration. Radiotherapy could be deferred for patients with low-grade glioma who are in a good condition, provided they are carefully monitored.

Quality of life after radiation therapy of cerebral low-grade gliomas of the adult: results of a randomised phase III trial on dose response (EORTC trial 22844). EORTC Radiotherapy Co-operative Group.

In 1985, the EORTC Radiotherapy Co-operative Group launched a randomised phase III study comparing high-dose (59.4 Gy in 6.5 weeks) versus low-dose (45 Gy in 5 weeks) radiotherapy with conventional techniques in patients diagnosed with low-grade cerebral glioma. The primary endpoint of the study was survival. No difference in survival was observed between the two treatment strategies. A quality of life (QoL) questionnaire consisting of 47 items assessing a range of physical, psychological, social, and symptom domains was included in the trial to measure the impact of treatment over time. Patients who received high-dose radiotherapy tended to report lower levels of functioning and more symptom burden following completion of radiotherapy. These group differences were statistically significant for fatigue/malaise and insomnia immediately after radiotherapy and in leisure time and emotional functioning at 7-15 months after randomisation. These findings suggest that for conventional radiotherapy for low-grade cerebral glioma, a schedule of 45 Gy in 5 weeks not only saves valuable resources, but also spares patients a prolonged treatment at no loss of clinical efficacy.

Results of radiotherapy and vitamin E in the treatment of Peyronie's disease.

PURPOSE: A retrospective analysis of 38 patients with Peyronie's disease treated with primary radiotherapy in the period of 1975-1993. METHODS AND MATERIALS: Important complaints were curvature of the penis during erection for 92% of the patients, painful erection for 68%, and problems with sexual intercourse for 37.5%. Average size of all indurated plaques was 2.5 cm. The average pretreatment duration of symptoms was 9.5 months. All 38 patients were irradiated with orthovoltage radiotherapy (200 and 250 kV photons) with a total dose of 9 Gy in 5 alternating days (regimen A). Because of minimal response, 16 patients were irradiated again with another 9 Gy in 5 days and finally received 18 Gy (regimen B). RESULTS: With regimen A, a satisfying improvement was achieved for the majority of the patients: 65% experienced less penile pain during erection, 40% reported less curvature of the penis, and 47% experienced an improvement of their sex life. With the higher dose of regimen B there was an additional improvement for a minority of the patients: 25% reported less pain during erection, 21% had less curvature, and 29% experienced an improved sex life. With regimen A, pain improvement was statistically significantly superior when compared to regimen B. For all other improvements (curvature, sexual intercourse, and induration) no dose-response relation could be demonstrated between regimen A and the higher dose regimen B. No patient experienced any radiation-induced morbidity. After evaluating regimen A and regimen B, the overall result was that 76% experienced less pain, 60% reported an improved sex life, and 48% had a diminished curvature during erection. CONCLUSION: From this analysis it can be concluded that the distressing symptoms of Peyronie's disease can be treated successfully with radiotherapy. Radiotherapy proves to be a safe, noninvasive treatment method without causing morbidity. Low-dose radiotherapy with only a few fractions is recommended for an effective treatment result.

Curative radiotherapy for technically operable stage I nonsmall cell lung cancer.

PURPOSE: Retrospective study of patients with Stage I nonsmall cell lung cancer (NSCLC) unable to undergo surgery or refusing surgery. METHODS AND MATERIALS: Between 1984 and 1990, 47 patients with technically operable Stage I NSCLC received hypofractionated radiotherapy. The total dose varied from 32 Gy in six fractions (two fractions/week) or 40 Gy split course in ten fractions (low-dose schedules) to 48 Gy in 12 fractions or 56 Gy in 20 fractions (high-dose schedules). The mean age of the patients was 75 years. Three patients refused surgery and 44 patients were inoperable due to their medical condition. Severe associated disease was present in 34 patients (72.3%). RESULTS: The intrathoracic recurrence rate was 25.5%. In a multivariate analysis, tumor size was identified as the only significant factor predictive for intrathoracic failure (p < 0.001). Disease-specific survival was 90, 53, and 32% at 1, 3, and 5 years, respectively. In Cox's proportional hazards analysis, only tumor size was predictive for disease-specific survival. Overall survival (all causes) was 70, 33, and 15% at 1, 3, and 5 years, respectively. In Cox's proportional hazards analysis, only the presence of severe associated disease was predictive for overall survival (p < 0.01), while tumor size did not attain statistical significance (p = 0.08). There were no severe acute or late side-effects. CONCLUSION: Radiotherapy can effectively control small nonsmall cell tumors. The reported results are comparable to those achieved with more fractionated radiation schedules. In patients of age or in poor medical condition, hypofractionated radiotherapy can be given with curative intent, with minimal burden to the patient.

Hypofractionated radiation therapy in patients with glioblastoma multiforme: results of treatment and impact of prognostic factors.

PURPOSE: Median survival of patients with glioblastoma multiforme (GBM) is only about 4 months with surgery and about 9 months for surgery followed by radiotherapy. Prolonged treatment is futile for many patients and the time of treatment and hospitalization should be minimized. METHODS AND MATERIALS: This was a prospective, nonrandomized study of 30 patients treated with a hypofractionated radiation scheme (42 Gy in 14 fractions). RESULTS: Median survival was 36 weeks. Age, Karnofsky performance status (KPS) and extent of surgery were strongly interrelated and all correlated with survival (p < 0.05). Three prognostic groups were identified. Patients with three favorable prognostic factors (age <50, KPS 80-100, and > or = 75% of the tumor removed) had the best prognosis (median survival 50 weeks). Patients with no favorable prognostic factors (age > or = 50, KPS < or = 70, and < 75% of the tumor removed) had the worst prognosis (median survival 25 weeks). Median survival of the intermediate group (with one or two favorable prognostic factors) was 38 weeks. No severe acute or late toxicity was observed. CONCLUSION: The treatment results are comparable to those achieved with conventional radiotherapy schemes. Based on the number of favorable prognostic factors (age < 50, KPS 80-100 and > or = 75% of tumor resected) the radiation schedule should be selected.

Radiation therapy for advanced (T3T4N0-N3M0) laryngeal carcinoma: the need for a change of strategy: a radiotherapeutic viewpoint.

Since 1974 through 1984, 137 selected patients with loco-regionally advanced carcinoma of the larynx (T3T4 N0-N3) were treated primarily with quality controlled high dose megavoltage radiation therapy with salvage surgery in reserve. This policy of treatment has yielded 67% loco-regional control probability with primary radiotherapy and 85% with salvage surgery at 3 years. Fourteen patients (14/38) had moderate to severe complications after salvage surgery. The quality of life of the patients successfully treated by radiation therapy is obviously and unquestionably better. Primary radiotherapy with salvage surgery in reserve should be accepted as the strategy of choice in at least a selected group of patients with advanced laryngeal carcinoma.

Local control in T3 laryngeal cancer treated with radical radiotherapy, time dose relationship: the concept of nominal standard dose and linear quadratic model.

In a retrospective study of the Dutch cooperative head and neck group 104 evaluable patients with T3NxMO squamous cell carcinoma of the larynx were treated primarily with a full course of radiotherapy. The results of treatment are presented in terms of locoregional control. The actuarial 3-year local control rate was 53%. Regional control was 77% for node positive patients and 96% for N0 patients (p = 0.01). Surgical salvage was successful in 53% of cases with a local recurrence and in 3/8 regional recurrences, resulting in an ultimate locoregional control rate of 83% for N0 patients and 68% for N+ patients. A uni- and multivariate analysis of local control rate versus total dose, nominal standard dose, and extrapolated response dose has been done. To calculate extrapolated response dose the linear quadratic equation was used, assuming an a/b of 10 and a potential doubling time of clonogenic cells of 3, 5, and 7 days. In multivariate analysis the extrapolated response dose with a potential doubling time of 5 days was the only independent prognostic factor for local control (p = 0.069) and ultimate locoregional control (p = 0.0015). Nominal standard dose showed no dose-response relationship. Based on the S-shaped dose response curve, using the LQ model, several therapeutical options are discussed.

Heterogeneity of stage II glottic carcinoma and its therapeutic implications.

The heterogeneity of glottic carcinoma results in variable loco-regional control probabilities from 40 to 80%. These widely different results may be due to two prognostic parameters of the tumor: the mobility of the vocal cord and the volume of the tumor. On the other hand radiation dose and technique may influence the treatment results. Stringent work-up has been prospectively undertaken in 156 patients with Stage II glottic carcinoma since 1974 through 1983 in the Academic Hospital of the Free University in Amsterdam. Several subgroups were defined from the beginning to indicate one or both of these prognostic factors. All were treated with a high quality accurate radiation therapy program delivering high dose to all patients with worse prognostic factors and even higher dosages to voluminous tumors with impaired mobility of a cord or slowly regressing tumors. The latter was individually judged for each patient towards the end of the treatment period. The loco-regional control probability of around 80% for all the subgroups irrespective of the prognostic factors indicate that the heterogeneity of Stage II glottic cancer may be influenced by high dosages of quality controlled radiotherapy. Thus results hitherto reported in literature may be further improved by the dose-schedules outlined here.

Phase II trial of combined radiotherapy and daily low-dose cisplatin for inoperable, locally advanced non-small cell lung cancer (NSCLC).

With the use of cis-diamminedichloroplatinum(II), cisplatin, to enhance the effect of radiation a combined modality approach was designed to treat patients with inoperable, locally advanced NSCLC. The regimen consisted of radiation doses of 300 cGy for 4 days every week for 4 weeks with a 2 week split in between. Each radiation dose was followed by an i.v. injection of cisplatin 6 mg/m2 within 30 min. Hydration consisted on an oral fluid intake of 2 L only, enabling the patient to receive the treatment on an outpatient basis. Of 40 patients entered into the study, 37 were evaluable for toxicity and 33 for response. Overall response rate was 65% and complete response rate 22%. Median duration of local control was 7 months. The majority of all patients (76%) eventually progressed at the primary tumor site, while in 16 patients relapse occurred in distant sites first. Median duration of overall survival was 10.5 months, whereas that of complete responders was 29.5 months. Generally, acute side effects were transient and did not require discontinuation of treatment. One patient presented with thrombocytopenia 4 weeks after treatment had been finished. His death of cerebral bleeding was likely to be related with his therapy-resistant malignancy. Of late side effects three patients showed disabling symptoms consisting of uncontrollable pulmonary infections in the presence of tumor in two patients, one patient had radiation myelopathy and another experienced vertebral collapse with distal paresis. The combination of radiation and daily low-dose cisplatin is a tolerable treatment modality with most benefit for patients reaching a complete remission. Intensification of the regimen is being planned in those patients with inoperable, locally advanced squamous cell lung cancer to reach a complete remission.