Biomedical subjects

M S O'Dorisio

Publications and source records attributed to M S O'Dorisio.

At least 19 recordsLinked to original sources

PubMed2006

Caspase 8L, a novel inhibitory isoform of caspase 8, is associated with undifferentiated neuroblastoma.

Caspase 8 is a key apoptotic factor in the receptor/ligand apoptosis-signaling cascade. Absent caspase 8 expression is shown to correlate with poor prognosis in neuroblastoma. Paradoxically, the caspase 8 gene can produce as plice variant and novel inhibitor of itself-caspase 8l. The presence of caspase 8 alone in tumors may not necessarily portend a good prognosis. We sought to determine whether caspase 8l is present in neuroblastoma and whether over-expression of this protein could inhibit caspase 8-dependent apoptosis. Six of 6 histologically undifferentiated and 2 of 5 differentiated neuroblastoma tumors expressed the caspase 8l isoform, whereas caspase 8l was absent in 3 of 3 ganglioneuromas. Seven human neuroblastoma cell lines were surveyed. Two of the 5 cell lines that expressed caspase 8 also expressed the caspase 8l isoform and both were of a less differentiated neuronal phenotype. Over-expression of caspase 8l in cell lines afforded protection against TRAIL, but not against etoposide induced apoptosis. Conversely, blockade of Caspase 8l in cells that express this splice variant made them more sensitive to apoptosis induced cell death. We demonstrate the caspase 8l isoform is present in neuroblastoma and appears to be associated with undifferentiated cell lines and tumors. Furthermore, it suppresses caspase 8-dependent apoptosis.

Alternative Splicing↗

PubMed2002

111In-pentetreotide versus bone scintigraphy in the detection of bony metastases of neuroblastoma.

Bone scintigraphy (BS) is widely utilized for the assessment of bone metastases (BMs) of neuroblastoma (NB). Since 111In-pentetreotide scintigraphy (PS) has been used to image NB with high sensitivity, we compared the sensitivity and specificity of PS with that of BS for the detection of BMs of NB. Nine patients with NB underwent both PS and BS for staging and/or restaging of their disease. The sensitivity and specificity of both imaging approaches were compared based on the findings of histopathology, other conventional imaging methods and subsequent clinical follow-up. In five of the nine patients, both PS and BS were negative for BMs. Radiographic bone surveys (RBSs) were also negative in these patients, except in one who showed a suspicious tibial lesion, but a computed tomography-guided biopsy failed to show evidence of disease. These patients remained without clinical evidence of BMs after a median duration of more than 15 months (range, 6-19 months). In three of four remaining patients, both PS and BS were positive for BMs, whilst only PS was positive in one patient. Overall, PS showed a greater number of BMs (30 vs. 7) with greater conspicuity compared with BS. The initial experience comparing BS with PS suggests that PS may provide a better assessment of the extent of BMs of NB, and that it may be useful as an adjunct to BS at institutions in which 131I- or 123I-metaiodobenzylguanidine is not available, particularly if BS is negative. In patients with similarly positive BS, PS might still provide unique prognostic information beyond that provided by BS. Further studies are therefore warranted.

3-Iodobenzylguanidine↗

PubMed2001

Aberrant promoter methylation of previously unidentified target genes is a common abnormality in medulloblastomas--implications for tumor biology and potential clinical utility.

Medulloblastomas exhibit an array of diverse cytogenetic abnormalities. To evaluate the significance of epigenetic rather than genetic lesions in medulloblastomas and other primitive neuroectodermal tumors (PNETs) of the childhood CNS we performed a systematic analysis of gene specific and global methylation. Methylation-specific PCR detected no methylation for p15(INK4B), von Hippel Lindau and TP53 and only limited methylation for E-Cadherin and p16(INK4A) in tumors. The cell lines Daoy and MHH-PNET-5 in which the p16(INK4A) promoter was methylated did not express the gene, but demonstrated abnormalities by SSCP. Immunohistochemistry for p16 was negative in all examined normal cerebella and medulloblastomas. Using the technique of Restriction Landmark Genomic Scanning we detected methylation affecting up to 1% of all CpG islands in primary MB/PNETs and 6% in MB cell lines. Methylation patterns differed between medulloblastomas and PNETs. Examination of several methylated sequences revealed homologies to known genes and expressed sequences. Analysis of survival data identified seven of 30 hypermethylated sequences significantly correlating with poor prognosis. We suggest that DNA hypermethylation has an outstanding potential for the identification of novel tumor suppressors as well as diagnostic and therapeutic targets in MBs and other PNETs of the CNS.

Adolescent↗

PubMed2001

Growing vascular endothelial cells express somatostatin subtype 2 receptors.

We hypothesized that non-proliferating (quiescent) human vascular endothelial cells would not express somatostatin receptor subtype 2 (sst 2) and that this receptor would be expressed when the endothelial cells begin to grow. To test this hypothesis, placental veins were harvested from 6 human placentas and 2 mm vein disks were cultured in 0.3% fibrin gels. Morphometric analysis confirmed that 50-75% of cultured vein disks developed radial capillary growth within 15 days. Sst 2 gene expression was determined by reverse transcription-polymerase chain reaction (RT-PCR) analysis of the RNA from veins before culture and from tissue-matched vein disks that exhibited an angiogenic response. The sst 2 gene was expressed in the proliferating angiogenic sprouts of human vascular endothelium. The presence of sst 2 receptors on proliferating angiogenic vessels was confirmed by immunohistochemical staining and in vivo scintigraphy. These results suggest that sst 2 may be a unique target for antiangiogenic therapy with sst 2 preferring somatostatin analogues conjugated to radioisotopes or cytotoxic agents.

Animals↗

PubMed2001

Distribution and functional significance of somatostatin receptors in malignant melanoma.

Malignant melanoma is a neuroendocrine tumor that contains somatostatin receptors (SSTRs). Adjuvant therapy for melanoma is limited. Because melanomas arise from neural crest cells, we sought to evaluate the distribution of SSTR subtypes found in these tumors and their functional significance by imaging with 111In-pentetreotide scintigraphy (OctreoScan). Octreotide binds with greatest affinity to SSTR2 and SSTR5. Studying the expression of SSTRs in melanoma may demonstrate a potential role for octreotide in the treatment of melanoma. A series of 23 melanomas from 17 patients who underwent resection of regional or distant metastases were evaluated for the presence of SSTRs by the reverse transcriptase-polymerase chain reaction (RT-PCR) using primers specific for SSTR1 through SSTR5. Identity of RT-PCR products was confirmed by Southern blot analysis. Sixteen patients underwent preoperative OctreoScan. SSTR1 was expressed in 96% of tumors, SSTR2 in 83%, SSTR3 in 61%, SSTR4 in 57%, and SSTR5 in 9%. OctreoScan imaged 63% of tumors. There was no correlation between SSTR subtype expression and OctreoScan result. Most of the melanomas expressed mRNA for SSTR1 and SSTR2, with approximately half expressing SSTR3 and SSTR4. The SSTR mRNA for SSTR2 appears to be transcribed into functional protein that binds 111In-pentetreotide in more than half of these patients. Although OctreoScan has limited sensitivity for localizing melanomas, tumors that can be imaged by OctreoScan may be amenable to adjuvant therapy with octreotide or targeted therapy with high-energy radioisotope-labeled octreotide. These studies clearly define melanoma as a neuroendocrine tumor, which may open new avenues for tumor control.

Adult↗

PubMed2001

Segmental expression of somatostatin receptor subtypes sst(1) and sst(2) in tubules and glomeruli of human kidney.

Somatostatin is known to modulate mesangial and tubular cell function and growth, but the somatostatin receptor (sst) subtypes responsible for these effects have not been defined. There are at least five different sst receptor subtypes (sst(1)-sst(5)). We used RT-PCR to demonstrate that normal human kidney consistently expresses mRNA for sst(1) and sst(2) (9 of 9 donors). Some donors expressed sst(4) or sst(5) mRNA, but none expressed sst(3) mRNA. Expression of sst(1) and sst(2) was further assessed by staining serial sections of normal human kidney with sst(1) and sst(2) antisera, Arachis hypogaea (AH) lectin (to define distal tubule/collecting duct cells), Phaseolus vulgaris lectin (proximal tubules), and Tamm-Horsfall protein (THP) antiserum (thick ascending limb of the loop of Henle). Specificity of antisera was demonstrated by transfection and absorption studies. Sst(2), but not sst(1), was expressed in glomeruli. Intense sst(1) and sst(2) staining localized exclusively to AH+ and THP+ tubules. Thus sst(1) and sst(2) subtype-selective analogs may be useful to beneficially modulate renal cell function in pathological conditions.

Adult↗

PubMed2001

Expression and fine mapping of murine vasoactive intestinal peptide receptor 1.

Vasoactive intestinal peptide (VIP) plays multiple roles in the nervous, endocrine, and immune systems as a neurotransmitter, a hormone, and a cytokine. VIP is widely distributed in neurons of the central and peripheral nervous systems (CNS/PNS), and recently has been found to be an important neuroprotective agent. VIP actions are mediated through specific G protein-coupled receptors. We have cloned the cDNA of VIP receptor subtype 1 (VIPR1 or VPAC1) and have demonstrated the quantitative expression profile in mice. Fluorometric real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that VPAC1 is expressed in all tissues examined. Expression was highest in the small intestine and colon followed by the liver and brain. The high level of VPAC1 expression in forebrain and cerebellum suggests that VPAC1 may mediate the neuroprotective effect of VIP. We have refined the chromosomal localization of the mouse, rat, and human VPAC1 genes. This fine mapping of the VPAC1 gene extends the respective regions of synteny between the distal region of mouse chromosome 9, rat chromosome 8q32, and human chromosome 3p21.33-p21.31. Thus, VPAC, constitutes a functional-positional candidate for the tumor-suppressor function mapped to human 3p22-p21 where loss-of-heterozygosity is observed in small-cell lung carcinoma (SCLC) cell lines and primary tumors. Availability of the cDNA sequences for mouse VPAC1 will facilitate the generation of VPAC1 null mutant animals. Such studies will ultimately enhance our understanding of the role of VIP in the nervous system.

Amino Acid Sequence↗

PubMed2001

Aberrant hypermethylation of the major breakpoint cluster region in 17p11.2 in medulloblastomas but not supratentorial PNETs.

Deletions of 17p have been consistently reported in up to 50% of medulloblastomas (MBs), and the major breakpoint interval has been localized to chromosome segment 17p11.2. Based on several reports linking aberrant DNA methylation and chromosomal disruption, we examined the methylation pattern in this region by employing restriction landmark genomic scanning (RLGS). Several CpG islands located in the major breakpoint cluster region were identified using a bacterial artificial chromosome (BAC) contig of the breakpoint region. A long-range methylation map was established for 20 MBs and 5 supratentorial primitive neuroectodermal tumors (stPNETs). Selected CpG islands were examined using Southern and bisulfite sequencing analysis. Aberrantly hypermethylated CpG islands in 17p11. 2 were found in 33% of MBs. Interestingly, one CpG island was methylated in MBs, but not in any of the examined stPNETs. A BAC clone covering three of the methylated CpG islands was partially sequenced in the search for a potential tumor suppressor gene. None of the expressed sequence tag sequences and full-length mouse/human cDNAs that were associated with aberrant methylation showed a change in expression levels due to methylation. The potential link between chromosomal instability in 17p11.2 and hypermethylation in this region is discussed.

Adolescent↗

PubMed2001

Somatostatin receptor gene expression in human ocular tissues: RT-PCR and immunohistochemical study.

PURPOSE: Somatostatin (SST) analogues have been used to treat proliferative diabetic retinopathy, pseudotumor cerebri, thyroid orbitopathy, and cystoid macular edema. There is a paucity of published data in regards to cell-specific distribution of SST receptors (SSTR) in normal human eye tissues. Gene expression for all five known SSTRs in normal human ciliary body/iris, retina, choroid, and cultured retinal pigment epithelial (RPE) cells were studied. METHODS: mRNA was isolated from human ocular tissues (iris/ciliary body, retina, and choroid) dissected from eight pairs of normal eyes (9-62 years) and from RPE cells grown in culture. RT-PCR was done for all five SSTRs in all analyzed tissues. Immunohistochemistry for SSTR1 and SSTR2 was performed on eight pairs of normal human eyes (28-74 years) imbedded in paraffin. RESULTS: SSTR1 to 5 genes are expressed in retina, SSTR1 and SSTR2 genes in cultured RPE cells, and SSTR1, 2, and 4 in ciliary body and choroid. SSTR1 and SSTR2 immunoreactivity (-ir) was observed on a variety of cells within all analyzed tissues including cornea, iris, trabecular meshwork, Schlemm's canal, ciliary processes, ciliary muscle, retina, choroid, cultured RPE cells, and optic nerve. CONCLUSIONS: SSTR genes are widely expressed in normal human eye tissues, with genes for SSTR1 and SSTR2 being the most widely expressed. Genes for all SSTRs are expressed in retina. SSTR1-ir and SSTR2-ir were observed in all analyzed ocular tissues. Detailed knowledge of SSTRs distribution and function in the human eye will result in a better understanding of their role in health and disease.

Adolescent↗

PubMed2000

Somatostatin receptor gene expression in neuroblastoma.

Somatostatin receptor expression is a favorable prognostic factor in human neuroblastoma. Somatostatin receptors have been demonstrated in vitro by pharmacologic analysis of tumor tissue and in vivo by diagnostic radioreceptor scintigraphy. However, which receptor subtypes (sst(1), sst(2), sst(3), sst(4), and sst(5)) are expressed in these tumors has not yet been delineated. We used RT-PCR to analyze expression of the five somatostatin receptor genes in 32 neuroblastoma tumor specimens. All 32 tumor specimens expressed mRNA for c-abl and sst(1); sst(2) mRNA was detected in 27/32 samples and somatostatin mRNA was detected in 30/32 tumor specimens. The remaining receptor subtypes, sst(3), sst(4), and sst(5) were variably expressed. Receptor protein for sst(1) and sst(2) was visualized in tumor neuroblasts as well as in endothelial cells of tumor vessels using immunostaining with specific anti-receptor antibodies. The effect of high expression of somatostatin receptors on cell proliferation was examined in SKNSH neuroblastoma cells transfected with sst(1) and sst(2). SS(14) binding to wild-type SKNSH cells was undetectable; but the native peptide bound with high affinity to the SKNSH/sst(1) and SKNSH/sst(2) neuroblastoma cell lines. Pharmacologic analysis of binding with two long-acting analogues, CH275 and octreotide, confirmed selective expression of sst(1) and sst(2) in stably transfected SKNSH cells. Formation of neuroblastoma xenograft tumors in nude mice was significantly delayed for both SKNSH/sst(1) (P<0.001) and SKNSH/sst(2) (P<0.05) cells compared to wild-type SKNSH. We conclude that: (1) Somatostatin receptors, sst(1) and sst(2), are expressed in the majority of neuroblastomas at diagnosis; and (2) upregulation of functional sst(1) or sst(2) in neuroblastoma cell lines suppresses tumorigenicity in a xenograft model. These observations suggest that somatostatin receptors may be a useful therapeutic target in neuroblastoma.

Animals↗

PubMed2000

Aberrant CpG-island methylation has non-random and tumour-type-specific patterns.

CpG islands frequently contain gene promoters or exons and are usually unmethylated in normal cells. Methylation of CpG islands is associated with delayed replication, condensed chromatin and inhibition of transcription initiation. The investigation of aberrant CpG-island methylation in human cancer has primarily taken a candidate gene approach, and has focused on less than 15 of the estimated 45,000 CpG islands in the genome. Here we report a global analysis of the methylation status of 1,184 unselected CpG islands in each of 98 primary human tumours using restriction landmark genomic scanning (RLGS). We estimate that an average of 600 CpG islands (range of 0 to 4,500) of the 45,000 in the genome were aberrantly methylated in the tumours, including early stage tumours. We identified patterns of CpG-island methylation that were shared within each tumour type, together with patterns and targets that displayed distinct tumour-type specificity. The expression of many of these genes was reactivated by experimental demethylation in cultured tumour cells. Thus, the methylation of particular subsets of CpG islands may have consequences for specific tumour types.

Adenocarcinoma↗

PubMed2000

Vasoactive intestinal peptide (VIP) receptor type 2 (VPAC2) is the predominant receptor expressed in human thymocytes.

Vasoactive intestinal peptide (VIP) binding sites have been identified in the human thymus, but the receptor subtype and how these receptors are distributed in the human thymus subsets is unknown. To assess gene expression, distribution, and receptor regulation of the two G-protein-associated VIP receptors, VPAC1 and VPAC2 mRNAs were quantified using a novel fluorometric-based kinetic (real-time) RT-PCR. Bulk and fractionated thymocytes were stimulated via the TCR/CD3 receptor complex and anti-CD28. Our results demonstrate that thymocytes express higher levels of VPAC2 compared to VPAC1 expression in bulk thymocytes, CD4+CD8+ selected double positives (DP), and CD8 depleted thymocytes. Double negative cells express low levels of VPAC2 mRNA. We demonstrate T-cell activation-dependent down-regulation of VPAC1, but not VPAC2, in human thymocytes. This study reports the first direct evidence of a differential distribution and selective regulation of VPAC1 and VPAC2 gene expression in normal human thymocyte subsets.

CD4-Positive T-Lymphocytes↗

PubMed2000

Regulation of vasoactive intestinal peptide receptor expression in developing nervous systems.

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide that has several functions, including the regulation of water and electrolyte secretion, hormone and cytokine release, bronchodilitation, and neurogenesis. VIP effects are mediated by specific G-protein coupled receptors. Three distinct receptor subtypes, with differing affinity for VIP, have been cloned and characterized as receptors 1 and 2 (VPAC1 and VPAC2) and pituitary adenylate cyclase activating polypeptide receptor (PAC1). Our laboratory has demonstrated that upregulation of VPAC1 in SK-N-SH neuroblastoma cells results in marked shift in cell type to the glial lineage with a corresponding loss of neuronal lineage and suppression of xenograft tumor growth. To understand the molecular mechanisms responsible for regulation of the VPAC1 gene in neuronal lineage, we have cloned and sequenced 2.6-kb of the 5'-flanking sequences of the human VPAC1 gene. Sequence analysis demonstrated that the human VPAC1 promoter sequence contains putative binding sites for several known transcription factors, including Sp1, NFkB, and cETS-1. To study the temporal and spatial expression pattern of human VPAC1 promoter sequences, we have generated transgenic mice expressing the bacterial beta-galactosidase gene under the control of the 2.6-kb 5'-flanking and promoter sequence of the human VPAC1 gene. Transgene expression was detected in brain, spinal cord, and lung in 14-day-old animals. Taken together, these results demonstrate that VPAC1 may play an important role in the nervous system, and suggest a role for VIP in neuronal differentiation.

Animals↗

PubMed2000

Gene amplification in PNETs/medulloblastomas: mapping of a novel amplified gene within the MYCN amplicon.

OBJECTIVES: The pathological entity of primitive neuroectodermal tumour/medulloblastoma (PNET/MB) comprises a very heterogeneous group of neoplasms on a clinical as well as on a molecular level. We evaluated the importance of DNA amplification in medulloblastomas and other primitive neuroectodermal tumours (PNETs) of the CNS. METHOD: Restriction landmark genomic scanning (RLGS), a method that allows the detection of low level amplification, was used. RLGS provides direct access to DNA sequences circumventing positional cloning efforts. Furthermore, we analysed several samples by CGH. DESIGN: Twenty primary medulloblastomas, five supratentorial PNETs, and five medulloblastoma cell lines were studied. RESULTS: Although our analysis confirms that gene amplification is generally a rare event in childhood PNET/MB, we found a total of 17 DNA fragments that were amplified in seven different tumours. Cloning and sequencing of several of these fragments confirmed the previous finding of MYC amplification in the cell line D341 Med and identified novel DNA sequences amplified in PNET/MB. We describe for the first time amplification of the novel gene, NAG, in a subset of PNET/MB. Despite genomic amplification, NAG was not overexpressed in the tumours studied. We have determined that NAG maps less than 50 kb 5' of DDX1 and approximately 400 kb telomeric of MYCN on chromosome 2p24. CONCLUSION: We found a similar but slightly higher frequency of amplification than previously reported. We present several DNA fragments that may belong to the CpG islands of novel genes amplified in a small subset of PNET/MB. As an example we describe for the first time the amplification of NAG in the MYCN amplicon in PNET/MB.

Blotting, Northern↗

PubMed1999

A new tool for the rapid cloning of amplified and hypermethylated human DNA sequences from restriction landmark genome scanning gels.

Restriction landmark genome scanning (RLGS) is an effective genome-scanning technique capable of identifying DNA amplification and aberrant DNA methylation. Previously published methods for the cloning of human DNA fragments from RLGS gels have been successful only for high-copy-number fragments (repetitive elements or DNA amplifications). We present here the first technique capable of efficiently cloning single-copy human DNA fragments ("spots") identified in RLGS profiles. This technique takes advantage of a plasmid-based, human genomic DNA, NotI/EcoRV boundary library. The library is arrayed in microtiter plates. When clones from a single plate are pooled and mixed with genomic DNA, the resultant RLGS gel is a normal profile with a defined set of spots showing enhanced intensity for that particular plate. This was performed for a set of 32 plates as well as their pooled rows and columns. Thus, we have mapped individual RLGS spots to exact plate, row, and column addresses in the library and have thereby obtained immediate access to these clones. The feasibility of the technique is demonstrated in examples of cloning methylated DNA fragments identified in human breast tumor and testicular tumor RLGS profiles and in the cloning of an amplified DNA fragment identified in a human medulloblastoma RLGS profile.

Cloning, Molecular↗

PubMed1999

Vasoactive intestinal peptide (VIP) and VIP receptors: gene expression and growth modulation in medulloblastoma and other central primitive neuroectodermal tumors of childhood.

Vasoactive intestinal peptide (VIP) is a neuromodulator and growth regulator in the developing nervous system. We analyzed 10 primitive neuroectodermal tumor (PNET) cell lines, 29 central PNET (cPNET) and 17 tumors of the Ewing's sarcoma/peripheral PNET family (ESFT) using reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern hybridization. Each of the 10 cell lines and 86.2% of cPNET expressed mRNA for VIP receptor 1 (VIPR1) compared to 52.9% of ESFT. VIPR2 was expressed in 75.8% of cPNET, in 28.6% of ESFT and in all 10 cell lines. cPNET demonstrated high-affinity binding of 125I-VIP on quantitative autoradiography and in competitive binding assays. VIP inhibited tumor cell proliferation in a dose-dependent manner in 5 of 7 PNET cell lines. We conclude that VIPR1 and VIPR2 are highly expressed in cPNET and demonstrate that VIP is a growth modulator in these tumors.

Autoradiography↗

PubMed1999

Intraoperative gamma detection of 125I-lanreotide in women with primary breast cancer.

BACKGROUND: Somatostatin receptors are present in most human breast cancers. We performed a pilot trial of intraoperative tumor-gamma detection using the radiolabeled somatostatin analog 125I-lanreotide in 13 women with 14 primary breast carcinomas. METHODS: All patients were given 125I-lanreotide intravenously before surgery. Patients underwent lumpectomy, and postresection margins were evaluated with the gamma probe. Axillary dissection specimens were evaluated ex vivo. RESULTS: Seven of 13 women had gamma probe-positive or clinically suspicious margins re-excised at the time of lumpectomy. Four of six probe-positive margins were histologically positive, and two of six probe-positive margins were histologically negative; a single clinically suspicious margin was histologically positive. A total of 270 axillary lymph nodes were evaluated ex vivo by gamma probe and histology. McNemar's contingency tests demonstrated a highly statistical correlation between histology and gamma probe counts (P < .0001). CONCLUSIONS: The overall accuracy of nodal evaluation with 125I-lanreotide/intraoperative gamma detection was 77%; the negative predictive value of this technique was 97%, however. This technique predicted the presence of tumor in 20% of axillary lymph nodes that were negative by routine histology. This technique appears safe and is able to detect positive tumor resection margins and accurately predict axillary lymph node negativity. Further trials of this technique are required to validate its utility.

Aged↗

PubMed1999

Synthesis and characterization of multiply-tyrosinated, multiply-iodinated somatostatin analogs.

Radio-labeled somatostatin analogs have recently gained popularity as agents useful in intraoperative tumor localization, external scintigraphy and in situ radiotherapy. We have synthesized and characterized a series of novel N-terminally extended multiply-tyrosinated somatostatin analogs that possess high binding affinity for somatostatin receptors, exhibit biological activity comparable to the native peptide and retain these characteristics after iodination. These analogs can be radio-iodinated to high specific activities. Following radioiodination, these analogs exhibit minimal radiolysis and may be clinically useful for tumor localization, scanning and therapy.

Adenocarcinoma, Bronchiolo-Alveolar↗