Perspectives on joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards for [18F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumors.

Response assessment in the context of immunomodulatory treatments represents a major challenge for the medical imaging community and requires a multidisciplinary approach with involvement of oncologists, radiologists, and nuclear medicine specialists. There is evolving evidence that [18F]FDG PET/CT is a useful diagnostic modality for this purpose. The clinical indications for, and the principal aspects of its standardization in this context have been detailed in the recently published "Joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards on recommended use of [18F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumors version 1.0". These recommendations arose from a fruitful collaboration between international nuclear medicine societies and experts in cancer treatment. In this perspective, the key elements of the initiative are reported, summarizing the core aspects of the guidelines for radiologists and nuclear medicine physicians. Beyond the previous guidelines, this perspective adds further commentary on how this technology can advance development of novel therapeutic approaches and guide management of individual patients.

Joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards on recommended use of [18F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumors version 1.0.

PURPOSE: The goal of this guideline/procedure standard is to assist nuclear medicine physicians, other nuclear medicine professionals, oncologists or other medical specialists for recommended use of [18F]FDG PET/CT in oncological patients undergoing immunotherapy, with special focus on response assessment in solid tumors. METHODS: In a cooperative effort between the EANM, the SNMMI and the ANZSNM, clinical indications, recommended imaging procedures and reporting standards have been agreed upon and summarized in this joint guideline/procedure standard. CONCLUSIONS: The field of immuno-oncology is rapidly evolving, and this guideline/procedure standard should not be seen as definitive, but rather as a guidance document standardizing the use and interpretation of [18F]FDG PET/CT during immunotherapy. Local variations to this guideline should be taken into consideration. PREAMBLE: The European Association of Nuclear Medicine (EANM) is a professional non-profit medical association founded in 1985 to facilitate worldwide communication among individuals pursuing clinical and academic excellence in nuclear medicine. The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote science, technology and practical application of nuclear medicine. The Australian and New Zealand Society of Nuclear Medicine (ANZSNM), founded in 1969, represents the major professional society fostering the technical and professional development of nuclear medicine practice across Australia and New Zealand. It promotes excellence in the nuclear medicine profession through education, research and a commitment to the highest professional standards. EANM, SNMMI and ANZSNM members are physicians, technologists, physicists and scientists specialized in the research and clinical practice of nuclear medicine. All three societies will periodically put forth new standards/guidelines for nuclear medicine practice to help advance the science of nuclear medicine and improve service to patients. Existing standards/guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated. Each standard/guideline, representing a policy statement by the EANM/SNMMI/ANZSNM, has undergone a thorough consensus process, entailing extensive review. These societies recognize that the safe and effective use of diagnostic nuclear medicine imaging requires particular training and skills, as described in each document. These standards/guidelines are educational tools designed to assist practitioners in providing appropriate and effective nuclear medicine care for patients. These guidelines are consensus documents based on current knowledge. They are not intended to be inflexible rules or requirements of practice, nor should they be used to establish a legal standard of care. For these reasons and those set forth below, the EANM, SNMMI and ANZSNM caution against the use of these standards/guidelines in litigation in which the clinical decisions of a practitioner are called into question. The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals considering the unique circumstances of each case. Thus, there is no implication that an action differing from what is laid out in the guidelines/procedure standards, standing alone, is below standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the standards/guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources or advances in knowledge or technology subsequent to publication of the guidelines/procedure standards. The practice of medicine involves not only the science, but also the art of dealing with the prevention, diagnosis, alleviation and treatment of disease. The variety and complexity of human conditions make it impossible for general guidelines to consistently allow for an accurate diagnosis to be reached or a particular treatment response to be predicted. Therefore, it should be recognized that adherence to these standards/ guidelines will not ensure a successful outcome. All that should be expected is that practitioners follow a reasonable course of action, based on their level of training, current knowledge, clinical practice guidelines, available resources and the needs/context of the patient being treated. The sole purpose of these guidelines is to assist practitioners in achieving this objective. The present guideline/procedure standard was developed collaboratively by the EANM, the SNMMI and the ANZSNM, with the support of international experts in the field. They summarize also the views of the Oncology and Theranostics and the Inflammation and Infection Committees of the EANM, as well as the procedure standards committee of the SNMMI, and reflect recommendations for which the EANM and SNMMI cannot be held responsible. The recommendations should be taken into the context of good practice of nuclear medicine and do not substitute for national and international legal or regulatory provisions.

The imaging of immunotherapy-related hypophysitis and other pituitary lesions in oncology patients.

Immunotherapy has revolutionised the treatment of metastatic disease from a variety of different primaries, but is frequently associated with immune-related adverse events. This review illustrates the imaging features of immunotherapy-related hypophysitis (IH) and some of the important differential diagnoses in oncology patients. The key radiological characteristic of IH is diffuse, modest enlargement of the pituitary gland with temporal evolution attributable to immunotherapy. Pituitary enlargement is transient, and the gland size returns to baseline size or smaller within months. IH is usually associated with homogeneous enhancement of the pituitary gland, and the pituitary stalk may be thickened. Larger pituitary size, deviation of the pituitary stalk, the presence of a discrete lesion surrounding by normal pituitary tissue, sellar expansion, and clival invasion are not typical of IH and suggest alternate diagnoses. On integrated 2-[18F]-fluoro-2-deoxy-d-glucose positron-emission tomography (PET)/computed tomography (CT), a transient increase in the metabolic activity of the pituitary gland with subsequent decline to background activity is also suggestive of IH. We suggest that the sella is assessed routinely on imaging performed in the first 6 months after commencing immunotherapy to detect subtle changes. Radiologists should also be aware of features that either support a diagnosis of IH or suggest alternate diagnoses.

Diacylglycerol kinase η modulates oncogenic properties of lung cancer cells.

PURPOSE: Lung cancer is a leading cause of cancer deaths and efforts are underway to identify novel therapies to treat these tumors. Diacylglycerol kinase η (DGKη), an enzyme that phosphorylates diacylglycerol to form phosphatidic acid, has been shown to modulate MAPK signaling downstream of EGFR, which is an oncogenic driver in some lung cancers. Since mutations in EGFR and K-Ras are common in lung cancer, we hypothesized that limiting the function of DGKη would attenuate oncogenic properties of lung cancer cells. METHODS: We determined the expression levels of DGKη in a mouse models of mutant EGFR and K-Ras lung cancer and in human lung cancer cell lines with activating mutations in either EGFR or K-Ras. We also tested the effects of shRNA-mediated depletion of DGKη in lung cancer cells and tested if DGKη depletion augmented the effects of afatinib, a new generation EGFR inhibitor. RESULTS: DGKη was expressed in malignant epithelium from mice with mutant EGFR or K-Ras lung cancer. It was also expressed in human lung cancer cell lines with EGFR or K-Ras mutations. Depleting DGKη in lung cancer cell lines, harboring mutant EGFR, reduced their growth on plastic and in soft agar and also augmented the effects of afatinib, an EGFR inhibitor. DGKη depletion also reduced growth of one of two lung cancer cell lines that harbored mutant K-Ras. CONCLUSIONS: Our data indicate that DGKη is a potential therapeutic target in lung cancers, especially those harboring EGFR mutations. Our findings warrant further studies to examine the effects of limiting its function in vivo.

A Metabonomic Study of the Effect of Methanol Extract of Ginger on Raji Cells Using (1)HNMR Spectroscopy.

Cancer is currently a major international health problem. The development of resistance to chemotherapy has resulted in the search for herbal drugs. Ginger is a medicinal plant with several clinical applications. Metabolomics is a simultaneous detection of all the metabolites by use of (1)HNMR or mass spectroscopy and interpretation by modeling software. The purpose of this study was to detect the altered metabolites of Raji cells in the presence of ginger extract in vitro. Cells were cultured in the presence and absence of methanolic ginger extract in RPMI medium. IC50 determined by MTT and lipophilic and hydrophilic extracts were prepared from control and treated groups which were analyzed by (1)HNMR. The IC50 was 1000 µg/mL. Modeling of spectra was carried out on the two groups using OSC-PLS with MATLAB software and the main metabolites detected. Further analysis was carried out using MetaboAnalyst database. The main metabolic pathways affected by the ginger extract were detected. Ginger extract was seen to effect the protein biosynthesis, amino acid, and carbohydrate metabolism and had a strong cytotoxic effect on Raji cells in vitro.

A metabolomic study on the effect of intravascular laser blood irradiation on type 2 diabetic patients.

Intravenous laser blood irradiation (ILBI) is widely applied in the treatment of different pathologies including diabetes mellitus. The aim of this study is to evaluate the effects of ILBI on the metabolites of blood in diabetic type 2 patients using metabolomics. We compared blood samples of nine diabetic type 2 patients, using metabolomics, before and after ILBI with blue light laser. The results showed significant decrease in glucose, glucose 6 phosphate, dehydroascorbic acid, R-3-hydroxybutyric acid, L-histidine, and L-alanine and significant increase in L-arginine level in blood and blood sugar in the patients have reduced significantly (p < 0.05). This study clearly demonstrated a significant positive effect of ILBI on metabolites of blood in diabetic type 2 patients. These findings support the therapeutic potential of ILBI in diabetic patients.

A trial comparing low-dose, short-course ciprofloxacin and standard 7 day therapy with co-trimoxazole or nitrofurantoin in the treatment of uncomplicated urinary tract infection.

The study was undertaken to compare the safety and efficacy of twice-daily ciprofloxacin for 3 days with standard 7 day therapy with either co-trimoxazole or nitrofurantoin in the treatment of women with acute, uncomplicated urinary tract infections (UTI). This multicentre, prospective, randomized, double-blind trial compared oral ciprofloxacin (100 mg bd) for 3 days with co-trimoxazole (160/800 mg bd) or nitrofurantoin (100 mg bd) for 7 days. Bacteriological and clinical evaluations were performed at study entry, during therapy and 4-10 days and 4-6 weeks after the completion of therapy. The primary efficacy parameter was eradication of the causative organism 4-10 days following treatment. Of 713 women enrolled and evaluable for safety, 521 were evaluable for efficacy (168 ciprofloxacin, 174 co-trimoxazole, 179 nitrofurantoin). Escherichia coli (83%) was the most frequently isolated pathogen in all treatment groups. Bacteriological eradication was reported in 88% of ciprofloxacin patients, 93% of co-trimoxazole patients and 86% of nitrofurantoin patients. At the 4-6 week follow-up, ciprofloxacin had statistically significantly higher eradication rates (91%) than co-trimoxazole (79%; 95% confidence limit (CL) = -20.6%, -3.9%) and nitrofurantoin (82%; 95% CL = -17.1%, -0.9%). Clinical resolution 4-10 days after therapy and at the 4-6 week follow-up was similar among the three treatment groups. The overall incidence of treatment-emergent adverse events was not significantly different (P = 0.093) among the three drug regimens, although co-trimoxazole was associated with a greater number of adverse events than ciprofloxacin (P < or = 0.05). Ciprofloxacin also caused fewer episodes of nausea than either of the other agents (P < or = 0.01).

Tc-99m DMSA SPECT imaging in patients with acute symptoms or history of UTI. Comparison with ultrasonography.

Although planar cortical scintigraphy has been demonstrated to be a sensitive test for the detection of renal infection and scarring, one criticism has been radiation dose to the renal cortex. Recent studies of cortical SPECT suggest a sensitivity for detection of lesions equal to, or greater than, that of planar scans. The authors prospectively performed SPECT scans on 36 patients referred for recurrent urinary tract infection (UTI) (11 of 36), or recent onset of symptoms of UTI (25/36) after 30-40% of the standard 130 MBq (3.5 mCi) adult dose of Tc-99m DMSA was administered. Comparison was made with ultrasonography (US) performed at, or near, the same time. Of 67 kidneys evaluated, 34 (51%) demonstrated focal cortical loss on Tc-99m DMSA scintigraphy, 1 kidney was small in size, and 32 kidneys were normal. Abnormalities were noticed in only 13 (19%) of kidneys on US. Previously, US has been the primary imaging modality in the evaluation of the young patient with UTI. Triple-headed Tc-99m DMSA SPECT scintigraphy is a more sensitive, low-dose (12 mGy, 1.2 r) method of detecting renal cortical abnormalities. As such, it is a more appropriate test for identifying sites of cortical infection and scarring and for following patients on prophylactic therapy for evidence of asymptomatic break-through infections.

Antibiotic therapy for urinary tract infections.

Loracarbef, a member of the carbacephem class of beta-lactam antibiotics, was tested in randomized, double-blind, parallel studies for the treatment of uncomplicated urinary tract infections (UTIs). In one study conducted in the United States, a 7-day course of once-daily doses of loracarbef (200 mg) was compared with a 7-day course of multiple daily doses of cefaclor (250 mg three times a day). Analysis of data from a small, homogeneous patient population of 108 college-aged women showed that loracarbef produced clinical and bacteriologic responses similar to those produced by cefaclor. At 5-9 days posttherapy, bacteriologic cure was observed in 96% of patients in the loracarbef group and 90% of patients in the cefaclor group (p = 0.614); at 4-6 weeks post-therapy, the same cure rate (81%) was observed in both groups. Analysis of the larger (333 patients) and more heterogeneous study population containing several male and elderly female patients showed that loracarbef again produced responses similar to those produced by cefaclor, with no statistically significant differences seen between the groups at 5-9 days or at 4-6 weeks posttherapy. The adverse events reported by the loracarbef and cefaclor groups were also comparable in both the small and large patient populations analyzed. Similarly favorable results were seen when a 7-day regimen of loracarbef (200 mg once a day) was compared with a 7-day regimen of norfloxacin (400 mg twice a day) in a large European study of approximately 300 patients with uncomplicated cystitis. These studies demonstrate that the safety and efficacy of once-daily loracarbef are comparable to the safety and efficacy of multiple-dose/day therapy with other antimicrobial agents commonly used in the treatment of uncomplicated UTIs.

Comparative trials of cefaclor AF in uncomplicated cystitis and asymptomatic bacteriuria.

Two different doses of cefaclor advanced formulation (AF), a new sustained-release formulation of cefaclor, were compared with the regular formulation of cefaclor for efficacy and safety in the treatment of uncomplicated cystitis and asymptomatic bacteriuria. A 7-day course of treatment was used, and the trials were double-dummy and double-blind. In one trial, cefaclor AF 500 mg once daily (at night) was compared with cefaclor 250 mg three times a day. Satisfactory clinical and bacteriological responses were found in 179/189 (94.7%) and 160/191 (83.8%) patients, respectively, given cefaclor AF and in 82/87 (94.3%) and 74/90 (82.2%) patients given cefaclor, 5-9 days after the end of treatment. In the other trial, cefaclor AF 375 mg twice daily was compared with cefaclor 250 mg three times a day. Satisfactory clinical and bacteriological responses were obtained in 164/180 (91.1%) and 156/184 (84.8%) patients, respectively, given cefaclor AF, and in 86/92 (93.5%) and 81/93 (87.1%) patients taking cefaclor, 5-9 days after the end of treatment. Very similar results were found in both studies in those patients who were assessable 3-5 weeks later. Only 4.3% and 2.4% of patients treated with cefaclor AF (375 mg and 500 mg, respectively) and 2.2% of cefaclor patients discontinued therapy due to adverse events. The three most commonly reported events were vaginal moniliasis or vaginitis (8.6%), headache (5.0%) and nausea (4.8%). No significant differences were found between clinical efficacy and safety parameters in the different study groups, and it was concluded that cefaclor AF in a twice-daily or once-daily dosage is as effective and as safe as the currently recommened three-times-a-day dosage of cefaclor.

Loracarbef versus cefaclor in the treatment of cystitis and asymptomatic bacteriuria.

In this double-blind study, 333 patients (16 males, 317 females) with cystitis or asymptomatic bacteriuria were randomly assigned to receive 200 mg of loracarbef once daily (n = 164; mean age, 36 years) or 250 mg of cefaclor thrice daily (n = 169; mean age, 37 years) for seven days. Cystitis was diagnosed in 97.8% of the evaluable loracarbef-treated patients and 94.4% of the evaluable cefaclor-treated patients. Clinical and bacteriologic responses were assessed in 92 loracarbef-treated patients and 107 cefaclor-treated patients. At the five- to nine-day posttreatment evaluation, a clinical cure was found in 84.5% of the loracarbef-treated patients and in 79.4% of the cefaclor-treated patients and improvement in 3.3% and 7.5%, respectively. The pathogen was eliminated in 76.1% and 72.9%, respectively; new pathogens were identified in 4.3% and 4.7%, respectively; and the original pathogen was not eliminated or recurred in 19.6% and 21.5%, respectively. Nausea was the most frequently reported adverse event (in 4.5% of all patients). The results indicate that both loracarbef and cefaclor are safe and effective in the treatment of uncomplicated urinary tract infections.

Membranoproliferative glomerulonephritis in a fifteen-month-old boy.

A 15-month-old boy presented with hypertension, edema, heavy proteinuria, gross hematuria and renal insufficiency. A renal biopsy was consistent with classical membranoproliferative glomerulonephritis type I. Although usually thought of as a disease in older children and young adults, membranoproliferative glomerulonephritis can occur as early as the second year of life.

The use of the kidney biopsy to predict allograft loss in a pediatric transplant population.

Forty-seven biopsy specimens of renal allografts from pediatric transplant recipients were evaluated by light microscopy using a 117 item survey of histopathologic changes. The presence and distribution of immunofluorescent staining were also evaluated. Histopathologic findings associated with irreversible allograft rejection were determined using statistical methods and then correlated with one another. The effect on allograft survival when several of these features were present on the same specimen was assessed. Glomerular, arteriolar and small artery changes were associated with irreversible rejection. When several of these histologic findings occurred on the same biopsy specimen the allograft was always lost. Interstitial and tubular changes generally not predictive of rejection and immunofluorescent staining was not associated with graft loss.

Hyperparathyroidism and anemia in chronic renal failure.

The clinical course of an adolescent on chronic hemodialysis with severe hyperparathyroidism, osteodystrophy and profound anemia is described. After 1,25,dihydroxycholecalciferol was instituted for therapy, bone disease improved as evidenced by radiographic findings. Transfusion requirements diminished and bone marrow fibrosis on serial biopsies decreased significantly. These therapeutic results link hyperparathyroidism with the pathogenesis of anemia in chronic renal failure.

Urinary tract infection caused by Staphylococcus saprophyticus.

This study was designed to determine whether Staphylococcus saprophyticus was an important cause of urinary tract infection (UTI), as has been reported by European, but not by American, investigators, S. saprophyticus was the second most common cause of UTI in young (mean age, 20 years), sexually active female outpatients without known preexisting kidney disease or preceding manipulation of the urinary tract. Most cases presented as acute cystitis, but frank pyelonephritis and UTI in pregnant females were observed. The organism was rarely found as a contaminant in urine cultures. When present in the mucocutaneous flora of the anal-urogenital area, the organism was significantly associated with UTI by the same organism. These results show that S. saprophyticus should be accepted as an important urinary tract pathogen of young female patients in the United States. A simple adequate laboratory identification may be based on resistance to novobiocin (disk diffusion test), absence of hemolysis and coagulase, and intense pigment production (65% of strains yellow, 35% white).