Consistent and effective method to define the mouse estrous cycle stage by a deep learning-based model.

The mouse estrous cycle is divided into four stages: proestrus (P), estrus (E), metestrus (M), and diestrus (D). The estrous cycle affects reproductive hormone levels in a wide variety of tissues. Therefore, to obtain reliable results from female mice, it is important to know the estrous cycle stage during sampling. The stage can be analyzed from a vaginal smear under a microscope. However, it is time-consuming, and the results vary between evaluators. Here, we present an accurate and reproducible method for staging the mouse estrous cycle in digital whole-slide images (WSIs) of vaginal smears. We developed a model using a deep convolutional neural network (CNN) in a cloud-based platform, Aiforia Create. The CNN was trained by supervised pixel-level multiclass semantic segmentation of image features from 171 hematoxylin-stained samples. The model was validated by comparing the results obtained by CNN with those of four independent researchers. The validation data included three separate studies comprising altogether 148 slides. The total agreement attested by the Fleiss kappa value between the validators and the CNN was excellent (0.75), and when D, E, and P were analyzed separately, the kappa values were 0.89, 0.79, and 0.74, respectively. The M stage is short and not well defined by the researchers. Thus, identification of the M stage by the CNN was challenging due to the lack of proper ground truth, and the kappa value was 0.26. We conclude that our model is reliable and effective for classifying the estrous cycle stages in female mice.

[Urinary stress incontinence after radical prostatectomy in treatment reality : Results of a rehabilitation clinic-2009 compared to 2016]. / Belastungsharninkontinenz nach radikaler Prostatektomie in der Versorgungswirklichkeit : Ergebnisse einer Reha-Klinik 2009 und 2016.

PURPOSE: Based on the work of Lent et al., the aim of this study was to compare and to evaluate the 2009 outcomes of maintaining continence after radical prostatectomy (rp) with those of patients from 2016. PATIENTS AND METHODS: The data of all patients who underwent follow-up treatment 1 to 8 weeks after rp in 2016 (n = 1392) were evaluated by quantitative measuring all day incontinence under a defined graduation and compared to the results of 2009 (n = 1750). RESULTS: The basic data of the patients including age (p < 0.001), prostate-specific antigen (PSA) value (median 10.8/13.76 ng/ml in 2009/2016), cancer stage (p = 0.001) and Gleason score (p = 0.001) were significantly higher in 2016. Robot-assisted prostatectomy (RARP; 12% in 2009 to 45% in 2016) was performed much more often than radical retropubic prostatectomy. Laparoscopic and perineal prostatectomy were rarely performed. Significantly fewer patients achieved pad-free continence at discharge in 2016 (23%) vs. 33.9% in 2009; p ≤ 0.001. Within the same age group, there was a significant worsening of continence (p = 0.01). The results of maintaining continence did not significantly differ between patients with open retropubic prostatectomy and RARP (p = 0.078). The certification type of a clinic had no effect on continence preservation (p = 0.12). CONCLUSION: Incontinence rates after discharge from a rehabilitation clinic are high and have not improved over time or with new surgical techniques. The patient should be prepared for this in the patient information discussion prior to the surgery.

The lack of HSD17B3 in male mice results in disturbed Leydig cell maturation and endocrine imbalance akin to humans with HSD17B3 deficiency.

Hydroxysteroid (17ß) dehydrogenase type 3 (HSD17B3) deficiency causes a disorder of sex development in humans, where affected males are born with female-appearing external genitalia, but are virilized during puberty. The hormonal disturbances observed in the Hsd17b3 knockout mice (HSD17B3KO), generated in the present study, mimic those found in patients with HSD17B3 mutations. Identical to affected humans, serum T in the adult HSD17B3KO mice was within the normal range, while a striking increase was detected in serum A-dione concentration. This resulted in a marked reduction of the serum T/A-dione ratio, a diagnostic hallmark for the patients with HSD17B3 deficiency. However, unlike humans, male HSD17B3KO mice were born with normally virilized phenotype, but presenting with delayed puberty. In contrast to the current belief, data from HSD17B3KO mice show that the circulating T largely originates from the testes, indicating a strong compensatory mechanism in the absence of HSD17B3. The lack of testicular malignancies in HSD17B3KO mice supports the view that testis tumors in human patients are due to associated cryptorchidism. The HSD17B3KO mice presented also with impaired Leydig cell maturation and signs of undermasculinization in adulthood. The identical hormonal disturbances between HSD17B3 deficient knockout mice and human patients make the current mouse model valuable for understanding the mechanism of the patient phenotypes, as well as endocrinopathies and compensatory steroidogenic mechanisms in HSD17B3 deficiency.

Insights into the role of androgen receptor in human testicular peritubular cells.

Contractile smooth muscle-like peritubular cells build the wall of seminiferous tubules in men. They are crucial for sperm transport and complement the functions of Sertoli cells by secreting factors, including glial cell line-derived neurotrophic factor. Previous studies revealed that they also secrete the chemokine C-X-C motif chemokine ligand 12 (CXCL12), which has known roles in spermatogenesis. Peritubular cells express the androgen receptor (AR), which is retained in isolated human testicular peritubular cells. We aimed to explore AR-regulated functions in human testicular peritubular cells. Bearing in mind that infertile men often have high aromatase activity, which may lower intratesticular androgen concentrations, an animal model for male infertility was studied. These mice display an age-dependent loss in spermatogenesis due to high aromatase activity. Human testicular peritubular cells were exposed to dihydrotestosterone or the antiandrogen flutamide. We studied AR, smooth muscle cell markers, glial cell line-derived neurotrophic factor and 15 secreted factors previously identified, including CXCL12. We used qPCR, Western blotting, ELISA or selected reaction monitoring (SRM). In the animal model for male infertility, we employed qPCR and immunohistochemistry. Dihydrotestosterone increased AR and flutamide prevented these actions. The smooth muscle cell markers calponin and smooth muscle actin were likewise increased, while cell size or cellular proliferation was not changed. Dihydrotestosterone did not increase glial cell line-derived neurotrophic factor or CXCL12 secretion but increased levels of serine proteinase inhibitor (SERPIN) E1. The animal model for male infertility with high aromatase activity showed reduced numbers of AR-immunoreactive testicular peritubular cells, suggesting that altered androgen and/or oestrogen levels could influence AR-mediated responses in peritubular cells. Androgens act on human testicular peritubular cells to enhance AR levels, their contractile phenotype and to modulate the secretion of some secreted factors. This study suggests that some aspects of human peritubular cell functions are regulated by androgens.

Phase 2 placebo-controlled, double-blind trial of dasatinib added to gemcitabine for patients with locally-advanced pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate with limited treatment options. Gemcitabine provides a marginal survival benefit for patients with advanced PDAC. Dasatinib is a competitive inhibitor of Src kinase, which is overexpressed in PDAC tumors. Dasatinib and gemcitabine were combined in a phase 1 clinical trial where stable disease was achieved in two of eight patients with gemcitabine-refractory PDAC. Patients and methods: This placebo-controlled, randomized, double-blind, phase II study compared the combination of gemcitabine plus dasatinib to gemcitabine plus placebo in patients with locally advanced, non-metastatic PDAC. Patients received gemcitabine 1000 mg/m2 (30-min IV infusion) on days 1, 8, 15 of a 28-day cycle combined with either 100 mg oral dasatinib or placebo tablets daily. The primary objective was overall survival (OS), with safety and progression-free survival (PFS) as secondary objectives. Exploratory endpoints included overall response rate, freedom from distant metastasis, pain and fatigue progression and response rate, and CA19-9 response rate. Results: There was no statistically significant difference in OS between the two treatment groups (HR = 1.16; 95% confidence interval [CI]: 0.81-1.65; P = 0.5656). Secondary and exploratory endpoint analyses also showed no statistically significant differences. The burden of toxicity was higher in the dasatinib arm. Conclusions: Dasatinib failed to show increased OS or PFS in patients with locally advanced PDAC. Alternative combinations or trial designs may show a role for src inhibition in PDAC treatment.

Sterile inflammation as a factor in human male infertility: Involvement of Toll like receptor 2, biglycan and peritubular cells.

Changes in the wall of seminiferous tubules in men with impaired spermatogenesis imply sterile inflammation of the testis. We tested the hypothesis that the cells forming the wall of seminiferous tubules, human testicular peritubular cells (HTPCs), orchestrate inflammatory events and that Toll like receptors (TLRs) and danger signals from the extracellular matrix (ECM) of this wall are involved. In cultured HTPCs we detected TLRs, including TLR2. A TLR-2 ligand (PAM) augmented interleukin 6 (IL-6), monocyte chemo-attractant protein-1 (MCP-1) and pentraxin 3 (PTX3) in HTPCs. The ECM-derived proteoglycan biglycan (BGN) is secreted by HTPCs and may be a TLR2-ligand at HTPCs. In support, recombinant human BGN increased PTX3, MCP-1 and IL-6 in HTPCs. Variable endogenous BGN levels in HTPCs derived from different men and differences in BGN levels in the tubular wall in infertile men were observed. In testes of a systemic mouse model for male infertility, testicular sterile inflammation and elevated estradiol (E2) levels, BGN was also elevated. Hence we studied the role of E2 in HTPCs and observed that E2 elevated the levels of BGN. The anti-estrogen ICI 182,780 blocked this action. We conclude that TLR2 and BGN contribute to sterile inflammation and infertility in man.

From pilot fish to analyst: Finding a path between symbiotic and autistic defences.

This paper presents the clinical case of a patient with autistic features. One of the main difficulties in his treatment was the particular rapid rhythm of his projections, introjections and re-projections that constrained the analyst's capacity for reverie and hindered the use of effective projective identification processes. These alternating defensive constellations lead either to an expelling autistic barrier or to an engulfing symbiotic fusion. Their combination can be seen as the expression of a defence against an unintegrated and undifferentiated early experience of self that was in this way kept at bay to prevent it from invading his whole personality. Maintaining the symbiotic link, in which I kept included by staying partially fused to what was being projected and using my analytic function in a reduced way, helped to relate to what was in the patient's inside. Leaving this symbiotic link let my interpretations appear to 'force' their way through the autistic barrier. Yet as the process developed they allowed to show the patient how he ejected me and what was happening in his inside, behind his autistic barrier. So I found myself on the one hand accepting the symbiotic immobilization and on the other hand interpreting in a way that seemed forced to the patient, because it implied a breaking of the symbiotic position. The inordinate speed of projections and introjections could thus be interrupted, creating a space for awareness, reflection and transformation, and allowed the emergence of a connection between the patient's inside and outside. In the course of treatment I realized that this kind of dual defence system has been described by the late Argentinian analyst José Bleger. He assumes the existence of an early "agglutinated nucleus" that is held together by a psychic structure he calls the "glischro-caric" position, in which projective identification cannot take place because there is no self/object differentiation. I have considered the rapid and fugitive use of projection and re-introjection I met in my patient to be a manifestation of the dual defence system Bleger describes. Although he does not specifically mention this particular vicissitude of operative defences he does give hints about a rhythm in the patients' projections and introjections.

Unveiling the molecular basis of antimicrobial resistance in Staphylococcus aureus from the Democratic Republic of the Congo using whole genome sequencing.

Staphylococcus aureus from sub-Saharan Africa is frequently resistant to antimicrobial agents that are commonly used to treat invasive infections in resource-limited settings. The underlying mechanisms of resistance are largely unknown. We therefore performed whole genome sequencing (WGS) on S. aureus from the Democratic Republic of the Congo (DRC) to analyse the genetic determinants of antimicrobial resistance. One hundred S. aureus samples were collected from community-associated asymptomatic nasal carriers in the metropolitan area of Kinshasa, DRC, between 2013 and 2014. Phenotypic resistance against 15 antimicrobial agents was compared to the genotypic results that were extracted from WGS data using Mykrobe predictor and the SeqSphere(+) software that screened for 106 target genes associated with resistance. Isolates were phenotypically resistant against penicillin (97%, n=97), trimethoprim (72%, n=72) and tetracycline (54%, n=45). Thirty-three isolates (33%) were methicillin-resistant S. aureus (MRSA). Of these, nine isolates (27.3%) were oxacillin-susceptible MRSA (OS-MRSA) and belonged to ST8 (t1476). The Y195F mutation of FemA was associated with OS-MRSA (p 0.015). The majority of trimethoprim resistant isolates carried dfrG. Tetracycline resistance was associated with tet(K). The concordance between phenotypic susceptibility testing and both WGS analysis tools was similar and ranged between 96% and 100%. In conclusion, a high proportion of OS-MRSA in the DRC was linked to mutations of FemA. Genotypic and phenotypical antimicrobial susceptibility testing showed high concordance. This encourages the future use of WGS in routine antimicrobial susceptibility testing.

Weight gain and inflammation regulate aromatase expression in male adipose tissue, as evidenced by reporter gene activity.

Obesity and white adipose tissue (WAT) inflammation are associated with enhanced aromatization in women, but little is known about the regulation of aromatase (CYP19A1) gene expression in male WAT. We investigated the impact of weight gain and WAT inflammation on the regulation of CYP19A1 in males, by utilizing the hARO-Luc aromatase reporter mouse model containing a >100-kb 5'-region of the human CYP19A1 gene. We show that hARO-Luc reporter activity is enhanced in WAT of mice with increased adiposity and inflammation. Dexamethasone and TNFα, as well as forskolin and phorbol 12-myristate 13-acetate, upregulate hARO-Luc activity, suggesting the involvement of promoters I.4 and I.3/II. Furthermore, we show that diet enriched with antioxidative plant polyphenols attenuates WAT inflammation and hARO-Luc activity in obese males. In conclusion, our data suggest that obesity-associated WAT inflammation leads to increased peripheral CYP19A1 expression in males, and that polyphenol-enriched diet may have the potential to attenuate excessive aromatization in WAT of obese men.

[Stress incontinence after prostatectomy in treatment reality: results from a rehabilitation clinic]. / Belastungsinkontinenz nach Prostatektomie in der Versorgungswirklichkeit : Ergebnisse einer Reha-Klinik.

BACKGROUND: In the current discussion on the operative therapy of prostate cancer, not only"if" but also"how" play a major role. Both questions are closely related as, e.g. a possible excessive therapy will result in additional suffering due to stress incontinence. For the most common, troublesome and expensive consequences of prostatectomy it is of interest to know which factors play a role in treatment reality and which could possibly be avoided. PATIENTS AND METHODS: The hospital records of all patients who underwent follow-up treatment after prostatectomy in 2009 at the clinic in the spa park in Bad Wildungen-Reinhardshausen were evaluated with respect to relevant data on outcome and clinical endpoints. RESULTS: Of the 1,750 patients 405 (23.1 %) were continent on admission and discharge and a further 189 (10.8 %) were continent on discharge so that a total of 594 patients (33.9 %) were continent on discharge. Of the 1,155 patients (66.0 %) who were incontinent on admission and discharge, this remained the same during the rehabilitation period for 727 (62.9 %) who were diurnally incontinent and 659 (57.1 %) who were nocturnally incontinent. For 387 patients (33.5 %) the incontinence decreased during the day and for 370 (32.0 %) during the night, for 34 (3.4 %) the incontinence increased during the day and for 45 (3.9 %) during the night. An age < 60 years was advantageous for maintaining continence and in contrast > 70 years was disadvantageous. Retention of nerves showed a significant effect on maintaining continence. Statistically significant differences between the results of operative procedures and the results of the type of clinic (KKP communal, confessional and private or UK university clinic) were not observed. However, the results of maintaining continence (up to termination of rehabilitation treatment) for the 594 patients (33.9 %) was only achieved by 94 (51 %) of all 183 clinics, i.e. 78 (49.7 %) of the KKP clinics and 14 (53.9 %) of UK clinics. For the certified prostate centers of KKP and UK clinics this amounted to 17 (81 %) and 5 (83.3 %), respectively. CONCLUSIONS: In treatment reality of follow-up treatment of patients after prostatectomy in rehabilitation clinics approximately one third (33.9 %) achieved retention of continence up to discharge. An age < 60 years was advantageous and > 70 years disadvantageous. Bilateral and unilateral retention of nerves significantly improved retention of continence. The operative procedure and type of clinic did not significantly affect the results. However, in approximately one third of patients (33.9 %) retention of continence was achieved by only approximately one half (51.4 %) of all clinics. This shows that in treatment reality, stress incontinence following prostatectomy is avoidably underdeveloped and can be demonstrably increased by suitable operative techniques for sphincter protection.

High levels of the extracellular matrix proteoglycan decorin are associated with inhibition of testicular function.

Decorin (DCN), a component of the extracellular matrix of the peritubular wall and the interstitial areas of the human testis, can interact with growth factor (GF) signalling, thereby blocking downstream actions of GFs. In the present study the expression and regulation of DCN using both human testes and two experimental animal models, namely the rhesus monkey and mouse, were examined. DCN protein was present in peritubular and interstitial areas of adult human and monkey testes, while it was almost undetectable in adult wild type mice. Interestingly, the levels and sites of testicular DCN expression in the monkeys were inversely correlated with testicular maturation markers. A strong DCN expression associated with the abundant connective tissue of the interstitial areas in the postnatal through pre-pubertal phases was observed. In adult and old monkeys the DCN pattern was similar to the one in normal human testes, presenting strong expression at the peritubular region. In the testes of both infertile men and in a mouse model of inflammation associated infertility (aromatase-overexpressing transgenic mice), the fibrotic changes and increased numbers of tumour necrosis factor (TNF)-α-producing immune cells were shown to be associated with increased production of DCN. Furthermore, studies with human testicular peritubular cells isolated from fibrotic testis indicated that TNF-α significantly increased DCN production. The data, thus, show that an increased DCN level is associated with impaired testicular function, supporting our hypothesis that DCN interferes with paracrine signalling of the testis in health and disease.

Comparing a narcissistic and an autistic retreat: 'looking through or at the window'.

In this paper I discuss two different forms of psychic retreats that I encountered in the treatment of a patient who suffered from two traumatic experiences: the loss of his mother when he was 2 years old and his 'near-death' experience when he was five. In the parasitic narcissistic retreat, using intensive projective identification enabled him to create an impasse in the form of a 'high tide - low tide' scenario in which alternating hope and disappointment kept the process going, yet paralyzed development. The autistic retreat, for its part, led to the collapse of projective identification mechanisms, dismantling and disrupting the transference/countertransference negotiations. The emerging state of non-communication and 'near death' seemed to act as a protection against the unbearable pain of abandonment and desolation.

Mast cell tryptase stimulates production of decorin by human testicular peritubular cells: possible role of decorin in male infertility by interfering with growth factor signaling.

BACKGROUND: Myofibroblastic, peritubular cells in the walls of seminiferous tubules produce low levels of the extracellular matrix (ECM) protein decorin (DCN), which has the ability to interfere with growth factor (GF) signaling. In men with impaired spermatogenesis, fibrotic remodeling of these walls and accumulation of tryptase-positive mast cells (MCs) occur. METHODS: Human testicular biopsies with normal and focally impaired spermatogenesis (mixed atrophy) were subjected to immunohistochemistry and laser micro-dissection followed by RT-PCR. Primary human testicular peritubular cells (HTPCs), which originate from normal and fibrotically altered testes (HTPC-Fs), were studied by qRT-PCR, western blotting, enzyme-linked immunosorbent assay measurements and Ca(2+) imaging. Phosphorylation and viability/proliferation assays were performed. RESULTS: Immunohistochemistry revealed DCN deposits in the walls of tubules with impaired spermatogenesis. Mirroring the situation in vivo, HTPC-Fs secreted more DCN than HTPCs (P < 0.05). In contrast to HTPCs, HTPC-Fs also responded to the main MC product, tryptase, and to a tryptase receptor (PAR-2) agonist by further increased production of DCN (P < 0.05). Several GF receptors (GFRs) are expressed by HTPCs and HTPC-Fs. DCN acutely increased intracellular Ca(2+)-levels and phosphorylated epidermal GF (EGFR) within minutes. Platelet-derived GF (PDGF) and EGF induced strong mitogenic responses in HTPC/-Fs, actions that were blocked by DCN, suggesting that DCN in the ECM interferes with GF/GFRs signaling of peritubular cells of the human testis. CONCLUSIONS: The data indicate that the increase in testicular DCN found in male infertility is a consequence of actions of MC-derived tryptase. We propose that the increases in DCN may consequently imbalance the paracrine signaling pathways in human testis.

Sunitinib in metastatic thymic carcinomas: laboratory findings and initial clinical experience.

BACKGROUND: Thymic carcinoma (TC) is a rare aggressive tumour. Median survival with current treatments is only 2 years. Sunitinib is a multi-targeted tyrosine kinase inhibitor that has shown benefit in various other cancers. METHODS: Laboratory analyses of snap-frozen tumour tissues were performed to detect activation and genetic mutations of receptor tyrosine kinases (RTKs) in TC samples. On the basis of molecular analyses showing activation of multiple RTKs in their tumour, four patients with metastatic TCs refractory to conventional therapies were treated with sunitinib according to standard protocols. RESULTS: RTK analysis in three of the patients showed activation of multiple RTKs, including platelet-derived growth factor-beta and vascular endothelial growth factor 3. Mutations of EGFR, c-KIT, KRAS, and BRAF genes were not found. Administration of sunitinib yielded a partial remission (lasting 2 to 18+ months) according to the RECIST criteria in three patients and stable disease with excellent metabolic response in 18F-FDG-PET in another one. The overall survival with sunitinib treatment ranges from 4 to 40+ months. Withdrawal of the drug in one patient prompted rapid tumour progression that could be controlled by re-administration of sunitinib. CONCLUSIONS: Sunitinib is an active treatment for metastatic TC. A panel of molecular analyses may be warranted for optimal patient selection.

T cell-tumor interaction directs the development of immunotherapies in head and neck cancer.

The competent immune system controls disease effectively due to induction, function, and regulation of effector lymphocytes. Immunosurveillance is exerted mostly by cytotoxic T-lymphocytes (CTLs) while specific immune suppression is associated with tumor malignancy and progression. In squamous cell carcinoma of the head and neck, the presence, activity, but also suppression of tumor-specific CTL have been demonstrated. Functional CTL may exert a selection pressure on the tumor cells that consecutively escape by a combination of molecular and cellular evasion mechanisms. Certain of these mechanisms target antitumor effector cells directly or indirectly by affecting cells that regulate CTL function. This results in the dysfunction or apoptosis of lymphocytes and dysregulated lymphocyte homeostasis. Another important tumor-escape mechanism is to avoid recognition by dysregulation of antigen processing and presentation. Thus, both induction of functional CTL and susceptibility of the tumor and its microenvironment to become T cell targets should be considered in CTL-based immunotherapy.

[Antiangiogenic and anti-immunosuppressive therapeutic strategies in human head and neck squamous cell carcinoma (HNSCC)]. / Tumorangiogenese und Immunsuppression. Strategische Angriffspunkte für neue Therapieansätze beim Plattenepithelkarzinom der Mundhöhle (HNSCC).

BACKGROUND: Angiogenesis and tumor-associated immunosuppression are two of the hallmarks of carcinogenesis. In previous studies we demonstrated in vitro that HNSCC tumor cells attract monocytes via monocyte chemotactic protein-1 (MCP-1) and activate them via transforming growth factor-beta 1(TGF-beta1) to secrete interleukin (IL)-1alpha, which in turn stimulates tumor cells to secrete increased levels of the angiogenic and immunosuppressive vascular endothelial growth factor (VEGF). These findings suggest that interaction between the immune system and VEGF-mediated angiogenesis is important for progression of HNSCC. Recent studies in vitro show that retinoic acid (RA) downregulates the release of MCP-1 and TGF-beta1 by tumor cells. Therefore, we investigated the ability of RA to modulate the ability of tumor cells to recruit and activate monocytes for participation in VEGF-mediated angiogenesis and immunosuppression in vivo. MATERIAL AND METHODS: Mice (ten/group) were injected daily with RA (160 microg/kg) for 3 weeks. After that time mice were sacrificed, and paraffin sections of tumors were obtained and stained for VEGF-A, CD68, and PECAM (CD31) by immunohistochemistry. The lungs, liver, and myocardium were analyzed for macro- and micrometastases. The plasma protein levels of VEGF-A and MCP-1 were determined by ELISA. RESULTS: In RA-treated mice tumors regressed completely and RA prevented metastases (p=0.00) and macrophage infiltration (p=0.007). Treated mice downregulated VEGF-A (0 pg/ml) and MCP-1 (12 pg/ml) in peripheral blood (p=0.001). CONCLUSION: Our findings suggest a new therapeutic possibility: the development of treatment protocols that can block each of the ways in which tumors induce new blood vessel growth and immunosuppression of the host.

Feasibility study of the use of similarity maps in the evaluation of oncological dynamic positron emission tomography images.

A preliminary study is presented on the potential role of similarity mapping (SM) in the evaluation of oncological dynamic 18F-fluorodeoxyglucose positron emission tomography studies, mainly in lesion localisation and detectability. Similarity maps were calculated using previously described (correlation coefficient (COR) and normalised correlation coefficient (NCOR)) and newly introduced similarity measures (sum of squares coefficient (SSQ), squared sum coefficient (SQS), sum of cubes coefficient (SC) and cubed sum coefficient (CS)). The results were evaluated using simulated and clinical data. The study revealed that the best-suited similarity measure for such applications was the CS similarity coefficient, which provided the best parametric images, delineating structures of interest and supporting the visual interpretation of data sets. It was shown that SM and standardised uptake value (SUV) images had comparable diagnostic performance, although SM was able to offer additional time-related information in a single image. For the case of colorectal recurrences (17 cases), the measured contrast values for the CS and SUV images were 2.36 +/- 0.47 and 4.12 +/- 0.42, respectively, whereas, for three cases of giant cell tumours, these values were 11.6 +/- 2.1 and 11.9 +/- 1.8, respectively.

PET-FDG as predictor of therapy response in patients with colorectal carcinoma.

AIM: The purpose of this study was to evaluate the prognostic value of quantitative dynamic FDG PET studies in patients with metastastic colorectal cancer receiving FOLFOX (fluorouracil, folinic acid and oxaliplatin) chemotherapy. METHODS: The evaluation includes 28 patients with 55 metastases from primary colorectal cancer. Reference for the FDG studies was the clinical response data, according to the WHO classification. Three response groups were defined: progressive disease (PD), stable disease (SD) and partial response (PR). The FDG studies were accomplished as dynamic series for 60 min. The evaluation of the FDG kinetics was performed using the SUV, and fractal dimension (FD) of the time activity curves based on the box counting procedure (parameter for the inhomogeneity of the tumors). RESULTS: The median SUV as measured in the tumor lesions prior to onset to FOLFOX was 3.15, in comparison with 2.68 SUV after the first cycle and 2.61 SUV after the second cycle. Discriminant analysis (DA) was used for the classification of the data into the 3 categories. Both parameters SUV and FD provided 2 of the 3 "predicted" categories, namely PD and SD. It was possible to correctly classify PR in only 10% of the patients, using the FD of both studies. Generally, DA inclined to misclassify the data towards PD. Even the first PET study was predictive with respect to therapy outcome (96% for PD and 47% for SD using only the baseline SUV). Metastases with a baseline SUV lower than 4.6 did not respond to FOLFOX chemotherapy. The combination of SUV and FD of the first study lead to a correct classification of 93% of PD and 60% of SD. Best results were obtained for the FD of the initial PET study (90% for PD and 75% for SD) as well as for the FD of both studies (77% for PD, 73% for SD, 10% for PR). CONCLUSION: Quantitative, dynamic FDG-PET should be used preferentially for monitoring patients with metastatic colorectal cancer receiving chemotherapy. Even the first FDG study prior to onset to chemotherapy is predictive for the therapy outcome.