Response Evaluation and Survival Prediction After PD-1 Immunotherapy in Patients with Non-Small Cell Lung Cancer: Comparison of Assessment Methods.

Immunotherapy using programmed death-1 blockers is a promising modality for non-small cell lung cancer (NSCLC). Therefore, defining the most accurate response criteria for immunotherapy monitoring is of great importance in patient management. This study aimed to compare the correlation between survival outcome and response assessment by PERCIST, version 1.0; immunotherapy-modified PERCIST (imPERCIST); RECIST, version 1.1; and immunotherapy-modified RECIST (iRECIST) in NSCLC patients. Methods: Seventy-two patients with NSCLC who were treated with nivolumab or pembrolizumab and had baseline and follow-up 18F-FDG PET/CT data were analyzed. The patients were categorized into responders (complete or partial response) and nonresponders (stable or progressive disease) according to PERCIST1 and PERCIST5 (analyzing the peak SUV normalized by lean body mass [SULpeak] of 1 or up to 5 lesions), imPERCIST1, imPERCIST5, RECIST, and iRECIST. The correlation between achieved response and overall survival (OS) was compared. Results: The overall response rate and the overall disease control rate of the study population were 29% and 74%, respectively. The OS and progression-free survival (PFS) of patients with complete and partial response were statistically comparable. The OS and PFS were significantly different between responders and nonresponders (20.3 vs. 10.6 mo, P = 0.001, for OS and 15.5 vs. 2.2 mo, P < 0.001, for PFS, respectively). Twenty-three (32%) patients with progressive disease according to PERCIST5 had controlled disease according to imPERCIST5; follow-up of patients showed that 22% of these patients had pseudoprogression. The overall incidence of pseudoprogression was 7%. The response rate was 25% and 24% according to PERCIST1 and PERCIST5 (P = 0.2) and 32% and 29% according to imPERCIST1 and imPERCIST5 (P = 0.5), respectively, indicating no significant difference between analyzing the SULpeak of only the most 18F-FDG-avid lesion and analyzing up to the 5 most 18F-FDG-avid lesions. Conclusion: The achieved response by all conventional and immunotherapy-modified methods correlated strongly with patients' survival outcome, with significantly longer OS and PFS in responders than in nonresponders according to all assessed definitions. The most 18F-FDG-avid lesion according to PERCIST and imPERCIST accurately reflects the overall metabolic response.

Diagnostic evaluation for interventional bronchoscopists and radiologists in lung cancer practice.

The global epidemic of lung cancer shows no signs of abating. It is generally accepted that accurate and cost-efficient diagnostic evaluation is the first important step to achieve the best outcomes of treatment. This is true in the context of disease confirmation, treatment planning, treatment monitoring, detection of and management of treatment failure or prognostication. Fortunately, major advances in the diagnostic evaluation of lung cancer have been made in the past three decades allowing more patients to get the appropriate treatment at the right time. This paper outlines how computed tomography, positron emission tomography/computed tomography and endobronchial ultrasound contribute to lung cancer management and discuss their strengths and weaknesses and their complimentary roles at different stages of lung cancer management. Due to financial constraint and reimbursement restrictions, not all clinically important advances in the diagnostic evaluation of lung cancer have been readily accepted into routine clinical care. This enforces the need to maintain ongoing dialogue between cancer clinicians, imaging specialists and health-care economists.

Somatostatin receptor imaging with 68Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation.

Gallium 68 ((68)Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE, GaTate) positron emission tomography (PET)/computed tomography (CT) is an imaging technique for detecting and characterizing neuroendocrine tumors (NETs). GaTate, a somatostatin analog, has recently been accorded orphan drug status by the U.S. Food and Drug Administration, thereby increasing interest in and availability of this radiotracer. GaTate PET/CT allows whole-body imaging of cell surface expression of somatostatin receptors (SSTRs) and is rapidly evolving as the new imaging standard of reference for the detection and characterization of NETs. The authors discuss the normal appearance at GaTate PET/CT and the utility of this modality in a variety of these tumors, including gastrointestinal, pancreatic, and bronchial NETs as well as pheochromocytoma, paraganglioma, meningioma, and oncogenic osteomalacia. In addition, they discuss potential causes of false-positive findings, including pancreatic uncinate process activity, inflammation, osteoblastic activity, and splenosis. They also highlight the complementary role of 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) PET/CT, including the advantages of using both GaTate PET/CT and FDG PET/CT to evaluate sites of well- and poorly differentiated disease. The use of GaTate PET/CT together with FDG PET/CT allows identification of tumor heterogeneity, which provides prognostic information and can be pivotal in guiding biopsy. It also allows optimal patient management, including theranostic application of peptide receptor radionuclide therapy, and the restaging of patients following therapy.

Localization and prediction of malignant potential in recurrent pheochromocytoma/paraganglioma (PCC/PGL) using 18F-FDG PET/CT.

BACKGROUND: To our knowledge, data are lacking on the role of 18F-FDG PET/CT in the localization and prediction of neuroendocrine tumors, in particular the pheochromocytoma/paraganglioma (PCC/PGL) group. PURPOSE: To evaluate the role of 18F-FDG PET/CT in localizing and predicting the malignant potential of PCC/PGL. MATERIAL AND METHODS: Twenty-three consecutive patients with a history of PCC/PGL, presenting with symptoms related to catecholamine excess, underwent 18F-FDG PET/CT. Final confirmation of the diagnosis was made using the composite references. PET/CT findings were analyzed on a per-lesion basis and a per-patient basis. Tumor SUVmax was analyzed to predict the dichotomization of patient endpoints for the local disease and metastatic groups. RESULTS: We investigated 23 patients (10 men, 13 women) with a mean age of 46.43 ± 3.70 years. Serum catecholamine levels were elevated in 82.60% of these patients. There were 136 sites (mean SUVmax: 16.39 ± 3.47) of validated disease recurrence. The overall sensitivities for diagnostic CT, FDG PET, and FDG PET/CT were 86.02%, 87.50%, and 98.59%, respectively. Based on the composite references, 39.10% of patients had local disease. There were significant differences in the SUVmax distribution between the local disease and metastatic groups; a significant correlation was noted when a SUVmax cut-off was set at 9.2 (P<0.05). CONCLUSION: In recurrent PCC/PGL, diagnostic 18F-FDG PET/CT is a superior tool in the localization of recurrent tumors. Tumor SUVmax is a potentially useful predictor of malignant tumor potential.

18[F]FDG-PET/CT is a useful molecular marker in evaluating tumour aggressiveness: a revised understanding of an in-vivo FDG-PET imaging that alludes the alteration of cancer biology.

Molecular imaging employing (18)[F]FDG-PET/CT enables in-vivo visualization, characterisation and measurement of biological process in tumour at the molecular and cellular level. In oncology, this approach can be directly applied as translational biomarkers of disease progression. In this article, the improved roles of FDG as an in-vivo glycolytic marker which reflect biological changes across in-vitro cellular environment are discussed. New understanding in how altered metabolism via glycolytic downstream drivers of malignant transformation as reviewed below offers unique promise as to monitor tumour aggressiveness and hence optimize the therapeutic management.

Clinically important detection of infection as an 'incidental' finding during cancer staging using FDG-PET/CT.

BACKGROUND: FDG-PET/CT is widely used in the management of a variety of malignancies with excellent overall accuracy, despite the potential for false positive results related to infection and inflammation. AIM: As cancer patients can develop clinically inapparent infections, we evaluated the prevalence and nature of incidental findings reported to be suggestive of infections that had been identified during clinical cancer staging with FDG-PET/CT. METHODS: The study involved a retrospective analysis of 60 patients managed primarily at our facility from a total of 121 cases identified as having possible infection on clinical reporting of more than 4500 cancer staging investigations performed during the calendar year of 2008. RESULTS: Occult infections were uncommon overall (≤1%), but most often because of pneumonia (31.6%), upper respiratory tract infections (21.1%) or wound infections (15.8%). Abnormal scans contributed to patients' management in 52.7% of cases. Two out of 13 patients whose scan abnormalities were not investigated further had worsening changes on repeated scan and one of these patients had clinical deterioration. CONCLUSIONS: In patients with FDG-PET/CT scans suggestive of infection and in whom a final diagnosis could be reached, the positive predictive value for FDG-PET/CT scans was 89% suggesting that abnormal scans indicative of infection should be investigated further in this population.

Endoscopic ultrasound-guided fine-needle aspiration when combined with positron emission tomography improves specificity and overall diagnostic accuracy in unexplained mediastinal lymphadenopathy and staging of non-small-cell lung cancer.

BACKGROUND: The aim of this study was to assess the incremental value of endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) to positron emission tomography (PET) in the diagnosis of unexplained mediastinal lymphadenopathy and staging of non-small-cell lung cancer (NSCLC). METHODS: Patients who had both EUS-guided FNA and PET were retrospectively identified from an EUS database at a tertiary hospital. All EUS-guided FNA were carried out by one endoscopist between August 2002 and April 2005, either for the diagnosis of unexplained mediastinal lymphadenopathy or for the staging of NSCLC. Results of PET and EUS were compared with histology. A true histological positive result was defined as histological involvement in either surgery (mediastinoscopy or resection) or EUS-guided FNA. A true histological negative result was defined as negative involvement at surgery (mediastinoscopy or resection). RESULTS: Forty-nine patients who had both PET scanning and EUS-guided FNA for diagnosis of unexplained mediastinal lymphadenopathy or staging of NSCLC were identified. Of these, 33 (73% males, n = 24, age range = 44-78 years, mean = 62 years) had surgical confirmation of mediastinal lymph node pathology. In these patients, PET alone showed sensitivity, 95%; specificity, 90%; positive predictive value, 87%; negative predictive value, 90% and accuracy, 88%; whereas the addition of EUS-guided FNA increased the overall specificity and positive predictive value to 100%, with an overall accuracy of 97%. CONCLUSIONS: This study suggests that EUS-guided FNA complements PET by improving the overall specificity and thereby the accuracy for diagnosis of unexplained mediastinal lymphadenopathy. It provides a minimally invasive technique to assess the mediastinum in patients with NSCLC and is particularly valuable in cases in which PET findings are equivocal.

Clinical experience of the first digital mammographic unit in Australia in its first year of use.

In April 2004, Melbourne's Peter MacCallum Cancer Centre, Australia's only stand-alone dedicated cancer hospital, became the first Australian site to offer digital mammography (DM). In the first year of DM operation, 1208 mammograms were performed on 1157 women; 17 new cases of invasive carcinoma and six new cases of ductal carcinoma-in-situ (DCIS) were detected; and 30 hook-wire needle localisations were conducted in 29 patients. We developed a unit policy to manage indeterminate microcalcifications newly demonstrated on DM that were not previously detected by conventional screen-film mammography (CM): those believed to have malignant morphology were recommended for biopsy, and those without were recommended for 6-month DM follow-up to confirm microcalcification stability. DM detected 56 new stand-alone microcalcifications (18 suspicious and 38 indeterminate). Tissue diagnosis of 12 suspicious microcalcifications yielded four cases of DCIS and one of atypical ductal hyperplasia. Of the indeterminate microcalcifications, 35 have demonstrated stability at DM follow-up to date, over a mean period of 23.6 months. From our experience, we believe DM's superior demonstration ability uncovered microcalcifications previously undetected by CM, rather than microcalcification progression. We suggest that routine review with DM, rather than biopsy, is appropriate management when new indeterminate microcalcifications without malignant characteristics are identified by DM.

Mycobacterium tuberculosis infection in patients with cancer, the role of 18-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring treatment response.

Active tuberculosis (TB) infection including asymptomatic and extrapulmonary disease may be detected with 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). This report highlights the promising role of FDG-PET/CT for evaluation of TB in high-risk, immunocompromised patients with cancer. PET/CT performed for cancer evaluation may detect asymptomatic infection and guide definitive diagnosis. It may also be a useful tool in the assessment of latent TB, to exclude active disease prior to treatment. PET/CT has potential for monitoring response to anti-tuberculosis treatment. Metabolic response may indicate clinical response and guide duration of anti-microbial therapy.

Ovarian vascular pedicle sign in ovarian metastasis arising from gall bladder carcinoma.

A case of a large mass in the pelvis confirmed to be a rare ovarian metastasis arising from a primary adenocarcinoma of the gall bladder is presented. The value of the recently described ovarian pedicle sign in confirming the organ of origin of the pelvic mass is emphasized.

Management of paediatric thyroid carcinoma: recent experience with recombinant human thyroid stimulating hormone in preparation for radioiodine therapy.

BACKGROUND: Thyroid carcinoma in children is rare and raises unique management issues. Although metastatic disease is more common in this age group, prognosis remains good with appropriate treatment. The aim of the study was to report recent experience in the management of differentiated thyroid carcinoma in children, especially in the use of radioiodine after recombinant human thyroid stimulating hormone (rhTSH) stimulation. METHODS: Eight patients, aged 5-17 years (five were boys) presented following total thyroidectomy for thyroid carcinoma between May 2003 and June 2005. Seven had papillary carcinoma and one had follicular carcinoma. Five had known lymph node metastases and one had pulmonary metastases at presentation. Four patients had previously received therapeutic irradiation for malignancy. All eight underwent diagnostic iodine scans, seven with rhTSH stimulation. Seven went on to receive radioiodine treatment as hospital inpatients, comanaged by the paediatric and nuclear medicine units. The dosage of 131I ranged from 1.5 to 3.7 x 10(9) Bq. All except one were prepared by rhTSH stimulation. RESULTS: Seven of eight patients had significant uptake in the neck on diagnostic scan and two had pulmonary abnormalities. Six of seven evaluable patients achieved complete thyroid ablation. Both patients with pulmonary abnormalities had scan resolution, although one of them only after a second radioiodine treatment. All patients had thyroxine replacement in doses to suppress TSH and all remain alive and well at time of carrying out this study. CONCLUSION: Optimal management of paediatric thyroid carcinoma necessitates a multidisciplinary approach. Radioiodine therapy under rhTSH is an effective and safe adjuvant treatment in this special subgroup.

Clinical experience with the first combined positron emission tomography/computed tomography scanner in Australia.

Metabolic imaging with fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) is increasing rapidly worldwide because of superior accuracy compared with conventional non-invasive techniques used for evaluating cancer. Limited anatomical information from FDG-PET images alone dictates that complementary use with structural imaging is required to optimise benefit. Recently, combined positron emission tomography/computed tomography (PET/CT) scanners have overtaken standalone PET scanners as the most commonly purchased PET devices. We describe our experience of over 5500 scans performed since the first PET/CT scanner in Australia was commissioned at the Peter MacCallum Cancer Centre (PMCC), Melbourne, in January 2002. Clinical indications for PET/CT scans performed at PMCC largely reflect current Medicare reimbursement policy. Advantages of PET/CT include greater patient comfort and higher throughput, greater diagnostic certainty and accuracy, improved biopsy methods, and better treatment planning. We believe PET/CT will underpin more effective and efficient imaging paradigms for many common tumours, and lead to a decrease in imaging costs.

Fluoroscopically guided percutaneous radiological gastrostomy: technique, methodology and pitfalls.

Fluoroscopically guided percutaneous gastrostomy tube placement is an uncommon but well-established interventional procedure. We present our experience of this procedure in a series of 23 patients, concentrating on the methodology, technique and pitfalls.

Cloning and expression of immunoreactive antigens from Mycobacterium tuberculosis.

Four immunoreactive proteins, B.4, B.6, B.10, and B.M, with molecular weights ranging from 16,000 to 58,000, were observed from immunoblots of Mycobacterium tuberculosis total lysates screened with sera from individuals with active tuberculosis. These proteins were identified from microsequence analyses, and genes of proteins with the highest homology were PCR amplified and cloned into the pQE30 vector for expression studies. In addition, a 37.5-kDa protein, designated C17, was identified from a phage expression library of M. tuberculosis genomic DNA. Preliminary immunoblot assays indicated that these five resultant recombinant proteins could detect antibodies in individuals with active pulmonary and extrapulmonary tuberculosis. The overall ranges of sensitivities, specificities, positive predictive values, and negative predictive values for the recombinant antigens were 20 to 58, 88 to 100, 69 to 100, and 56 to 71%, respectively. The B.6 antigen showed preferential reactivity to antibodies in pulmonary compared to nonpulmonary tuberculosis serum specimens. All of these recombinant antigens demonstrated potential for serodiagnosis of tuberculosis.

A pseudopeptide incorporating the tetrahydrophthalazine nucleus, a constrained aza analog of phenylalanine.

Replacement of the alpha-carbon with a nitrogen in alpha-amino acids gives rise to azaamino acids. Most examples of azaamino acids that have been incorporated into peptides are linear analogs, in which conformational effects are restricted to the immediate vicinity of the urea bond. In contrast to the linear azaamino acids, the heterocyclic analogs might be expected to exhibit stronger conformational preferences, but examples of this class of azaamino acids are very limited. We synthesized tetrahydrophthalazine (THPhth) as a constrained phenylalanine analog and elaborated it into the model pseudotripeptide N-¿([N-alanyl]-1,2,3,4-tetrahydro-2-phthalazinyl)carbonyl)¿-L-alan ine (1). As shown by NMR studies, tetrahydrophthalazine 1A has a secondary structure in which psi THphth is fixed at 16-18 degrees and there are two equal populations of cis and trans amide bonds from the N-terminal alanine.

Molecular modeling studies of novel retro-binding tripeptide active-site inhibitors of thrombin.

A novel series of retro-binding tripeptide thrombin active-site inhibitors was recently developed (Iwanowicz, E. I. et al. J. Med. Chem. 1994, 37, 2111(1)). It was hypothesized that the binding mode for these inhibitors is similar to that of the first three N-terminal residues of hirudin. This binding hypothesis was subsequently verified when the crystal structure of a member of this series, BMS-183,507 (N-[N-[N-[4-(Aminoiminomethyl)amino[-1-oxobutyl]-L- phenylalanyl]-L-allo-threonyl]-L-phenylalanine, methyl ester), was determined (Taberno, L.J. Mol. Biol. 1995, 246, 14). The methodology for developing the binding models of these inhibitors, the structure-activity relationships (SAR) and modeling studies that led to the elucidation of the proposed binding mode is described. The crystal structure of BMS-183,507/human alpha-thrombin is compared with the crystal structure of hirudin/human alpha-thrombin (Rydel, T.J. et al. Science 1990, 249,227; Rydel, T.J. et al. J. Mol Biol. 1991, 221, 583; Grutter, M.G. et al. EMBO J. 1990, 9, 2361) and with the computational binding model of BMS-183,507.