The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

The soft-tissue sarcomas (STS) of childhood are a relatively rare and heterogeneous group of tumors that may occur anywhere in the body and respond quite differently to therapy. STSs account for 7.4% of all cancers in children younger than 20 years [1]. These soft tissue sarcomas are divided almost equally between rhabdomyosarcomas originating from striated muscle and nonrhabdomyosarcoma soft tissue sarcomas (NRSTS). Sarcomas are malignant tumors of mesenchymal cell origin. They are named according to the normal tissue they resemble — for example, rhabdomyosarcoma (skeletal muscle), leiomyosarcoma (smooth muscle), and fibrosarcoma and malignant fibrous histiocytoma (connective tissue), neurofibrosarcoma or malignant peripheral nerve sheath tumor (neurofibrosarcomas, as seen in patients with neurofibromatosis), liposarcoma (adipose), synovial sarcoma (synovium), peripheral nerve sheath tumors (peripheral nerve), and angiosarcoma (blood and/or lymphatic vessels). Other sarcomas include rare entities such as alveolar softpart sarcoma, extraosseous Ewing’s sarcoma, peripheral neuroectodermal tumors, epitheloid sarcoma, and hemangiopericytoma.

Soft Tissue Sarcoma

UNLABELLED: (18)F-FDG PET measurement of standardized uptake value (SUV) is increasingly used for monitoring therapy response and predicting outcome. Alternative parameters computed through textural analysis were recently proposed to quantify the heterogeneity of tracer uptake by tumors as a significant predictor of response. The primary objective of this study was to evaluate the reproducibility of these heterogeneity measurements. METHODS: Double baseline (18)F-FDG PET scans were acquired within 4 d of each other for 16 patients before any treatment was considered. A Bland-Altman analysis was performed on 8 parameters based on histogram measurements and 17 parameters based on textural heterogeneity features after discretization with values between 8 and 128. RESULTS: The reproducibility of maximum and mean SUV was similar to that in previously reported studies, with a mean percentage difference of 4.7% ± 19.5% and 5.5% ± 21.2%, respectively. By comparison, better reproducibility was measured for some textural features describing local heterogeneity of tracer uptake, such as entropy and homogeneity, with a mean percentage difference of -2% ± 5.4% and 1.8% ± 11.5%, respectively. Several regional heterogeneity parameters such as variability in the intensity and size of regions of homogeneous activity distribution had reproducibility similar to that of SUV measurements, with 95% confidence intervals of -22.5% to 3.1% and -1.1% to 23.5%, respectively. These parameters were largely insensitive to the discretization range. CONCLUSION: Several parameters derived from textural analysis describing heterogeneity of tracer uptake by tumors on local and regional scales had reproducibility similar to or better than that of simple SUV measurements. These reproducibility results suggest that these (18)F-FDG PET-derived parameters, which have already been shown to have predictive and prognostic value in certain cancer models, may be used to monitor therapy response and predict patient outcome.

https://jnm.snmjournals.org/content/jnumed/53/5/693.full.pdf

Reproducibility of Tumor Uptake Heterogeneity Characterization Through Textural Feature Analysis in 18F-FDG PET

Microglia have a variety of functions in the brain, including synaptic pruning, CNS repair and mediating the immune response against peripheral infection. Microglia rapidly become activated in response to CNS damage. Depending on the nature of the stimulus, microglia can take a number of activation states, which correspond to altered microglia morphology, gene expression and function. It has been reported that early microglia activation following traumatic brain injury (TBI) may contribute to the restoration of homeostasis in the brain. On the other hand, if they remain chronically activated, such cells display a classically activated phenotype, releasing pro-inflammatory molecules, resulting in further tissue damage and contributing potentially to neurodegeneration. However, new evidence suggests that this classification is over-simplistic and the balance of activation states can vary at different points. In this article, we review the role of microglia in TBI, analyzing their distribution, morphology and functional phenotype over time in animal models and in humans. Animal studies have allowed genetic and pharmacological manipulations of microglia activation, in order to define their role. In addition, we describe investigations on the in vivo imaging of microglia using translocator protein (TSPO) PET and autoradiography, showing that microglial activation can occur in regions far remote from sites of focal injuries, in humans and animal models of TBI. Finally, we outline some novel potential therapeutic approaches that prime microglia/macrophages toward the beneficial restorative microglial phenotype after TBI.

/pdf/microglial-activation-in-traumatic-brain-injury-45z9wydn45.pdf

Microglial Activation in Traumatic Brain Injury

Alzheimer's disease is characterized by the histopathological presence of amyloid-β plaques and tau-containing neurofibrillary tangles. Microglial activation is also a recognized pathological component. The relationship between microglial activation and protein aggregation is still debated. We investigated the relationship between amyloid plaques, tau tangles and activated microglia using PET imaging. Fifty-one subjects (19 healthy controls, 16 mild cognitive impairment and 16 Alzheimer's disease subjects) participated in the study. All subjects had neuropsychometric testing, MRI, amyloid (18F-flutemetamol), and microglial (11C-PBR28) PET. All subjects with mild cognitive impairment and Alzheimer's disease and eight of the controls had tau (18F-AV1451) PET. 11C-PBR28 PET was analysed using Logan graphical analysis with an arterial plasma input function, while 18F-flutemetamol and 18F-AV1451 PET were analysed as target:cerebellar ratios to create parametric standardized uptake value ratio maps. Biological parametric mapping in the Statistical Parametric Mapping platform was used to examine correlations between uptake of tracers at a voxel-level. There were significant widespread clusters of positive correlation between levels of microglial activation and tau aggregation in both the mild cognitive impairment (amyloid-positive and amyloid-negative) and Alzheimer's disease subjects. The correlations were stronger in Alzheimer's disease than in mild cognitive impairment, suggesting that these pathologies increase together as disease progresses. Levels of microglial activation and amyloid deposition were also correlated, although in a different spatial distribution; correlations were stronger in mild cognitive impairment than Alzheimer's subjects, in line with a plateauing of amyloid load with disease progression. Clusters of positive correlations between microglial activation and protein aggregation often targeted similar areas of association cortex, indicating that all three processes are present in specific vulnerable brain areas. For the first time using PET imaging, we show that microglial activation can correlate with both tau aggregation and amyloid deposition. This confirms the complex relationship between these processes. These results suggest that preventative treatment for Alzheimer's disease should target all three processes.

Microglial activation correlates in vivo with both tau and amyloid in Alzheimer’s disease

We studied the distribution and expression of translocator protein in the human brain using 11C-[R]-PK-11195 positron emission tomography (PK11195 PET) and evaluated age-related changes. A dynamic PK11195 PET scan was performed in 15 normal healthy adults (mean age: 29 ±8.5 years (range: 20 to 49); 7 males) and 10 children (mean age: 8.8 ±5.2 years (range: 1.2 to 17); 5 males), who were studied for potential neuroinflammation but showed no focally increased PK11195 binding. The PET images were evaluated by calculating standard uptake values and regional binding potential, based on a simplified reference region model, as well as with a voxel-wise analysis using statistical parametric mapping. PK11195 uptake in the brain is relatively low, compared with the subcortical structures, and symmetrical. The overall pattern of PK11195 distribution in the brain does not change with age. PK11195 uptake was lowest in the frontal-parietal-temporal cortex and highest in the pituitary gland, midbrain, thalamus, basal ganglia, occipital cortex, hippocampus and cerebellum, in descending order. White matter showed negligible PK11195 uptake. Overall, brain PK11195 uptake increased with age, with midbrain and thalamus showing relatively higher increases with age compared with other brain regions. The brain shows low PK11195 uptake, which is lower in the cortex and cerebellum compared with subcortical structures, suggesting a low level of translocator protein expression. There is no hemispheric asymmetry in PK11195 uptake and the overall pattern of PK11195 distribution in the brain does not change with age. However, brain PK11195 uptake increases with age, with the thalamus and midbrain showing relatively higher increases compared with other brain regions. This increase in uptake suggests an age-related increase in translocator protein expression or the number of cells expressing these receptors or both.

/pdf/evaluation-of-age-related-changes-in-translocator-protein-32owrbpg1h.pdf

Evaluation of age-related changes in translocator protein (TSPO) in human brain using 11C-[R]-PK11195 PET

Aim To determine the efficacy of positron emission tomography-computed tomography using F-18 fluoro-deoxy-glucose (F-18 FDG PET-CT) in diagnosing the recurrence of renal cell carcinoma (RCC) in patients treated earlier with partial or radical nephrectomy. Methods We assessed 63 patients with suspected recurrent RCC after nephrectomy. PET-CT findings were interpreted as positive if the focal area of FDG uptake in the abdomen or outside the abdomen was more than the surrounding background tissue. The final diagnosis of the recurrence of RCC was based on histological examination and/or clinical follow-up and conventional imaging modalities. Results A total of 103 PET-CT studies were done in these 63 patients, of which 63 studies were true positive, 30 studies were true negative, seven studies were false negative and remaining three studies were false positive. In 63 true-positive scans, PET-CT showed 109 lesions. Of these, 28 lesions were in the lungs, 21 lesions were at a locoregional site, 21 were in the bones, 12 in the retroperitoneal lymph nodes and 27 at other sites. The sensitivity, specificity and accuracy of PET-CT were 90, 91 and 90%, respectively. Conclusion Our results seem to confirm the useful role of PET-CT in the evaluation of post-surgical recurrence in patients who had undergone radical surgery for RCC.

Role of FDG PET-CT in recurrent renal cell carcinoma.

AimTo evaluate the treatment response of rhenium-188 (188Re) tin colloid radiosynovectomy (188Re-RSV) in patients with inflammatory knee joint conditions refractory to conventional treatment.Materials and methodsSixty-one knee joints in 48 patients with chronic synovitis caused by various inflammato

Role of rhenium-188 tin colloid radiosynovectomy in patients with inflammatory knee joint conditions refractory to conventional therapy.

The common childhood cancers are leukemia, CNS tumors, lymphomas, soft-tissue tumors (such as rhabdomyosarcoma and fibrosarcoma), neuroblastoma, malignant bone tumors, germ cell tumors with neoplasms of gonads and hepatic tumors. Usually the conventional imaging modalities, such as x-ray, ultrasound, computed tomography (CT) and MRI, are being routinely used for the management of these pediatric malignancies. However, most of these modalities provide structural information and are lacking in functional/metabolic status of these malignancies. Recently, PET and PET/CT have emerged as a functional diagnostic imaging modality for the management of various cancers in adult population. Up to now most of the data published in the literature are on PET alone. PET used in conjunction with CT is useful as it provides an enhanced view of the anatomical details and the malignant focus then can be located with highest accuracy. PET and PET/CT has been found to be useful in, for example, CNS tumors, lymphomas, soft-tissue tumors, neuroblastoma, malignant bone tumors and germ cell tumors. PET/CT has a limited role in early diagnosis, however, it plays an important role in initial staging, treatment response evaluation and detection of metastatic disease in these cancers. Despite the fact that PET/CT has better diagnostic value when compared with conventional imaging, such as CT and MRI, in the management of many pediatric cancers, there are certain limitations. PET/CT has a limited role in detection of lesions smaller than 5 mm, well-differentiated tumors and tumors with low metabolic rate. Many infections and inflammation can lead to false-positive PET/CT results. In the present review we will discuss the various clinical indications of PET and PET/CT in pediatric cancers.

Clinical applications of PET and PET/CT in pediatric malignancies.

OBJECTIVE To characterize the clinical features of isolated elevated plasma homocysteine (eHcy)-induced peripheral neuropathy (IHIN) in adults. METHODS Charts of subjects with the diagnosis of IHIN who visited neuromuscular clinic from January 01, 2012 to September 30, 2014 were reviewed. Subjects with identifiable etiologies for neuropathy, such as B12/folate deficiency; metabolic, toxic, endocrinologic, infectious/inflammatory renal or liver diseases; or traumatic nerve injury, were excluded. Their clinical presentations were recorded and analyzed. RESULTS Thirty subjects (age: 63.2 ± 14.8 years, 13 males) were included. They all had an isolated increased homocysteine level (15.4 ± 5.3 μmol/L) but normal levels of B12, folate, and methylmalonic acid. Of 30, 14 (46.7%) had numb feet, 11 (36.7%) had numb hands, 7 (23.3%) had pain in lower extremities, and 10 (33.3%) had tingling in feet. Distal sensory deficits were present in 18/30 (60%) patients. Distal limb weakness was seen in 4 and decreased tendon reflexes in 12 patients. CONCLUSIONS Sensory deficits are predominant components of IHIN. Characterizing clinical features of IHIN would help better understand eHcy-related neuropathy and improve its management.

Varun Shandal

Papers

Evaluation of age-related changes in translocator protein (TSPO) in human brain using 11C-[R]-PK11195 PET

Role of FDG PET-CT in recurrent renal cell carcinoma.

Role of rhenium-188 tin colloid radiosynovectomy in patients with inflammatory knee joint conditions refractory to conventional therapy.

Clinical applications of PET and PET/CT in pediatric malignancies.

Clinical Manifestations of Isolated Elevated Homocysteine-Induced Peripheral Neuropathy in Adults.