Treatment of patients with gastro-entero-pancreatic -LRB- GEP -RRB- tumours with the novel radiolabelled somatostatin analogue -LSB- 177Lu-DOTA0 , Tyr3 -RSB- octreotate Medical treatment and chemotherapy are seldom successful in achieving objective tumour reduction in patients with metastatic neuroendocrine tumours . Treatment with the radiolabelled somatostatin analogue -LSB- 90Y-DOTA0 , Tyr3 -RSB- octreotide may result in partial remissions in 10 -- 25 % of patients . The newer analogue -LSB- DOTA0 , Tyr3 -RSB- octreotate -LRB- octreotate -RRB- has a ninefold higher affinity for the somatostatin receptor subtype 2 as compared with -LSB- DOTA0 , Tyr3 -RSB- octreotide . Also , labelled with the beta - and gamma-emitting radionuclide 177Lu , it has proved very successful in achieving tumour regression in animal models . The effects of 177Lu-octreotate therapy were studied in 35 patients with neuroendocrine gastro-entero-pancreatic -LRB- GEP -RRB- tumours who underwent follow-up for 3 -- 6 months after receiving their final dose . Patients were treated with doses of 100 , 150 or 200 mCi 177Lu-octreotate , to a final cumulative dose of 600 -- 800 mCi , with treatment intervals of 6 -- 9 weeks . Nausea and vomiting within the first 24 h after administration were present in 30 % and 14 % of the administrations , respectively . WHO toxicity grade 3 anaemia , leucocytopenia and thrombocytopenia occurred after 0 % , 1 % and 1 % of the administrations , respectively . Serum creatinine and creatinine clearance did not change significantly . The effects of the therapy on tumour size were evaluable in 34 patients . Three months after the final administration , complete remission was found in one patient -LRB- 3 % -RRB- , partial remission in 12 -LRB- 35 % -RRB- , stable disease in 14 -LRB- 41 % -RRB- and progressive disease in seven -LRB- 21 % -RRB- , including three patients who died during the treatment period . Tumour response was positively correlated with a high uptake on the octreoscan , limited hepatic tumour mass and a high Karnofsky Performance Score . Because of the limited efficacy of alternative therapies , many physicians currently adopt an expectant attitude when dealing with patients with metastatic GEP tumours . However , in view of the high success rate of therapy with 177Lu-octreotate and the absence of serious side-effects , we advocate its use in patients with GEP tumours without waiting for tumour progression . Introduction Neuroendocrine gastro-entero-pancreatic -LRB- GEP -RRB- tumours , which comprise pancreatic islet cell tumours , non-functioning neuroendocrine pancreatic tumours and carcinoids , are usually slow growing . If the tumour is localized , the therapy of choice is surgery . When a metastatic tumour causes a syndrome by hormonal overproduction -LRB- i.e. carcinoid syndrome , hypergastrinaemia -RRB- , treatment with somatostatin analogues results in symptomatic relief in most cases . In terms of objective tumour reduction -LRB- complete and partial remission -RRB- , however , treatment with somatostatin analogues is seldom successful , whether or not it is given in combination with interferon-α -LSB- 1 , 2 , 3 -RSB- . A new development in cytoreductive therapy for GEP tumours is the use of radiolabelled somatostatin analogues . Initial studies with high doses of -LSB- 111In-DTPA0 -RSB- octreotide -LRB- 111In-octreotide ; Octreoscan -RRB- in patients with metastatic neuroendocrine tumours were encouraging , although partial remissions were exceptional -LSB- 4 , 5 -RSB- . However , 111In-coupled peptides are not ideal for peptide receptor radionuclide radiotherapy -LRB- PRRT -RRB- because of the small particle range and therefore short tissue penetration . Therefore , another radiolabelled somatostatin analogue , -LSB- 90Y-DOTA0 , Tyr3 -RSB- octreotide , was developed . Using this compound , partial remissions have been reported in 10 -- 25 % of patients with neuroendocrine tumours -LSB- 6 , 7 , 8 -RSB- . Recently , it was reported that the somatostatin analogue -LSB- DOTA0 , Tyr3 -RSB- octreotate has a ninefold higher affinity for the somatostatin receptor subtype 2 as compared with -LSB- DOTA0 , Tyr3 -RSB- octreotide -LSB- 9 -RSB- . Also , labelled with the beta - and gamma-emitting radionuclide 177Lu , this compound was shown to be very successful in achieving tumour regression and animal survival in a rat model -LSB- 10 -RSB- . In a comparison in patients , we found that the uptake of radioactivity , expressed as a percentage of the injected dose of -LSB- 177Lu-DOTA0 , Tyr3 -RSB- octreotate -LRB- 177Lu-octreotate -RRB- , was comparable to that after 111In-octreotide for kidneys , spleen and liver , but was three - to fourfold higher for four of five tumours -LSB- 11 -RSB- . We concluded that 177Lu-octreotate potentially represents an important improvement because of -LRB- a -RRB- the higher absorbed doses that can be delivered to most tumours with about equal doses to potentially dose-limiting organs and -LRB- b -RRB- the lower tissue penetration range of 177Lu as compared with 90Y , which may be especially important for small tumours . In this study we present the first data on the side-effects as well as the antitumoral effects of 177Lu-octreotate therapy in 35 patients with GEP tumours , who had a follow-up of 3 -- 6 months after receiving their final dose . Materials and methods Patients Thirty-five patients with GEP tumours were studied . All patients had tumour uptake on the octreoscan preceding the therapy that was at least as high as the uptake in the normal liver tissue . None of the patients had received prior treatment with other radiolabelled somatostatin analogues . Eight patients used Sandostatin s.c. ; this medication was discontinued from 1 day before to 1 day after the treatment . Prerequisites for treatment were : Hb ≥ 6 mmol/l , WBC ≥ 2 × 109/l , platelets ≥ 80 × 109/l , creatinine ≤ 150 μmol/l and Karnofsky Performance Score ≥ 50 . All patients gave written informed consent to participate in the study , which was approved by the medical ethical committee of the hospital . Methods -LSB- DOTA0 , Tyr3 -RSB- octreotate was obtained from Mallinckrodt , St Louis , Mo. , USA . 177LuCl3 was obtained from NRG , Petten , the Netherlands and Missouri University Research Reactor -LRB- MURR -RRB- , Missouri , Mo. , USA , and was distributed by IDB , Baarle-Nassau , the Netherlands . 177Lu-octreotate was prepared as described previously -LSB- 11 -RSB- . Granisetron 3 mg was injected i.v. and an infusion of amino acids -LRB- lysine 2.5 % , arginine 2.5 % in 1 l 0.9 % NaCl ; 250 ml/h -RRB- was started 30 min before the administration of the radiopharmaceutical and lasted up to 3.5 h afterwards . The radiopharmaceutical was co-administered via a second pump system . The treatment doses of 100 mCi were injected in 20 min and those of 150 and 200 mCi were injected in 30 min . The interval between treatments was 6 -- 9 weeks . Patients were treated up to a cumulative dose of 750 -- 800 mCi -LRB- 27.8 -- 29.6 GBq -RRB- -LRB- corresponding to a radiation dose to the bone marrow of 2 Gy -RRB- -LSB- 11 -RSB- , unless dosimetric calculations indicated that the radiation dose to the kidneys would then exceed 23 Gy ; in these cases the cumulative dose was reduced to 600 -- 700 mCi . Routine haematology , liver and kidney function tests , hormone measurements and serum tumour markers were measured 1 week prior to each therapy , as well as at follow-up visits . EORTC quality of life forms -LRB- QLQ-C30 -RRB- -LSB- 12 -RSB- were filled out by the patients at each visit . CT or MRI scanning was done within 3 months before the first therapy , and 6 -- 8 weeks , 3 months and 6 months after the last treatment . In vivo measurements . The tumours on the CT or MRI scans were measured and scored according to the WHO solid tumour response criteria . The uptake on the pretreatment octreoscans was scored visually on planar images on a 4-point scale : grade 1 , lower than normal liver tissue uptake ; grade 2 , equal to normal liver tissue uptake ; grade 3 , greater than normal liver tissue uptake ; grade 4 , higher than normal spleen/kidney uptake . Statistics Analysis of variance -LRB- ANOVA -RRB- , paired t tests and chi-square tests were used . P values < 0.05 were considered significant . Results The study population comprised 14 men and 21 women with a mean age of 54 years -LRB- range 19 -- 78 years -RRB- . Twelve had carcinoid tumour , 12 neuroendocrine pancreatic tumour , 8 neuroendocrine tumour of unknown origin and 3 gastrinoma . Twelve patients had been operated in the past , 1 had had radiotherapy , 3 had had chemotherapy and 14 had been treated with octreotide -LRB- Sandostatin -RRB- . Sixteen of the 35 -LRB- 46 % -RRB- patients had documented progressive disease within 1 year before the start of the therapy . Cycle doses were 100 mCi in seven patients , 150 mCi in 14 and 200 mCi in the remaining 14 . Higher dosages were not administered , since 200 mCi 177LuCl3 is typically bound to 180 -- 300 μg -LSB- DOTA0 , Tyr3 -RSB- octreotate , and higher doses would result in a lower percentage tumour uptake owing to receptor saturation . In 30 patients , the final intended cumulative dose of 600 -- 800 mCi was administered . Three of the five remaining patients had progressive disease and died before completing their treatment ; the other two patients , who were both elderly , stopped their treatment after reaching a cumulative dose of 600 mCi because of the burden they felt the treatment to be . Nausea and vomiting within the first 24 h after the administration were present in 30 % and 14 % of the administrations , respectively , and were independent of the administered dose . Some abdominal pain was noticed during 11 % of the administrations , especially in patients with liver metastases . Increased , mild hair loss was present in 17 of the 35 patients ; hair regrowth had occurred at follow-up 3 and 6 months after the final administration . WHO toxicity grade 2 or 3 anaemia -LRB- Hb 4.95 -- 6.2 or 4.0 -- 4.9 mmol/l , respectively -RRB- , leucocytopenia -LRB- WBC 2.0 -- 2.9 or 1.0 -- 1.9 × 109/l , respectively -RRB- and thrombocytopenia -LRB- platelets 50 -- 74.9 or 25.0 -- 49.9 × 109/l , respectively -RRB- occurred after 8 % and 0 % , 5 % and 1 % , and 3 % and 1 % of the administrations , respectively . Toxicity grade 2 or 3 leucocytopenia or thrombocytopenia occurred in two out of three -LRB- 67 % -RRB- patients who had had previous chemotherapy , as against seven out of 32 -LRB- 22 % -RRB- patients who had not . Mean haematological parameters rose again during the follow-up after the final administration . Serum creatinine , creatinine clearance and serum HbA1c did not change significantly -LRB- data not shown -RRB- . In patients without thyroid hormone medication , serum TSH and fT4 levels did not change . In women , serum LH and FSH concentrations did not change significantly ; in men , serum testosterone decreased and serum LH concentrations increased significantly . Also inhibin-B concentrations decreased and serum FSH levels increased significantly . The effects of the therapy on tumour size were evaluable in 34 patients . Three months after the final administration -LRB- on average 9 months from the start of the treatment -RRB- , a complete remission -LRB- CR -RRB- , evaluated with CT scanning , MRI and somatostatin receptor imaging , was found in one patient -LRB- 3 % -RRB- , partial remission -LRB- PR -RRB- in 12 -LRB- 35 % -RRB- , stable disease -LRB- SD -RRB- in 14 -LRB- 41 % -RRB- and progressive disease -LRB- PD -RRB- in 7 -LRB- 21 % -RRB- , including the three patients who died during the treatment period -LRB- Table 1 -RRB- -LRB- Figs. 1 , 2 -RRB- . Follow-up evaluation 6 months after the final therapy was available for 19 of the 34 patients . All seven patients who had PR after 3 months still had PR after 6 months ; in 10 of the 12 patients with SD , the evaluation was unchanged , whereas one had a minimal response -LRB- MR -RRB- and one had PD.Table 1 . Tumour responses in 34 patients , 3 months after the final administration of 177Lu-octreotate . Three patients with PD died before reaching their final doseTumour typeResponseTotalCRPRSDPDCarcinoid4 -LRB- 33 % -RRB- 6 -LRB- 50 % -RRB- 2 -LRB- 17 % -RRB- 12NE pancreas1 -LRB- 8 % -RRB- 1 -LRB- 8 % -RRB- 7 -LRB- 58 % -RRB- 3 -LRB- 25 % -RRB- 12NE unknown origin4 -LRB- 57 % -RRB- 1 -LRB- 14 % -RRB- 2 -LRB- 29 % -RRB- 7Gastrinoma3 -LRB- 100 % -RRB- 3Total1 -LRB- 3 % -RRB- 12 -LRB- 35 % -RRB- 14 -LRB- 41 % -RRB- 7 -LRB- 21 % -RRB- 34Fig . 1 . A -- C Planar scans of the abdomen , 3 days after the injection of 200 mCi 177Lu-octreotate in a patient with liver metastases of an operated neuroendocrine pancreatic tumour . A After the first treatment ; B after the second treatment ; C after the fourth treatment . Note the loss of intensity of uptake in the liver lesions -LRB- arrows in A -RRB- . This sign virtually always indicates a tumour volume response . D , E CT scans of the same patient : before treatment -LRB- D -RRB- and 3 months after the last treatment -LRB- E -RRB- . Tumour -LRB- arrows in D -RRB- is not demonstrated on E. Neither MRI nor octreoscan could demonstrate definite tumour deposits at that timeFig . 2 . A , B MRI scans in a woman with hepatic metastases of a gastrinoma . Before treatment -LRB- A -RRB- she was inoperable because of the size and localization of the metastases . Three months after completion of her treatment with 800 mCi 177Lu-octreotate she had a PR -LRB- B -RRB- . Note also that the hypertrophy of the gastric wall -LRB- arrow in A -RRB- had diminished . Concomitantly , serum concentrations of gastrin -LRB- closed dots -RRB- and chromogranin-A -LRB- open dots -RRB- had decreased markedly -LRB- C -RRB- . At 6 months the MRI showed no further regression . The patient underwent left partial hepatectomy and the two right-sided lesions were drained and injected with alcohol . MRI 3 months after surgery showed further regression of the right-sided lesions Tumour response -LRB- CR or PR -RRB- was significantly more frequent in patients whose tumours had a high uptake on the octreoscan -LSB- 6/7 -LRB- 86 % -RRB- with grade 4 uptake vs. 7/27 -LRB- 26 % -RRB- with grade 2 or 3 uptake ; chi-square test : P < 0.05 -RSB- . Five out of the seven patients -LRB- 71 % -RRB- with PD had hepatomegaly and diffuse liver metastases vs 6 out of 27 -LRB- 22 % -RRB- with CR , PR or SD -LRB- chi-square test : P < 0.05 -RRB- . Tumour response was more frequent in patients with documented PD within 1 year before the start of the treatment -LRB- 8/15 ; 53 % -RRB- than in those without -LRB- 5/19 ; 26 % -RRB- , although this difference was not statistically significant -LRB- P = 0.11 ; chi-square test -RRB- . Of the 15 patients with documented PD before the start of the treatment , 3 -LRB- 20 % -RRB- had SD at follow-up . Patients who had a Karnofsky Performance Score of less than 80 before the treatment more frequently had PD -LRB- 5/8 ; 63 % -RRB- than those who had higher scores -LRB- 2/26 ; 8 % -RRB- -LRB- P < 0.01 ; chi-square test -RRB- . The serum tumour marker chromogranin-A was elevated in 29 patients . During the treatment and follow-up , there was a clear decrease in serum chromogranin-A concentrations in patients with PR or CR , whereas these concentrations were virtually unchanged in patients with SD , and initially showed an increase in patients with PD -LRB- Fig. 3 -RRB- . Fig. 3 . Serum chromogranin-A concentrations during and after therapy in patients with PR , SD or PD . The reduction in the number of patients during the course of the follow-up was due to death or missing values . Note the logarithmic y-axis The patient-assessed quality of life , according to the EORTC-QLQ30 questionnaire , was evaluated in 25 patients . Ten patients were excluded because of progressive disease/death -LRB- n = 5 -RRB- or missing forms during the follow-up period -LRB- n = 5 , foreign patients -RRB- . Scores before the start of the treatment , after receiving 400 -- 600 mCi 177Lu-octreotate and at follow-up 3 months after the final treatment were evaluated . There were no significant differences for functional scales or single symptom scales . The global health scale , on which patients were asked to assign marks regarding both their general health and their quality of life , and which ranged from 0 to 100 , was judged as higher than 70 by nine patients -LRB- 36 % -RRB- before the start of the treatment , by 17 -LRB- 68 % -RRB- patients during the treatment and by 16 -LRB- 64 % -RRB- patients after the treatment -LRB- P < 0.05 ; chi-square test -RRB- . Discussion There are few treatment options for metastatic GEP tumours . The use of radiolabelled somatostatin analogues for tumour regression is a promising new development . With -LSB- 90Y-DOTA0 , Tyr3 -RSB- octreotide , PR -LRB- or CR -RRB- has been reported in 10 -- 25 % of patients with neuroendocrine tumours -LSB- 6 , 7 , 8 -RSB- . In the present study we found objective tumour shrinkage in 38 % of the patients , but PD before the start of the treatment was documented in only 46 % of the patients . This last fact is important , because documented PD was present in more than 80 % of patients in two of the reported series treated with -LSB- 90Y-DOTA0 , Tyr3 -RSB- octreotide -LSB- 6 , 8 -RSB- . As with chemotherapy , an objective tumour response after PRRT is more likely in patients with -LRB- fast -RRB- growing tumours . Indeed , in our series we also found a trend towards a more favourable treatment outcome in patients with documented PD before the start of the treatment . It may therefore be concluded that the percentage of patients with significant tumour shrinkage in our study might have been even higher had the percentage of patients with PD prior to treatment been comparable to that in studies with -LSB- 90Y-DOTA0 , Tyr3 -RSB- octreotide . The side-effects of treatment with 177Lu-octreotate are few and mostly transient , with mild bone marrow depression as the most common finding . Neither renal nor pituitary function deteriorated in any of our patients . Other side-effects can be ascribed to the radiation dose to the testes in men . This dose leads to significantly lower serum testosterone and inhibin-B levels which in turn give rise to higher serum LH and FSH concentrations , thereby substantiating that the pituitary function is unimpaired . The patient-assessed global health score improved in 30 % of patients during the treatment and the follow-up period . This is an important finding which reflects the improvement in patient well-being and stresses the scarcity of side-effects as perceived by patients . The fact that other scores mainly addressing symptoms did not change significantly is likely due to the diversity of symptoms between patients , the use of Sandostatin by symptomatic patients and the small size of the patient group . Many physicians adopt an expectant attitude when dealing with patients with metastatic GEP tumours owing to the low success rates of chemotherapy protocols . However , given that treatment with 177Lu-octreotate resulted in PR -LRB- or CR -RRB- in 38 % of our patients , this attitude may be questioned . Although there was a -LRB- statistically non-significant -RRB- tendency towards more frequent tumour regression in patients who had documented PD before the start of the treatment , those of our patients who had an objective tumour response more frequently had a limited tumour load . This implies that waiting for tumour progression might place patients in a worse position , as PD during or after treatment was more frequent in patients with an extensive tumour load , especially in the liver . We therefore advocate treatment with177Lu-octreotate at an earlier stage of metastatic disease , when even CR may be possible . Another argument in favour of early treatment is that neuroendocrine tumours can dedifferentiate in the course of the disease , and lose their somatostatin receptors , making treatment with radiolabelled somatostatin analogues impossible . If serious side-effects of treatment with 177Lu-octreotate remain absent during longer patient follow-up , such treatment could also be considered in an adjuvant setting in patients with neuroendocrine tumours who are operated on with curative intent . Lastly , as it has been shown in animal experiments that 90Y-labelled somatostatin analogues are more effective for larger tumours and 177Lu-labelled somatostatin analogues are more effective for smaller tumours -LSB- 13 , 14 -RSB- , combination therapy with 90Y-labelled and 177Lu-labelled octreotate may be tried in the near future . Such therapy might yield even better results than treatment with either of the radionuclides alone -LSB- 15 -RSB- .

O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O

somatostatin receptor
octreotate
gep tumours


Giant cervicothoracic extradural arachnoid cyst : case report The pathogenesis , etiology , and treatment of the spinal arachnoid cyst have not been well established because of its rarity . A 57-year-old male was presented with spastic quadriparesis predominantly on the left side . His radiological examination showed widening of the cervical spinal canal and left neural foramina due to a cerebrospinal fluid - filled extradural cyst that extended from C2 to T2 level . The cyst was located left anterolaterally , compressing the spinal cord . Through a C4 -- T2 laminotomy , the cyst was excised totally and the dural defect was repaired . Several features of the reported case , such as cyst size , location , and clinical features make it extremely unusual . The case is discussed in light of the relevant literature . Introduction Various types of cystic lesions are confronted in the spinal canal and are classified in respect of their relationship to the adjacent structures and nature of the cyst content . Amongst them , cerebrospinal fluid -LRB- CSF -RRB- - filled meningeal cysts constitute for the majority of the cases -LSB- 11 , 18 -RSB- and are called as `` arachnoid cysts , '' `` diverticula , '' -LSB- 5 , 9 -RSB- or `` pouches '' -LSB- 9 -RSB- . They may be located in the intradural , extradural , or perineural spaces . Depending on the location , size , and mechanism of origin , the clinical course varies between asymptomatic , incidentally-diagnosed cases -LSB- 17 -RSB- to severe myelopathy -LSB- 11 -RSB- . When they communicate freely with subarachnoid space , fluctuating symptoms related to changes in CSF pressure may occur -LSB- 8 , 9 -RSB- . Although arachnoid cysts can be observed anywhere along the length of the spinal canal , middle , and lower thoracic regions constitute for the most frequently involved areas . When progressive neurological findings exist , surgical treatment is warranted . Surgical techniques include excision , fenestration , or placement of a cysto - subarachnoid shunt -LSB- 6 , 11 -RSB- , as well as some less invasive techniques that have been proposed recently -LSB- 16 -RSB- . We present a case with a giant cervicothoracic extradural arachnoid cyst and its surgical management . Several features of the cyst , such as its size , location , and clinical features make the case extremely unusual . Case Report A 57-year-old male was referred with symptoms of difficulty in walking , weakness , numbness , and thinning of arms and legs , and impotency , which had all begun two years before . The patient had suffered a serious traffic accident when he was 10 years old , and has had a contracture of his right hand since then . Neurological examination revealed spastic quadriparesis predominantly on the left side -LRB- left upper extremity proximally had 2/5 muscle strength , distally had 1/5 , and left lower extremity globally had 4/5 -RRB- , left-sided atrophy , hypoesthesia and hypoalgesia in C5 - C8 dermatomes , hypoactivity of deep tendon reflexes at the upper extremity , hyperactivity in patellar reflex , and Babinski sign . Muscle tonus of bilateral lower extremities was increased . The anal sphincter tonus was weak , and the patient reported an intermittent sphincter control defect . Cervical radiographs showed widening of the left neural foramina and the spinal canal . Magnetic resonance imaging -LRB- MRI -RRB- revealed an extradural cystic mass extending from C2 to T2 vertebral bodies , located left anterolaterally , compressing the spinal cord -LRB- Figs. 1a , b , c and 2 -RRB- . It had the same CSF intensity on T1 and T2-weighted images and showed no contrast enhancement . The lesion had caused a concavity in the related vertebral bodies and widening of the neural foramina on the left side . Electrophysiological tests reported chronic severe neurogenic involvement and a delay in the somato - sensorial evoked potential responses in C6 - T1 innervated muscles . Fig. 1T2-weighted median -LRB- a -RRB- , slightly left paramedian -LRB- b -RRB- , and left paramedian -LRB- c -RRB- sagittal magnetic resonance images of the cervical region shows a cystic mass extending from C2 to T2 vertebral bodies , located left anterolaterally , enlarging left neural foramina -LRB- arrows -RRB- . -LRB- Arrowheads spinal cord -RRB- Fig. 2Axial magnetic resonance image taken from T1 level shows the CSF-filled extradural cyst , located left anterolaterally , compressing the spinal cord -LRB- SC spinal cord -RRB- A C4 -- T2 laminotomy was performed . An extradural cystic lesion , full of CSF and having a thin and transparent membrane , was observed compressing the dural sac . The lesion had caused widening of C5 -- C7 foramina and there was an active flow of CSF to the cyst through the defects located at the exiting points of these three roots . The cyst wall was excised and the dural defects were repaired using muscle pieces and sutures . Despite some degree of the spinal cord and dural sac expansion , the epidural and subarachnoid spaces left enlarged , since the canal was widened . The epidural space was left unfilled for the fear of compression . The samples taken from the cyst wall were reported as fibrohyalinized meningeal tissues . Postoperative course was uneventful . Although the spasticity gradually improved during two years of follow-up , muscle strength and other neurological findings did not change . Discussion Spinal arachnoid cyst is a rare entity . There are various classifications based on etiology , histopathology , or localization of the cysts . Many authors classify spinal meningeal cysts as both intradural and extradural . Extradural cysts include arachnoid cysts , synovial cysts , ganglias , cysts of ligamentum flavum , and cysts originating from the intervertebral discs . Intradural cysts include arachnoid cysts , enterogen -LRB- endodermal , neuroenteric -RRB- cysts , and ependymal cysts -LSB- 3 , 6 , 7 , 10 , 12 -- 15 , 18 -RSB- . The pathogenesis of spinal arachnoid cyst is not clear and probably not homogenous . Congenital -LSB- 13 -RSB- , traumatic -LSB- 1 -RSB- , or inflammatory -LSB- 15 -RSB- mechanisms were proposed . It was documented that congenital asymptomatic cysts could enlarge due to trauma and become symptomatic -LSB- 3 -RSB- . The size of arachnoid cysts may vary in relation to underlying mechanisms . For example , the arachnoid cysts related to arachnoiditis are usually localized and small -LSB- 6 , 18 -RSB- . Pulsatile CSF dynamics -LSB- 9 -RSB- , osmotic gradient between the subarachnoid space and cyst -LSB- 7 -RSB- , and the valve - like mechanism between the cyst and subarachnoid space -LSB- 10 -RSB- may play an important role in the enlargement of spinal extradural arachnoid cysts . Doita et al. -LSB- 4 -RSB- demonstrated that increased intra abdominal and intrathoracic pressure may lead to size changes of the spinal arachnoid cyst . A review demonstrated that arachnoid cysts involving the cervical region are extremely rare , that they never exceed three vertebral bodies in length , and that none extended into the thoracic region -LSB- 6 -RSB- , except the case reported by Safriel et al. -LSB- 14 -RSB- . That case was an intradural arachnoid cyst situated anteriorly to the spinal canal extending between C5 and T3 levels . The presented cyst was extradural , located at the cervicothoracic region , anterolateral to the spinal cord , and involved eight vertebral bodies extending from C2 to T2 level . To the authors ' knowledge , there is no extradural arachnoid cyst reported in the literature matching that size . The patient had no disposing factor other than trauma . He had suffered a serious traffic accident when he was a child and consequently had a contracture in his left upper extremity . Although there was an excessively long duration -LRB- 45 years -RRB- between trauma and appearance of new symptoms attributable to the cyst , the concordance of the former neurological deficit and location of the cyst convinced us that the etiology of the cyst might have been the childhood trauma . During the surgery , we did not observe any laminar signs that indicated a sustained compression fracture on the posterior elements . Thus , stretching and partial avulsion of the roots may have caused arachnoid and dural tearing during the childhood trauma , causing subsequent collection of the CSF at the epidural space , communicating freely both subarachnoid space and dural sleeves of the roots . Indeed , the occurrence of multiple dural defects , through which the CSF exits , is very rare . This point makes an extra implication on the case and further supports the avulsion theory as the cause of multiple dural tearings , since the neurological deficit due to childhood trauma is concordant with multiple root involvement . Long-standing progressive enlargement of the cyst explains radiological signs such as eroded vertebral bodies and enlarged intervertebral foramina . Conclusion The pathogenesis , etiology , and treatment of the spinal arachnoid cyst have not been well established because of its rarity . Symptomatic cases require surgical intervention . For long segment involvements , hemilaminectomy or laminotomy , as was performed in the current case is preferable to laminectomy in order to prevent postoperative deformity . In surgery , dural defect should be closed after excision . Neurological recovery depends on the size of the cyst and degree and duration of the spinal cord compression . A long-standing spastic myelopathy is unlikely to have a significant improvement -LSB- 2 -RSB- , as we observed in the current case . Except spasticity , the patient had no improvement on his neurological findings . Thus , in delayed cases , surgery may be taken and should be offered as a prophylactic intervention to prevent further impairment , rather than a curative one . In conclusion , the case presented here is a very unusual occurrence of this rare entity . Although probably traumatic , it had extremely delayed clinical presentation , its location was unusual , and as an extradural cervicothoracic arachnoid cyst , it was the largest amongst those reported .

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

arachnoid cysts
magnetic resonance imaging
spinal cord compression
surgical treatment