Kjell Öberg

Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors.

OBJECTIVEnTo determine the incidence of autoantibodies and autoimmune disease and their influence on therapeutic results during alpha-interferon treatment in patients with malignant midgut carcinoid tumors.nnnDESIGNnConsecutive sample of patients.nnnSETTINGnUniversity hospital.nnnPATIENTSnOne hundred thirty-five patients (70 women, 65 men; median age, 59 years) with biopsy-proven tumors, liver metastases, and no autoimmune disease.nnnINTERVENTIONSnLeukocyte alpha-interferon (n = 88) or alpha-interferon 2b (n = 47) three times a week.nnnMAIN OUTCOME MEASURESnSigns and symptoms of autoimmune disease or development of autoantibodies to thyroid antigens, nuclear antigens, or gastric parietal cells. Tumor responses were determined by reduced liver metastases or reduced urinary 5-hydroxyindole acetic acid excretion, or both.nnnRESULTSnTwenty-five patients (19%) developed the following autoimmune disorders after a median of 9 months of therapy: thyroid disease (n = 18), systemic lupus erythematosus (n = 1), pernicious anemia (n = 4), and vasculitis (n = 2). Antibodies to microsomal thyroid antigen or thyroglobulin were detected in 16 patients before therapy and in another 11 patients during therapy. Antinuclear antibodies were detected in 16 patients before and in another 19 patients during therapy. Clinical thyroid disease developed in more than 60% of patients who had or developed thyroid antibodies but in only 7% of initially autoantibody-negative patients. Autoimmunity did not correlate with objective tumor response.nnnCONCLUSIONnPatients with malignant carcinoid tumors may develop autoimmune disease during alpha-interferon therapy, especially when autoantibodies are present. They should therefore be monitored for autoimmunity, which does not appear, however, to influence tumor responses.

Possible induction of systemic lupus erythematosus by interferon-α treatment in a patient with a malignant carcinoid tumour

Abstract. Interferon‐α (IFN‐α) is currently used in the treatment of various malignant tumours. Development of different autoimmune disorders has been reported in some patients during IFN‐α therapy. Systemic lupus erythematosus (SLE) after treatment with IFN‐α has not been described, although a majority of SLE patients have demonstrable serum levels of IFN‐α, which correlate with disease activity and have been suggested to be of pathogenetic significance.

Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors

Patients with neuroendocrine gastrointestinal tumors usually present with inoperable metastatic disease and severe hormonal symptoms. Specific chemotherapy, interferon‐α (IFN), and somatostatin analogs are established therapies for these patients, but all of them eventually fail. Hepatic arterial embolization can provide reduction of both hormonal symptoms and tumor burden in these patients.

The role of interferons in the management of carcinoid tumors.

Malignant carcinoid tumors with the carcinoid syndrome has over the years presented a therapeutic challenge. Surgery is the treatment of choice in local disease but when liver metastases have developed other treatment procedures must be considered. Conventional chemotherapy has been of little benefit, whereas a new somatostatin analogue octreotide gives a good control of clinical symptoms but not of tumor progression. Interferon treatment was introduced in 1982 by our group and we are now presenting results of medical treatment in 130 patients with histologically verified malignant carcinoid tumors and liver metastases. One hundred and eleven patients were treated with alpha-interferon, whereas 19 patients received conventional chemotherapy. Forty-seven out of 111 patients (42%) treated with alpha-interferon demonstrated a significant biochemical response and 15% also more than 50% reduction of tumor size. In another 43 (39%) patients stabilization of the carcinoid disease was noted whereas 21 (19%) showed progressive disease. The median duration of response was 34 months. Subjective response with improvement of diarrheas, flush and/or bronchoconstriction was noticed in 76 patients (68%). Among the 19 patients treated with conventional chemotherapy only 2 showed biochemical response and it lasted only for 3-5 months. The patients treated with chemotherapy had a median survival of only 8 months compared with 80+ months in the group treated with alpha-interferon. The adverse reactions of alpha-interferon are manageable and consist mainly of fatigue, weight reduction and reduction of blood cell counts. Neutralizing interferon antibodies might occur in patients treated with recombinant alpha-interferons (5-15%).

Medical Treatment and Long-term Survival in a Prospective Study of 84 Patients With Endocrine Pancreatic Tumors

A prospective study was performed on 84 patients with neuroendocrine pancreatic tumors. Fifty‐nine (70%) had malignant tumors and received causal medical treatment. Streptozotocin in combination with 5‐fluorouracil or doxorubicin was used as first‐line treatment and produced overall objective responses in 20 of 44 (45%) patients with a median duration of response of 27.5 months. Thirty‐two patients who failed on chemotherapy subsequently received interferon treatment and 20 (63%) responded objectively with a median duration of 20.5 months. Octreotide, third‐line treatment in 14 patients, produced objective responses in four patients (28%) (median duration of response, 16 months). The median survival from diagnosis in malignant cases was 6.7 years. Even if none of the current medical therapies are curative for patients with malignant endocrine pancreatic tumors, a prolonged survival would be observed during the last decade. Since the age at diagnosis has not been dramatically reduced despite improvements in diagnostic methods, the prolonged survival might be attributed to causal medical treatment. Cancer 65:1883‐1890, 1990.

Neuroendrocine pancreatic tumours: clinical presentation, biochemical and histopathological findings in 84 patients

Abstract. A prospective study has been performed on 84 patients with endocrine pancreatic tumours evaluated at the Medical Department in Uppsala. Available information concerning the patients presenting symptoms, age at diagnosis, clinical syndrome, tumour location, location of metastases, diagnostic radiology, biochemical and histopathological findings has been analysed. Our results indicate that most patients initially show rather vague and non‐specific symptoms, with dyspepsia and pain being the most frequent presenting features. The median delay between appearance of the first symptom and diagnosis was 2 years; the delay was 3 5 months in sporadic cases and 14.5 months in familial cases. In spite of improvements in diagnostic methods, the median age at diagnosis (53 years) has not been reduced, and most patients are encountered when the tumour has reached an advanced stage. There is a need for a method of screening patients with still uncharacteristic abdominalsymptoms for a neuroendocrine tumour. The presence of elevated levels of plasma chromogranin in all patients with a proven tumour suggests that such possibilities exist, and the use of this biochemical marker in the future might reduce the age at diagnosis and thus improve the likelihood of cure and survival of patients with endocrine pancreatic tumours.

TREATMENT OF MALIGNANT ENDOCRINE PANCREATIC TUMOURS WITH HUMAN LEUCOCYTE INTERFERON

22 patients with advanced malignant endocrine pancreatic tumours were treated with human leucocyte interferon 3-6 X 10(6) IU per day. Objective responses (more than 50% reduction in tumour markers or tumour size) were seen in 7/7 with watery diarrhoea/hypokalaemia/achlorhydria syndrome, 3/4 with the Zollinger-Ellison syndrome, 6/9 with non-functioning tumours, and 1 with a mixed tumour mainly producing somatostatin. The median duration of response was 8.5 months, and all responders improved clinically. Adverse effects seemed more tolerable than those of cytotoxic treatment.

Pancreatic tumors in multiple endocrine neoplasia type 1 : clinical presentation and surgical treatment

Among 33 patients with endocrine pancreatic tumors due to multiple endocrine neoplasia type 1 (MEN-1), 19 (58%) patients had hypergastrinemia, 7 (21%) patients had hyperinsulinism, and 7 (21%) patients had clinically non-functioning lesions. At least one gross tumor was found in all patients undergoing pancreatic surgery, including those with negative localization studies prior to operation. The patients also had additional macroscopic tumors as well as numerous microadenomas, and the lesions frequently were positive for immunostaining with multiple hormones, mainly pancreatic polypeptide, insulin, glucagon, and somatostatin. Duodenal endocrine lesions were found in 4 of 5 investigated patients and stained with gastrin and somatostatin antibodies. Distal, mainly subtotal pancreatic resection, was performed in 18 patients, eventually combined with caput tumor enucleation or duodenotomy, while a few patients underwent only tumor enucleation or a Whipple procedure. The long-erm outcome of operation was most favorable in patients with hyperinsulinism; only 1 patient had clinical recurrence. Patients with hypergastrinemia experienced only transitory lowering of serum gastrin values after pancreatic surgery and 47% of them had or developed metastases. Such tumor spread was seen in 57% of the patients with non-functioning lesions. Nine patients died from progressive tumor disease during follow-up. Consistent with previous studies, we found that surgery is indicated in MEN-1 patients with hyperinsulinism even if a lesion is not visualized by radiology. In addition, these indications should be extended to also include patients with only biochemical markers of disease, including elevations of gastrin, as these indicate the presence of gross tumors. This strategy should be applied especially in patients with aggressive family histories to possibly reduce the risk of malignant tumor progression.RésuméParmi 33 patients ayant une tumeur pancréatique endocrine due à une néoplasie endocrine multiple de type 1 (MEN-1), 19 (58%) avaient une hypergastrinémie, 7 (21%) un hyperinsulinisme et 7 (21%) une lésion cliniquement muette. On a mis en évidence au minimum une grosse tumeur chez tous les patients, y compris chez ceux dont les examens préopératoires de dépistage tumoral étaient négatifs. Les patients étaient également porteurs de tumeurs macroscopiques et de nombreux microadénomes. Les lésions montraient souvent un immunomarquage positif pour de multiples hormones, principalement le polypeptide pancréatique, linsuline, le glucagon et la somatostatine. Des lésions endocrines duodénales furent retrouvées chez 4 des 5 patients explorés; elles montraient un immunomarquage avec les anticorps angigastrine et anti-somatostatine. Une résection pancréatique distale, le plus souvent subtotale, a été réalisée chez 18 patients. Elle était éventuellement complétée par une énucléation tmorale de la tête ou par une duodénotomie. Peu de patients ont bénéficié dune simple énucléation ou dune intervention de Whipple. Lévolution postopératoire à long terme a été plus favorable en cas dinsulinome puisque seul un patient a eu une récidive clinique. Les patients atteints de gastrinome nont présenté que transitoirement une diminution des taux sériques de gastrine après la chirurgie pancréatique. Quarante sept pour cent de ces patients avaient ou ont développé des métastases contre 57% des patients porteurs de lésions sans traduction clinique. Neuf patients sont décédés en raison de lextension tumorale au cours du suivi. Conformément à des suggestions antérieures, la chirurgie semble indiquée chez les patients atteints de MEN-1 avec hyperinsulinisme même si la radiologie ne visualise pas de lésion. Mais cette indication peut être élargie aux patients dont seuls les paramètres biologiques sont en faveur dune grosse tumeur (dont lhypergastrinémie). Cette stratégie pourrait convenir particulièrement aux patients ayant des antécédents familiaux importants; elle permettrait peut-être de réduire le risque dextension tumorale.ResumenEntre 33 individuos con tumores pancréaticos endocrinos como componente del síndrome de neoplasia endocrina múltiple tipo 1 (NEM-1), 19 pacientes (58%) tenían hipergastrinemia, 7 (21%) hiperinsulinismo y 7 (21%) lesiones clínicas “no funcionantes”. En la totalidad de los pacientes sometidos a cirugía pancreática fue hallado por lo menos un tumor, incluso en aquellos con examenes de localización negativos anteriores a la operación. Estos pacientes también albergaban tumores macroscópicos, así como numerosos microadenomas; con frecuencia las lesiones demostraron inmunocoloración con diferentes hormonas, principalmente polipéptido, insulina, glucagón y somatostatina. Se encontraron lesiones endocrinas duodenales en 4 de cada 5 pacientes investigados, las cuales colorearon con gastrina y anticuerpos a la somatostatina. Se practicó resección pancreática distal (principalmente resección subtotal) en 18 pacientes, eventualmente combinada con enucleación del tumor (cuando éste se hallaba ubicado en la cabeza del páncreas) o duodenectomía; solamente unos pocos pacientes fueron sometidos a simple enucleación del tumor o al procedimiento de Whipple. El resultado a largo plazo fue más favorable en los pacientes con hiperinsulinismo, puesto que sólo uno presentó recurrencia clínica. Los pacientes con hipergastrinemia exhibieron apenas una disminución transitoria de los valores de gastrina sérica luego de la cirugía pancreática. Cuarenta y siete por ciento del conjunto tuvo o desarrolló metástasis, en tanto que la extensión local del tumor se presentó en 57% de los casos con lesiones no funcionantes. Nueve pacientes murieron por progresión de la neoplasia en el curso del seguimiento. En acuerdo con sugerencias previas, se considero quo la cirugía está indicada en pacientes con NEM-1 e hiperinsulinismo, aún en los casos en que no se visualiza radiológicamente la lesión, pero que la indicación puede ser ampliada para incluir también pacientes con sólo marcadores bioquímicos, tales como niveles elevados de gastrina, indicativos de la presencia de tumores macroscópicos. Esta estrategia debe ser aplicada principalmente en aquellos pacientes con historia familiar agresiva, con lo cual tal vez se reduce el riesgo de progesión maligna del tumor.

Autoimmune Phenomena in Patients with Malignant Carcinoid Tumors During Interferon-α Treatment

Several previous reports suggest an association between treatment of patients with interferon-α (IFN-α) and development of autoantibodies and autoimmune disease. We here summarize the experience from a group of 135 patients with midgut carcinoid tumors treated with natural leukocyte IFN-α or recombinant IFN-α (rIFN-α). An unusual high incidence of antimicrosomal antibodies (MsAb) or anti-thyroglobulin antibodies (TgAb) and thyroid disease manifested as hyperthyroidism, hypothyroidism or a biphasic Hashimoto-like disease was seen, with female predominance. the incidence of antinuclear antibodies (ANA) was also increased, but equally in both sexes. Antibodies to parietal cells were found in 5 cases and 4 patients with pernicious anemia were detected. Two patients developed vasculitis of leukocytoclastic type and one a syndrome resembling systemic lupus erythematosus. Some patients treated with rIFN-α develop anti-IFN antibodies. Such antibodies may also be autoantibodies reacting with autologous IFN-α. They...

Cytotoxic Treatment in Patients with Malignant Carcinoid Tumors: Response to streptozocin—alone or in combination with 5-FU

Thirty-one patients with malignant carcinoid tumors were treated with streptozocin--alone (n = 7) or in combination with FU (n = 24). The responses to treatment were followed by the determination of tumor markers, urinary 5-HIAA, serum PP, HCG-alpha and -beta subunits, as well as determination of the size of liver metastases on computerized tomography or ultrasonography. Three patients (9.7%) showed objective responses with a mean remission time of 2.7 months. Eighteen patients (58%) showed stable disease, whereas ten patients (32.3%) showed progressive disease directly from the start of therapy. A good correlation was found between the changes in tumor markers and tumor size, although the changes occurred earlier in the markers than in the size. Estimated median survival from the time of histologically verified carcinoid tumor was 41 months and from start of therapy 22 months. Our data indicate that combination treatment with streptozocin and 5-fluorouracil is of little value for patients with malignant carcinoid tumors.