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Radiation-induced Proctosigmoiditis
1082
of
patients with dysphagia from strictures gain acceptable relief from dilatation, irrespective of the technique. One or two dilatations may be sufficient to afford prolonged relief and medical treatment will usually control any subsequent symptoms of reflux. Stricture dilatation is a procedure without much intellectual or aesthetic appeal, but it is now reasonably safe and the benefits it brings are great.
Radiation-induced
Proctosigmoiditis
AFTER radiation for pelvic malignant disease, damage to the sigmoid colon and rectum is common. The early injuries tend to be mild and reversible; the later changes can be severe and progressive. When 3000 to 4000 cGy is given over three to four weeks, early damage is invariable: the symptoms, which correspond to the phase of radiation-induced oedema and hyperaemia of the mucosa,’1 are’ incomplete evacuation, diarrhoea, and tenesmus. Conservative treatment with low residue diet and antidiarrhoeals will aid recovery and seldom are there any late sequelae. More serious damage becomes manifest between six and twelve months after treatment,I-3 with diarrhoea, rectal bleeding, pain, and constipation due to progressive radiation changes in the connective tissue and vasculature. Such changes-resulting in mucosal ulceration, fibrosis, and stricture formation-may be preceded by severe early injury or arise without any
previous symptoms.
.
The incidence of severe radiation-induced proctosigmoiditis ranges from 2-4 to 5%,1,4 being related to the total dose. With doses up to 4000 cGy over four weeks it is unlikely to arise, but the probability increases as doses exceed 6000 cGy in six weeks.5 The condition is most commonly seen in women treated for carcinoma of the cervix by intracavitary and external beam irradiation. Most cases of severe late damage have been in patients with stage III carcinoma of the cervix. In such patients the pelvic anatomy may be distorted by tumour, interfering with placement of intracavitary sources. The resultant hot-spots on the bowel mucosa may become foci of clinically important radiation damage. With intracavitary treatment dose rate may be 9. Lanza FL, Graham DY. Bougienage is effective therapy for most benign esophageal strictures. JAMA 1978; 240: 844-47. 10. Ogilvie AL, Ferguson R, Atkinson M. Outlook with conservative treatment of peptic oesophageal stricture. Gut 1980; 21: 23-5
P, Casarett GW. Clinical radiation pathology, vol 1. Philadelphia: WB Saunders, 1968: 193-240. 2. Smith JP, Goolden PE, Rutledge F. Surgical management of intestinal injuries following irradiation for carcinoma of the cervix. Cancer of the uterus and ovary. Chicago: Year Book, 1969. 3. Gilinksy NH, Burns DG, Barbezat GO, Levin W, Myers HG, Marks IN. The natural history of radiation induced proctosigmoiditis: An analysis of 88 patients. Quart J Med 1983; 52: 40-53.
important factor than total dose.6 Factors which predispose to radiation-induced proctosigmoiditis include previous or subsequent surgery, in which the vascular supply may be compromised, pelvic sepsis,
a more
and treatment in hyperbaric oxygen. Diabetes and atherosclerosis have also been implicated. However, in over a third of cases there is no obvious cause.’ The diagnosis is made by sigmoidoscopy, where findings may range from erythema and telangiectasia to ulceration and necrosis. Double-contrast barium enema is particularly helpful in confirming this. Changes include loss of distensibility of the rectum and colon, fixed stenosis, and stricture. Mucosal irregularities, ulcers, and areas with ragged margins may be seen and can be confused with recurrent carcinoma, although abrupt termination of changes at the junction of the sigmoid and descending colon are suggestive of radiation-induced damage. Multiple lesions are not infrequent and unsuspected fistulas may be revealed. Rectal biopsy is seldom helpful and, since , it may precipitate ulceration and fistula formation, should be avoided. Patients who do badly with conservative management and require surgery have a high morbidity and mortality.8 Complications include subsequent small-bowel obstruction, wound dehiscence, and sepsis. Faecal diversion is the most common operative procedure, although this may not control rectal bleeding.9 Transverse colostomies can be difficult to manage because of semiformed stools and prolapse of the colostomy. A loop ileostomy may be preferrable since there is no interference with the blood supply of the colon, particularly the middle-colic vessels. If the symptoms improve it may subsequently be possible to restore bowel continuity. Gilinsky3 reports that, of patients whose main symptom was lowgrade rectal bleeding, one-third had reversed spontaneously within six months and another third had stopped bleeding in a further eighteen months. Few of these patients required surgical treatment. Spontaneous recoveries were seen also in many patients with more severe symptoms-rectal bleeding requiring transfusion-but this took longer. A third of those surviving thirty months required surgery. No spontaneous remissions were seen in patients with severe symptoms of rectal bleeding, pain, and alteration in bowel habit that suggested pelvic fibrosis and stricture. By thirty months all required surgical treatment. Gilinsky found also that the outcome correlated well with the severity of clinical symptoms and that case-fatality rates increased with radiation
1. Rubin
4. Strickland P. Damage to the rectum in the radiation treatment of carcinoma of the cervix. Br J Radiol 1954; 27: 630-34. 5. Chau PM, Fletcher GH, Rutledge FN, Dodd GP. Complications in high dose whole pelvic irradiation in female pelvic cancer. A J R 1962; 87: 22-40.
6. Lee
KH, Kagan AR, Nussbaum H, Wollin MS, Winkley JH, Norman A Analysis of dose, dose-rate and treatment time in the production of injuries by radium treatment for carcinoma of the uterine cervix. Br JRadiol 1976; 49: 430-40 7. Jackson BT. Bowel damage from radiation. Proc Roy Soc Med 1976; 69: 683-86 8. Stuart M, Failes DG, Killingback MJ, DeLuca C. Irradiation injuries of the large intestine. Dis Colon Rectum 1980; 23: 94-97 9. Goligher GC. Surgery of anus, rectum and colon (2nd ed ) Springfield Charles C Thomas, 1967: 1012. 10. Cooke SAR, De Moor NG. The surgical treatment of the radiation-damaged rectum BrJSurg 1981; 68: 488-92.
1083
damage. Over the eight year reported period 65% of those with severe symptoms had died as a result of their radiation injury, compared with 34% of those with few symptoms. Most deaths occurred within the first year, but there was a continuing attrition rate, particularly in those with symptoms of intermediate severity, reflecting the progressive nature of the process. The risk of severe radiation damage can be kept to a minimum by careful radiation planning and avoidance of the local high dosage which can arise with intracavitary radiotherapy. Such radiation injury carries a poor prognosis and the dire consequences are particularly disappointing when, as in many cases, there proves to have been no recurrence of the primary tumour.
recipients of liver, pancreas, heart, and combined heartlung transplants the drug has given better control of rejection than did previous conventional regimens. The incidence of malignant disease in patients treated with cyclosporin has been analysed by Penn8 and by the manufacturers (Sandoz). More than 3000 patients have been treated-1800 renal, 130 heart, 850 bone marrow, and 170 other organ grafts and 100 patients not receiving grafts. Fifteen lymphomas have so far been reported, an incidence of 0-5% (0-4% for renal, 4-6% for heart, 0-18% for bone marrow grafts). With conventional immunosuppressive agents the incidence of de-novo tumour in renal allografts has been reported as between 2 and 11%.9 In Cambridge and in the multicentre European trial, once the modified cyclosporin treatment protocol was adopted, in which cyclosporin is the sole initial immunosuppressive In
methylprednisolone up to 6 g in two weeks for of established rejection, no further lymphoma has occurred (115 renal patients). It remains to be seen whether the addition of long-term low-dose corticosteroids to cyclosporin, as practised in North America, will improve graft survival without increasing tumour incidence. For the present, organ grafters can be reassured that cyclosporin, if used with care, is no more risky to the patient than conventional immunosuppression. Accurate risk calculation is not possible in patients treated for variable lengths of time at differing doses, some with additional immunosuppressive drugs. Of the 3000 patients given cyclosporin many have received the drug for short periods. There is no evidence that cyclosporin is directly carcinogenic; all data so far point to an indirect relation with neoplasia, due solely to the drug’s potent anti-T-cell immunosuppressive action. The main disadvantage of cyclosporin is its nephrotoxicity; this can limit its use, especially in recipients of renal allografts. Continued surveillance is required to ensure that cyclosporin does not produce structural renal damage, a possibility which has not yet been excluded. agent, with treatment
CYCLOSPORIN AND NEOPLASIA PHARMACOLOGICAL of organ
recipients malignant neoplasms.
immunosuppression, especially grafts, increases susceptibility
for to
The risk is greatest for tumours for which the evidence for a viral aetiology is strongest.’ In two epidemiological studies non-Hodgkin’s lymphoma arose at 49 and 28 times the incidence in matched untreated populations.2,3 Most lesions occurred in the first year after organ grafting. Skin cancer has been common in Australia and southern USA. The incidences of Kaposi’s sarcoma and primary hepatoma are also much increased. A special group of patients at risk are those with cardiomyopathy and heart grafts treated with azathioprine, corticosteroids, and antilymphocyte globulin; the original heart disease may involve a defect in immune regulation. A 167o frequency of lymphoma was reported in one series of such cases. A common feature to these observations is impaired thymusdependent immunity. Thus, an attack of infectious mononucleosis is normally brought to an end by T-cell action controlling the Epstein-Barr virus induced B-cell proliferation. If T-cell function is deficient, unchecked cell growth can result in a malignant tumour. It was therefore not surprising that, when cyclosporin was used in clinical organ grafting, lymphomas were reported.5 Cyclosporin is a potent suppressor of T-cell activity and when it was first tried the dosage was high and other immunosuppressive agents were given, so that treatment was excessive. Cyclosporin is difficult to use, being variable in absorption and effect, but with a modified protocol the results of renal allografting from cadaver donors have improved.6,7 1. Kinlen LJ Immunosuppressive therapy and cancer. Cancer Surveys 1982; 1: 565-83. 2 Hoover R, Fraumeni JF Jr. Risk of cancer in renal transplant recipients. Lancer 1973; ii: 55-57. 3 Kinlen LJ, Sheil AGR, Peto J, Doll R. Collaborative United Kingdom-Australasian study of cancer in patients treated with immunosuppressive drugs. Br Med J 1979;
ii 1461-66. 4 Anderson JL, Fowles
RE, Bieber CP, Stinson EB Idiopathic cardiomyopathy, age and suppressor-cell dysfunction as risk determinants of lymphoma after cardiac transplantation Lancet 1978; ii. 1174-77 5 Calne RY, Rolles K, White DJG, Thiru S, Evans DB, McMaster P, Dunn DC, Craddock GN, Henderson RG, Aziz S, Lewis P. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs, 32 kidneys, 2 pancreases and 2 livers Lancet 1979; ii: 1033-56. 6. Calne RY, White DJG, Evans DB, Thiru S, Henderson RG, Hamilton DV, Rolles K, McMaster P, Duffy TJ, MacDougall BRD, Williams R Cyclosporin A in cadaveric organ transplantation Br Med J 1981; 282: 934-36. 7 Preliminary results of a European multicentre trial: Cyclosporin A as a sole immunosuppressive agent in recipients of kidney allografts from cadaver donors. Lancer 1982;
ii
57-60
COLITIS IN TERM BABIES BLOOD in the stools is always an ominous sign. In the newborn it is mostly identified with the syndrome of necrotising enterocolitis (NEC)-an acute, frequently lethal condition of the bowel (mainly large) characterised by areas of patchy necrosis, ulceration, and sometimes perforation, and presenting typically with abdominal distension, apnoeic episodes, bile-stained aspirate, bloody diarrhoea, and a radiological appearance of gas within the bowel wall. Most commonly affected are prematurely born infants who have been severely ill in neonatal life. ]-3 The mechanism immediately responsible for the intestinal damage is probably an ischaemic necrosis, which is somehow precipitated by such diverse influences as infection, asphyxia, overfeeding, 8. Penn I Malignancies following the use of cyclosporin A in man. Cancer Surveys 1982; 1: 621-24 9. Penn I. Tumor incidence in human allograft recipients Transplant Proc 1979, 11:
1047-54.
necrotising enterocolitis surveillance. Communicable Disease Report 82/05: 3-5. London: Public Health Laboratory Service, 1982, unpublished. 2. Sarasohn C. Care of the very small premature infants. Pediat Clin N Am 1977; 24: 619-32. 3 Lake AM, Walker WA. Neonatal necrotising enterocolitis. A disease of altered host defence. Clin Gastroenterol 1977; 6: 463-80. 1. Neonatal
of
patients with dysphagia from strictures gain acceptable relief from dilatation, irrespective of the technique. One or two dilatations may be sufficient to afford prolonged relief and medical treatment will usually control any subsequent symptoms of reflux. Stricture dilatation is a procedure without much intellectual or aesthetic appeal, but it is now reasonably safe and the benefits it brings are great.
Radiation-induced
Proctosigmoiditis
AFTER radiation for pelvic malignant disease, damage to the sigmoid colon and rectum is common. The early injuries tend to be mild and reversible; the later changes can be severe and progressive. When 3000 to 4000 cGy is given over three to four weeks, early damage is invariable: the symptoms, which correspond to the phase of radiation-induced oedema and hyperaemia of the mucosa,’1 are’ incomplete evacuation, diarrhoea, and tenesmus. Conservative treatment with low residue diet and antidiarrhoeals will aid recovery and seldom are there any late sequelae. More serious damage becomes manifest between six and twelve months after treatment,I-3 with diarrhoea, rectal bleeding, pain, and constipation due to progressive radiation changes in the connective tissue and vasculature. Such changes-resulting in mucosal ulceration, fibrosis, and stricture formation-may be preceded by severe early injury or arise without any
previous symptoms.
.
The incidence of severe radiation-induced proctosigmoiditis ranges from 2-4 to 5%,1,4 being related to the total dose. With doses up to 4000 cGy over four weeks it is unlikely to arise, but the probability increases as doses exceed 6000 cGy in six weeks.5 The condition is most commonly seen in women treated for carcinoma of the cervix by intracavitary and external beam irradiation. Most cases of severe late damage have been in patients with stage III carcinoma of the cervix. In such patients the pelvic anatomy may be distorted by tumour, interfering with placement of intracavitary sources. The resultant hot-spots on the bowel mucosa may become foci of clinically important radiation damage. With intracavitary treatment dose rate may be 9. Lanza FL, Graham DY. Bougienage is effective therapy for most benign esophageal strictures. JAMA 1978; 240: 844-47. 10. Ogilvie AL, Ferguson R, Atkinson M. Outlook with conservative treatment of peptic oesophageal stricture. Gut 1980; 21: 23-5
P, Casarett GW. Clinical radiation pathology, vol 1. Philadelphia: WB Saunders, 1968: 193-240. 2. Smith JP, Goolden PE, Rutledge F. Surgical management of intestinal injuries following irradiation for carcinoma of the cervix. Cancer of the uterus and ovary. Chicago: Year Book, 1969. 3. Gilinksy NH, Burns DG, Barbezat GO, Levin W, Myers HG, Marks IN. The natural history of radiation induced proctosigmoiditis: An analysis of 88 patients. Quart J Med 1983; 52: 40-53.
important factor than total dose.6 Factors which predispose to radiation-induced proctosigmoiditis include previous or subsequent surgery, in which the vascular supply may be compromised, pelvic sepsis,
a more
and treatment in hyperbaric oxygen. Diabetes and atherosclerosis have also been implicated. However, in over a third of cases there is no obvious cause.’ The diagnosis is made by sigmoidoscopy, where findings may range from erythema and telangiectasia to ulceration and necrosis. Double-contrast barium enema is particularly helpful in confirming this. Changes include loss of distensibility of the rectum and colon, fixed stenosis, and stricture. Mucosal irregularities, ulcers, and areas with ragged margins may be seen and can be confused with recurrent carcinoma, although abrupt termination of changes at the junction of the sigmoid and descending colon are suggestive of radiation-induced damage. Multiple lesions are not infrequent and unsuspected fistulas may be revealed. Rectal biopsy is seldom helpful and, since , it may precipitate ulceration and fistula formation, should be avoided. Patients who do badly with conservative management and require surgery have a high morbidity and mortality.8 Complications include subsequent small-bowel obstruction, wound dehiscence, and sepsis. Faecal diversion is the most common operative procedure, although this may not control rectal bleeding.9 Transverse colostomies can be difficult to manage because of semiformed stools and prolapse of the colostomy. A loop ileostomy may be preferrable since there is no interference with the blood supply of the colon, particularly the middle-colic vessels. If the symptoms improve it may subsequently be possible to restore bowel continuity. Gilinsky3 reports that, of patients whose main symptom was lowgrade rectal bleeding, one-third had reversed spontaneously within six months and another third had stopped bleeding in a further eighteen months. Few of these patients required surgical treatment. Spontaneous recoveries were seen also in many patients with more severe symptoms-rectal bleeding requiring transfusion-but this took longer. A third of those surviving thirty months required surgery. No spontaneous remissions were seen in patients with severe symptoms of rectal bleeding, pain, and alteration in bowel habit that suggested pelvic fibrosis and stricture. By thirty months all required surgical treatment. Gilinsky found also that the outcome correlated well with the severity of clinical symptoms and that case-fatality rates increased with radiation
1. Rubin
4. Strickland P. Damage to the rectum in the radiation treatment of carcinoma of the cervix. Br J Radiol 1954; 27: 630-34. 5. Chau PM, Fletcher GH, Rutledge FN, Dodd GP. Complications in high dose whole pelvic irradiation in female pelvic cancer. A J R 1962; 87: 22-40.
6. Lee
KH, Kagan AR, Nussbaum H, Wollin MS, Winkley JH, Norman A Analysis of dose, dose-rate and treatment time in the production of injuries by radium treatment for carcinoma of the uterine cervix. Br JRadiol 1976; 49: 430-40 7. Jackson BT. Bowel damage from radiation. Proc Roy Soc Med 1976; 69: 683-86 8. Stuart M, Failes DG, Killingback MJ, DeLuca C. Irradiation injuries of the large intestine. Dis Colon Rectum 1980; 23: 94-97 9. Goligher GC. Surgery of anus, rectum and colon (2nd ed ) Springfield Charles C Thomas, 1967: 1012. 10. Cooke SAR, De Moor NG. The surgical treatment of the radiation-damaged rectum BrJSurg 1981; 68: 488-92.
1083
damage. Over the eight year reported period 65% of those with severe symptoms had died as a result of their radiation injury, compared with 34% of those with few symptoms. Most deaths occurred within the first year, but there was a continuing attrition rate, particularly in those with symptoms of intermediate severity, reflecting the progressive nature of the process. The risk of severe radiation damage can be kept to a minimum by careful radiation planning and avoidance of the local high dosage which can arise with intracavitary radiotherapy. Such radiation injury carries a poor prognosis and the dire consequences are particularly disappointing when, as in many cases, there proves to have been no recurrence of the primary tumour.
recipients of liver, pancreas, heart, and combined heartlung transplants the drug has given better control of rejection than did previous conventional regimens. The incidence of malignant disease in patients treated with cyclosporin has been analysed by Penn8 and by the manufacturers (Sandoz). More than 3000 patients have been treated-1800 renal, 130 heart, 850 bone marrow, and 170 other organ grafts and 100 patients not receiving grafts. Fifteen lymphomas have so far been reported, an incidence of 0-5% (0-4% for renal, 4-6% for heart, 0-18% for bone marrow grafts). With conventional immunosuppressive agents the incidence of de-novo tumour in renal allografts has been reported as between 2 and 11%.9 In Cambridge and in the multicentre European trial, once the modified cyclosporin treatment protocol was adopted, in which cyclosporin is the sole initial immunosuppressive In
methylprednisolone up to 6 g in two weeks for of established rejection, no further lymphoma has occurred (115 renal patients). It remains to be seen whether the addition of long-term low-dose corticosteroids to cyclosporin, as practised in North America, will improve graft survival without increasing tumour incidence. For the present, organ grafters can be reassured that cyclosporin, if used with care, is no more risky to the patient than conventional immunosuppression. Accurate risk calculation is not possible in patients treated for variable lengths of time at differing doses, some with additional immunosuppressive drugs. Of the 3000 patients given cyclosporin many have received the drug for short periods. There is no evidence that cyclosporin is directly carcinogenic; all data so far point to an indirect relation with neoplasia, due solely to the drug’s potent anti-T-cell immunosuppressive action. The main disadvantage of cyclosporin is its nephrotoxicity; this can limit its use, especially in recipients of renal allografts. Continued surveillance is required to ensure that cyclosporin does not produce structural renal damage, a possibility which has not yet been excluded. agent, with treatment
CYCLOSPORIN AND NEOPLASIA PHARMACOLOGICAL of organ
recipients malignant neoplasms.
immunosuppression, especially grafts, increases susceptibility
for to
The risk is greatest for tumours for which the evidence for a viral aetiology is strongest.’ In two epidemiological studies non-Hodgkin’s lymphoma arose at 49 and 28 times the incidence in matched untreated populations.2,3 Most lesions occurred in the first year after organ grafting. Skin cancer has been common in Australia and southern USA. The incidences of Kaposi’s sarcoma and primary hepatoma are also much increased. A special group of patients at risk are those with cardiomyopathy and heart grafts treated with azathioprine, corticosteroids, and antilymphocyte globulin; the original heart disease may involve a defect in immune regulation. A 167o frequency of lymphoma was reported in one series of such cases. A common feature to these observations is impaired thymusdependent immunity. Thus, an attack of infectious mononucleosis is normally brought to an end by T-cell action controlling the Epstein-Barr virus induced B-cell proliferation. If T-cell function is deficient, unchecked cell growth can result in a malignant tumour. It was therefore not surprising that, when cyclosporin was used in clinical organ grafting, lymphomas were reported.5 Cyclosporin is a potent suppressor of T-cell activity and when it was first tried the dosage was high and other immunosuppressive agents were given, so that treatment was excessive. Cyclosporin is difficult to use, being variable in absorption and effect, but with a modified protocol the results of renal allografting from cadaver donors have improved.6,7 1. Kinlen LJ Immunosuppressive therapy and cancer. Cancer Surveys 1982; 1: 565-83. 2 Hoover R, Fraumeni JF Jr. Risk of cancer in renal transplant recipients. Lancer 1973; ii: 55-57. 3 Kinlen LJ, Sheil AGR, Peto J, Doll R. Collaborative United Kingdom-Australasian study of cancer in patients treated with immunosuppressive drugs. Br Med J 1979;
ii 1461-66. 4 Anderson JL, Fowles
RE, Bieber CP, Stinson EB Idiopathic cardiomyopathy, age and suppressor-cell dysfunction as risk determinants of lymphoma after cardiac transplantation Lancet 1978; ii. 1174-77 5 Calne RY, Rolles K, White DJG, Thiru S, Evans DB, McMaster P, Dunn DC, Craddock GN, Henderson RG, Aziz S, Lewis P. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs, 32 kidneys, 2 pancreases and 2 livers Lancet 1979; ii: 1033-56. 6. Calne RY, White DJG, Evans DB, Thiru S, Henderson RG, Hamilton DV, Rolles K, McMaster P, Duffy TJ, MacDougall BRD, Williams R Cyclosporin A in cadaveric organ transplantation Br Med J 1981; 282: 934-36. 7 Preliminary results of a European multicentre trial: Cyclosporin A as a sole immunosuppressive agent in recipients of kidney allografts from cadaver donors. Lancer 1982;
ii
57-60
COLITIS IN TERM BABIES BLOOD in the stools is always an ominous sign. In the newborn it is mostly identified with the syndrome of necrotising enterocolitis (NEC)-an acute, frequently lethal condition of the bowel (mainly large) characterised by areas of patchy necrosis, ulceration, and sometimes perforation, and presenting typically with abdominal distension, apnoeic episodes, bile-stained aspirate, bloody diarrhoea, and a radiological appearance of gas within the bowel wall. Most commonly affected are prematurely born infants who have been severely ill in neonatal life. ]-3 The mechanism immediately responsible for the intestinal damage is probably an ischaemic necrosis, which is somehow precipitated by such diverse influences as infection, asphyxia, overfeeding, 8. Penn I Malignancies following the use of cyclosporin A in man. Cancer Surveys 1982; 1: 621-24 9. Penn I. Tumor incidence in human allograft recipients Transplant Proc 1979, 11:
1047-54.
necrotising enterocolitis surveillance. Communicable Disease Report 82/05: 3-5. London: Public Health Laboratory Service, 1982, unpublished. 2. Sarasohn C. Care of the very small premature infants. Pediat Clin N Am 1977; 24: 619-32. 3 Lake AM, Walker WA. Neonatal necrotising enterocolitis. A disease of altered host defence. Clin Gastroenterol 1977; 6: 463-80. 1. Neonatal