Radiolabeled somatostatin analog scintigraphy in oncology and immune diseases: an overview

[¹¹¹In-DTPA-D-Phe¹]-octreotide is a new radiopharmaceutical with a great potential for the visualization of somatostatin receptor-positive tumors, granulomas, and diseases in which activated leukocytes play a role. The overall sensitivity of [¹¹¹In-DTPA-D-Phe¹]-octreotide scintigraphy to localize neuroendocrine tumors is high. In several neuroendocrine tumor types, inclusion of somatostatin receptor imaging in the localization or staging procedure may be very rewarding, either in terms of cost-effectiveness, patient management, or quality of life. In our opinion, this holds true for patients with carcinoids, gastrinomas, paragangliomas, small-cell lung carcinoma, and selected cases of patients with insulinomas. The value of [¹¹¹In-DTPA-D-Phe¹]-octreotide scintigraphy in patients with other tumors, such as breast cancer, malignant lymphomas, or in patients with granulomatous diseases, has to be established. Received 19 June 1996; Revision received 28 October 1996; Accepted 6 November 1996     

Gallium scintigraphy in small cell lung cancer

We have undertaken gallium imaging studies in 49 patients with histologically proven small cell lung cancer. Tracer uptake in the primary tumour was seen in 98% of cases. Twenty five patients underwent repeat scanning after induction chemotherapy and a correlation was demonstrated between conventional parameters of response and gallium scan changes (P<0.01). There was no correlation between initial gallium activity and subsequent chemoresponse (which was evaluated in 32 patients) or survival (measured in 42 patients). Ten patients who had shown a complete response to induction treatment were followed up with gallium scans repeated at three monthly intervals. Such longitudinal studies were particularly helpful in excluding tumour activity when the appearance of the chest radiographs were difficult to interpret.     

Gallium scintigraphy in small cell lung cancer

We have undertaken gallium imaging studies in 49 patients with histologically proven small cell lung cancer. Tracer uptake in the primary tumour was seen in 98% of cases. Twenty five patients underwent repeat scanning after induction chemotherapy and a correlation was demonstrated between conventional parameters of response and gallium scan changes (P less than 0.01). There was no correlation between initial gallium activity and subsequent chemoresponse (which was evaluated in 32 patients) or survival (measured in 42 patients). Ten patients who had shown a complete response to induction treatment were followed up with gallium scans repeated at three monthly intervals. Such longitudinal studies were particularly helpful in excluding tumour activity when the appearance of the chest radiographs were difficult to interpret.     

18F-fluorodeoxyglucose positron emission tomography in small-cell lung cancer

Positron emission tomography (PET) imaging is not used routinely in small-cell lung cancer (SCLC) but has been proven useful in non-small-cell lung cancer. The performance of (18)F-fluorodeoxyglucose (FDG)-PET in patients with SCLC was evaluated in this study. Fifteen patients with proven SCLC were evaluated (8 men and 7 women; mean age, 68 years; range, 50-81 years). Among the 15 patients with SCLC, 3 were newly diagnosed and 12 had received chemotherapy or radiation therapy before PET. Five patients underwent surgery (3 newly diagnosed and 2 after therapy) after PET scan, and 14 received chemotherapy, radiation therapy, or both. The patient who was not treated with chemotherapy or radiation therapy underwent surgery only. All patients had computed tomographic (CT) scans before PET and had clinical follow-up for at least 2 months after PET. The patients received 3.4 to 4.15 mCi of (18)F-FDG intravenously after fasting for at least 4 hours. Whole-body PET scans were acquired approximately 50 min after injection by using an ADAC Laboratories C-PET plus scanner. Among the 12 patients treated before PET, 2 were found with solitary pulmonary nodules positive on PET. Subsequent surgical resection and pathology showed 1 true positive and 1 false positive (postradiation pneumonitis). Six of these 12 patients had extrapulmonary metastases or large intense hilar or pulmonary uptake on PET, or both. Four of these 12 had no evidence of abnormal FDG uptake and were considered true negatives. The 3 patients with newly diagnosed SCLC were all true positives on PET, confirmed by surgery. One false negative on CT scan was attributed to postradiation fibrosis. These preliminary data suggest that whole-body FDG-PET can provide the basis for determining which treatment modality would be the most appropriate during the early stages of SCLC, when surgery is still an option, and it is a useful tool to assess the effect of treatment in patients with this disease. A more accurate assessment of SCLC will be possible if FDG-PET scan is combined with CT during the early evaluation of these patients.     

Extracellular matrix regulation of drug resistance in small-cell lung cancer

PURPOSE: Lung cancer is the leading cause of cancer deaths in the developed world. Small cell lung cancer (SCLC) has the worst prognosis due to the emergence of resistance to chemotherapy. This article will review recent work that has defined mechanisms of chemo-resistance focusing on the role of integrins. RESULTS: SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) and high levels of expression correlate with poor prognosis. ECM protects SCLC cells against chemotherapy-induced cell death by activating beta1 integrins leading to activation of phosphoinositide-3-OH kinase (PI3-kinase), which prevents etoposide-induced caspase-3 activation and subsequent apoptosis. Engagement of ECM prevents etoposide and radiation induced G2/M cell cycle arrest in SCLC cells by blocking the up-regulation of p21Cip1/WAF1 and p27Kip1 and the down-regulation of cyclins E, A and B. These effects are abrogated by pharmacological and genetic inhibition of PI3-kinase signalling. CONCLUSIONS: Thus, ECM via beta1 integrin-mediated PI3-kinase activation allows SCLC cells to survive treatment induced cell cycle arrest and apoptosis with persistent DNA damage, providing a model to account for the emergence of acquired drug resistance. Novel therapeutic strategies may therefore be directed at inhibiting integrin-mediated cell survival signals improving response rates and cure in this devastating cancer.     

Extracellular matrix regulation of drug resistance in small-cell lung cancer

Purpose: Lung cancer is the leading cause of cancer deaths in the developed world. Small cell lung cancer (SCLC) has the worst prognosis due to the emergence of resistance to chemotherapy. This article will review recent work that has defined mechanisms of chemo-resistance focusing on the role of integrins.

Results: SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) and high levels of expression correlate with poor prognosis. ECM protects SCLC cells against chemotherapy-induced cell death by activating β1 integrins leading to activation of phosphoinositide-3-OH kinase (PI3-kinase), which prevents etoposide-induced caspase-3 activation and subsequent apoptosis. Engagement of ECM prevents etoposide and radiation induced G2/M cell cycle arrest in SCLC cells by blocking the up-regulation of p21Cip1/WAF1 and p27Kip1 and the down-regulation of cyclins E, A and B. These effects are abrogated by pharmacological and genetic inhibition of PI3-kinase signalling.

Conclusions: Thus, ECM via β1 integrin-mediated PI3-kinase activation allows SCLC cells to survive treatment induced cell cycle arrest and apoptosis with persistent DNA damage, providing a model to account for the emergence of acquired drug resistance. Novel therapeutic strategies may therefore be directed at inhibiting integrin-mediated cell survival signals improving response rates and cure in this devastating cancer.     

Bone scintigraphy in lung cancer: a reappraisal

The prognostic significance of bone scintigraphy was investigated by following 587 consecutive patients with lung cancer, in whom this investigation had been performed, for up to 9 years, or until death. Survival was unrelated to age, sex or cell type. However, pain and abnormal bone scintigraphy were both independently associated with a significantly reduced survival compared with those who were free of pain or who had normal bone scintigraphy. These factors were cumulative. The association remained equally valid for all cell types. Claims that a single metastasis is not prognostically significant are unfounded. It is suggested that the results of some chemotherapy trials must be reconsidered in the light of present findings, because of the lack of adequate control groups; the results could be construed to show a beneficial effect only in patients with bone metastases and a poor prognosis, but little or no effect in patients with normal bone scintigraphy. As judged by clinical and radiological follow-up and post-mortem examination, skeletal scintigraphy in patients with lung cancer had a sensitivity of 0.89, a non-specificity (false positives/true negatives) of 0.00 and an accuracy of 0.78. With existing radiopharmaceuticals there is an irreducible residue of false negatives due to deposits which provoke little or no osteoblastic response. Bone scintigraphy is, thus, indicated in any patient with lung cancer with unexplained symptoms and whenever staging is required, because of the prognostic implications. It should precede other staging investigations because the high detection rate may render other tests unnecessary.     

Radioiodinated fibrinogen distribution in cancer patients

The usefulness of radioiodinated fibrinogen in tumor localization and of coagulation in 80 cancer patients was investigated. Tumors externally detected demonstrated positive localization in 63% of all cases and in 100% of osteosarcomas of limbs. Fibrinogen half-life was reduced in cancer patients particularly in cases with lymphoma, Hodgkin's disease and osteosarcoma irrespectively of basal plasma fibrinogen levels.In lymphoma and ovarian cancer, fibrinogen degradation products were correlated to radiofibrinogen T/2 reduction. In patients with the lowest fibrinogen T/2 and platelet count, heparin infusion therapy returned the fibrinogen half-life to normal range.Present results suggest the existence of enhanced coagulation both inside and around the tumor and/or dissemination in early cancer as well as in the more advanced stage.Presented in part at the Second International Congress of World Federation of Nuclear Medicine and Biology (17–21 September, Washington D.C., USA     

Radioiodinated fibrinogen distribution in cancer patients

The usefulness of radioiodinated fibrinogen in tumor localization and of coagulation in 80 cancer patients was investigated. Tumors externally detected demonstrated positive localization in 63% of all cases and in 100% of osteosarcomas of limbs. Fibrinogen half-life was reduced in cancer patients particularly in cases with lymphoma, Hodgkin's disease and osteosarcoma irrespectively of basal plasma fibrinogen levels. In lymphoma and ovarian cancer, fibrinogen degradation products were correlated to radiofibrinogen T/2 reduction. In patients with the lowest fibrinogen T/2 and platelet count, heparin infusion therapy returned the fibrinogen half-life to normal range. Present results suggest the existence of enhanced coagulation both inside and around the tumor and/or dissemination in early cancer as well as in the more advanced stage.     

Octreotide scintigraphy localizes somatostatin receptor-positive islet cell carcinomas.

Tyr-3-Octreotide is a synthetic derivative of somatostatin and a somatostatin-receptor analogue. The iodine-123-labelled compound localizes somatostatin-receptor-positive tumours. In this paper two patients are reported in whom somatostatin receptors were demonstrated in vitro. In a 60-year-old female with an islet cell carcinoma of the pancreas, multiple liver metastases and previously unrecognized bone metastases in the right acetabulum could be diagnosed as the reason for a persistent hypoglycaemia. In a 60-year-old male an islet cell carcinoma of the pancreas was localized with 123I-Tyr-3-octreotide. The somatostatin receptors were demonstrated in vitro and the tumour was successfully treated with somatostatin. These studies demonstrate that 123I-Tyr-3-octreotide offers the possibility of localizing somatostatin-receptor-positive tumours and their metastases. Moreover the method makes it possible to determine the receptor status of a tumour in vivo.     

Comparison of FDG-PET findings of brain metastasis from non-small-cell lung cancer and small-cell lung cancer

OBJECTIVE: We compared the F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) findings of brain metastasis between patients with non-small-cell lung cancer (NSCLC) and small cell lung cancer (SCLC). METHODS: A whole-body FDG and a brain PET were performed in 48 patients (31 men, 17 women; 57 +/- 9 years, 42 NSCLC, 6 SCLC), who had brain metastasis on magnetic resonance (MR). All primary lung lesions were detected by FDG-PET and confirmed pathologically. We analyzed the PET findings, lesion sizes, and the pathological result of primary lung cancer. RESULTS: Of the 48 patients, 31 (64.6%) showed hypermetabolic lesions on FDG-PET of the brain image, and 14 (29.2%) showed hypometabolic lesions. Three patients (6.3%) had both hypermetabolic and hypometabolic lesions. On the lesion-based analysis, 74 lesions (67.3%) showed hypermetabolism on FDG-PET, and 36 lesions (32.7%) showed hypometabolism. All primary lung lesions were hypermetabolic on FDG-PET. When the FDG findings of metastatic brain lesions were analyzed with the pathological types of primary lung cancer, NSCLC was more frequently associated with hypermetabolic metastatic brain lesions than SCLC (80% and 26.7%, respectively, P < 0.01). On comparing the sizes of metastatic lesions between SCLC (1.3 +/- 1.2 cm) and NSCLC (1.8 +/- 1.2 cm), lesions of <1 cm were more frequent in SCLC than in NSCLC (P = 0.012). But no significant relationship was found between the size and PET finding of metastatic lesion (P = 0.412). CONCLUSIONS: Even when the primary lesion of lung cancer showed hypermetabolism in FDG-PET, FDG accumulation in metastatic brain lesions was variable. One-third of brain metastases from lung cancer showed hypometabolism. NSCLC was more frequently associated with hypermetabolic metastatic brain lesions than SCLC. The PET findings of brain lesions were affected not only by the size of lesion but also by its biological characteristics.     

CD105在非小细胞肺癌中的表达及意义

目的探讨CD105的表达在非小细胞肺癌发生、发展及转移中的作用。方法应用流式细胞术检测100例非小细胞肺癌和50例正常肺组织标本中CD105的表达,分析其在不同临床特征中的表达差别。结果 CD105在非小细胞肺癌组织中的表达量明显高于正常肺组织（P〈0.05）;有无胸膜侵犯、有无淋巴结转移的非小细胞肺癌患者肺癌组织之间CD105的表达差异有统计学意义（P〈0.05）。结论非小细胞肺癌患者有CD105高表达,并存在着CD105阳性的血管新生,检测CD105蛋白可能对判断患者的预后有一定价值。     

Iodine-131 MIBG scintigraphy in small cell lung cancer

There is a well documented relationship between small cell carcinoma of the lung and the amine precursor uptake and decarboxylation system of endocrine cells (APUD). We attempted to exploit this association by employing the unique radiopharmaceutical,¹³¹I-MIBG, which is recognized and taken up by the APUD system to monitor disease activity in patients with small cell carcinoma of the lung. A total of eight patients with biopsy proven, metastatic small cell carcinoma of the lung were studied.¹³¹I-MIBG was synthesized in our laboratory by reacting metaiodobenzylamine synthesized in our laboratory by reacting metaiodobenzylamine hydrochloride with cyanamide with subsequent solid phase radioiodination. A dose of 0.5 mCi radiopharmaceutical was injected and images obtained on a large field of view gamma camera with a high energy parallel hole collimator at 2, 24, and either 48 or 72 h. Images were compared with known focal areas of metastatic disease demonstrable on computed tomographic scan, chest roentgenogram or bone scan. We were unable to detect reproducible correlations between the images produced by conventional radiographic techniques and the images produced by our radiopharmaceutical. We conclude that this agent will probably not be useful for localization of metastatic small cell lung carcinoma.This work was supported by a Pilot Research Grant from the Education and Research Foundation of the Society of Nuclear Medicine     

Iodine-131 MIBG scintigraphy in small cell lung cancer

There is a well documented relationship between small cell carcinoma of the lung and the amine precursor uptake and decarboxylation system of endocrine cells (APUD). We attempted to exploit this association by employing the unique radiopharmaceutical, 131I-MIBG, which is recognized and taken up by the APUD system to monitor disease activity in patients with small cell carcinoma of the lung. A total of eight patients with biopsy proven, metastatic small cell carcinoma of the lung were studied. 131I-MIBG was synthesized in our laboratory by reacting metaiodobenzylamine hydrochloride with cyanamide with subsequent solid phase radioiodination. A dose of 0.5 mCi radiopharmaceutical was injected and images obtained on a large field of view gamma camera with a high energy parallel hole collimator at 2, 24, and either 48 or 72 h. Images were compared with known focal areas of metastatic disease demonstrable on computed tomographic scan, chest roentgenogram or bone scan. We were unable to detect reproducible correlations between the images produced by conventional radiographic techniques and the images produced by our radiopharmaceutical. We conclude that this agent will probably not be useful for localization of metastatic small cell lung carcinoma.     

Unilateral absence of lung perfusion on pulmonary scintigraphy secondary to lung cancer with extensive pleural metastases from lung cancer.

A man with a 20-year history of smoking who underwent Tc-99m MAA Pulmonary perfusion imaging, which showed virtually absent perfusion of the right lung and fairly normal perfusion of the left lung. Eighteen days after the study, the patient died; at autopsy poorly differentiated carcinoma of the right lung was confirmed, which included extensive thickened pleura and plaques deposits and compression of the right lung; 200 ml of bloody pleural effusion was also found on the right side. The unilateral absence of lung perfusion on Tc-99m MAA pulmonary scintigraphy might reflect the autopsy findings of the right lung and pleura.     

^99Tc^m-depreotide生长抑素受体显像在肺癌诊断中的应用

目的探讨^99Tc^m-地普奥肽（depreotide）生长抑素受体显像对肺癌的诊断价值。方法52例肺部肿瘤患者[小细胞肺癌（SCLC）8例,非小细胞肺癌（NSCLC）38例,良性结节6例]静脉注射^99Tc^m-depreotide（740±60）MBq后行平面及胸部SPECT显像,并勾画感兴趣区（ROI）,计算肿瘤和对侧正常肺组织的放射性（T／N）比值,所有病灶均经病理检查证实。采用SPSS 11.5软件,行两样本t检验。结果^99Tc^m-depreotide显像诊断52例肺癌的灵敏度、特异性、准确性分别为93．5％（43／46）、5／6和92．3％（48／52）;假阴性3例,假阳性1例。3例假阴性分别为2例鳞癌、1例腺癌,1例假阳性为炎性假瘤。SCLC和NSCLC组T／N比值分别为1．948±0．282和1．280±0．160。SCLC对^99Tc^m-depreotide的摄取明显高于NSCLC（t=0．130,P〈0．05）。结论^99Tc^m-depreotide生长抑素受体显像是一种无创、安全、有效、简便的检查方法,对肺癌尤其是SCLC有良好的诊断价值。     

Outcome and prognostic factors in single brain metastases from small-cell lung cancer

Purpose

Whole brain radiation therapy (WBRT) is historically the standard of care for patients with brain metastases (BM) from small-cell lung cancer (SCLC), although locally ablative treatments are the standard of care for patients with 1–4 BM from other solid tumors. The objective of this analysis was to find prognostic factors influencing overall survival (OS) and intracranial progression-free survival (iPFS) in SCLC patients with single BM (SBM) treated with WBRT.

Methods

A total of 52 patients were identified in the authors’ cancer center database with histologically confirmed SCLC and contrast-enhanced magnet resonance imaging (MRI) or computed tomography (CT), which confirmed SBM between 2006 and 2015 and were therefore treated with WBRT. A Kaplan-Meier survival analysis was performed for OS analyses. The log-rank (Mantel-Cox) test was used to compare survival curves. Univariate Cox proportional-hazards ratios (HRs) were used to assess the influence of cofactors on OS and iPFS.

Results

The median OS after WBRT was 5 months and the median iPFS after WBRT 16 months. Patients that received surgery prior to WBRT had a significantly longer median OS of 19 months compared to 5 months in the group receiving only WBRT (p = 0.03; HR 2.24; 95% confidence interval [CI] 1.06–4.73). Patients with synchronous disease had a significantly longer OS compared to patients with metachronous BM (6 months vs. 3 months, p = 0.005; HR 0.27; 95% CI 0.11–0.68). Univariate analysis for OS revealed a statistically significant effect for metachronous disease (HR 2.25; 95% CI 1.14–4.46; p = 0.019), initial response to first-line chemotherapy (HR 0.58; 95% CI 0.35–0.97; p = 0.04), and surgical resection (HR 0.36; 95% CI 0.15–0.88; p = 0.026). OS was significantly affected by metachronous disease in multivariate analysis (HR 2.20; 95% CI 1.09–4.45; p = 0.028).

Conclusions

Univariate analysis revealed that surgery followed by WBRT can improve OS in patients with SBM in SCLC. Furthermore, synchronous disease and response to initial chemotherapy appeared to be major prognostic factors. Multivariate analysis revealed metachronous disease as a significantly negative prognostic factor on OS. The value of WBRT, stereotactic radiosurgery (SRS), or surgery alone or in combination for patients with a limited number of BM in SCLC should be evaluated in further prospective clinical trials.

     

Delayed lung scintigraphy with N-isopropyl-I-123-p-iodoamphetamine in lung cancer and inflammatory disease

Lung studies with N-Isopropyl-I-123-p-Iodoamphetamine (IMP) were performed on patients with lung cancer or inflammatory disease. In the present study, we evaluated the usefulness of the delayed scintigraphy. The subjects consisted of 27 patients with lung cancer (34 lesions), 3 with radiation pneumonitis, 2 with interstitial pneumonitis, 2 with old tuberculous lesion (tuberculomas), 1 with diffuse panbronchiolitis, 1 with pneumonia and 1 with lung abscess. The delayed scintigraphy was performed 24 hr after intravenous injection of 3 mCi IMP, in sitting position. In 10 patients, SPECT images were obtained following the delayed scintigraphy. Delayed scintigraphic appearances of lung cancer were classified into 5 types, high IMP uptake in the area congruent with the lesion of atelectasis and/or obstructive pneumonia (Type I), high IMP uptake in the area surrounded the tumor (Type II), a defect in the area consistent with the tumor and no high IMP uptake in the area surrounded the tumor (Type III), high IMP uptake in the area almost congruent with the tumor (Type IV) and no significant change (Type V). Excluding 10 lesions with Type IV or V, no IMP uptake was seen in the areas congruent with the tumors. Type II was the most frequently observed pattern. Normal scintigrams (Type V) were observed in 8 lesions, whose sizes were fairly small. There was no definite trend caused by difference in histological types of cancers. In 8 patients with viable inflammatory disease of the lung, the delayed scintigrams showed high IMP uptake in the areas congruent with the abnormalities on chest roentgenograms.(ABSTRACT TRUNCATED AT 250 WORDS)