Development of novel imaging biomarkers using positron emission tomography for characterization of malignant phenotype and response evaluation

Positron emission tomography (PET) enables noninvasive tumour imaging, as changes in metabolic activity secondary to therapy can be measured before changes in tumour size are evident on standard anatomic imaging. Two imaging approaches representing proliferation dependent and independent technologies are evolving as potential methods for assessing growth signalling and, thus, treatment response: [18F]3’-deoxy-3’-fluorothymidine (FLT) and [11C]choline. The validity of the former in patients with pancreatic cancer is unproven and likewise, the role of the latter in response to androgen deprivation/radiotherapy in prostate cancer (PCa) remains unexplored. Using a variety of approaches, the aim of this thesis was to provide an understanding of the role of these tracers in lesion detection and response assessment in patients by PET/computed tomography (PET/CT). Given the high physiological hepatic localisation of FLT, a recently reported kinetic spatial filtering (KSF) algorithm was evaluated as a way to de-noise abdominal FLT-PET data from patients with advanced pancreatic cancer. Application of KSF led to improved lesion detection. FLT uptake (SUV60,max) significantly increased in mid-treatment (gemcitabine based) progressors (p=0.04). In this limited number of patients, reduction in FLT uptake did not predict overall survival. The role of [11C]choline PET/CT in lesion detection and response in prostate cancer (PCa) was also investigated using semi-quantitative and quantitative methods. As a prelude to the quantitative imaging studies, it was established that irreversible tracer uptake characterised tumour (breast cancer) [11C]choline kinetics. Similar irreversible uptake characterised PCa. An important finding was that tumour [11C]choline uptake (in 29 PCa patients) correlated with choline kinase (CHK) expression but not proliferation, as assessed by Ki67 labelling index. Immunohistochemistry of the above patients’ prostate cores with CHKα antibody demonstrated a spectrum of CHKα expression, ranging from expression in prostatic-intraepithelial-neoplasia to low to high expression in malignant cores. These findings were further corroborated in a larger cohort of 75 malignant cores derived from non-imaging studies. Having established [11C]choline as a proliferation independent marker of growth, its role in assessing treatment response was investigated. [11C]choline PET was sensitive to metabolic changes within prostate tumours following androgen deprivation and radical radiotherapy. While promising data were obtained with [11C]choline PET, the radiotracer is subject to metabolic degradation complicating data analysis. To this end, a novel metabolically stable analogue of choline ([18F]fluoromethyl-[1,2-2H4]-choline ([18F]D4FCH)) was transitioned into volunteers and patients to study its pharmacokinetics and preliminary diagnostic potential. This tracer embodies deuterium isotope substitution as a means to discourage systemic metabolism. The radiotracer had favourable dosimetry (effective-dose: 0.025mSv/MBq) and safety. Preliminary results in non-small cell lung cancer showed that the tracer is taken up in tumours. Further studies are warranted to characterise this new tracer in different tumour types. As a prelude to imaging cancer cell death in tumours, a caspase-3 specific radiotracer, [18F](S)-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4- difluorophenoxymethyl)-pyrrolidine-1-sulfonyl) isatin ([18F]ICMT-11) was also transitioned into volunteers. The radiotracer had favourable dosimetry (effective-dose: 0.025mSv/MBq) and safety. In summary, FLT-PET/CT combined with KSF and [11C]choline PET/CT were shown to be promising methods for imaging early treatment response in patients. Further work will be required to evaluate the clinical relevance of these data in terms of overall patient outcome. Furthermore, a new choline-based radiotracer and a caspase-3 specific radiotracer have been transitioned into humans.Open Acces

Uloga moderne anti-androgene terapije u liječenju lokaliziranog raka prostate

Anti-androgen therapy continues to be a basic pilar of treatment for both localized and metastatic prostate cancer. The advent of new generation of androgen receptor targeted agents (ARTA) transformed the care of patients with advanced disease. After such a success, the steps were taken to incorporate a new generation of ARTAs into the treatment landscape of localized prostate cancer. High-risk prostate cancer represents the most aggressive form of localized disease with significant metastatic potential and poor outcome. Here, the impact of novel therapies will likely be profound and transforming. This clinical space has already been a showcase for multidisciplinary treatment where the combination of local therapies with systemic treatment gradually improved patient outcomes and the chances of cure. The most recent step in redefining the treatment of localized disease is the adoption of novel ARTAs moving forward the multidisciplinary platform. In this narrative review, we discuss current clinical evidence supporting the use of novel ARTAs in patients with localized high-risk prostate cancer and cover recent developments in biomarker-driven strategies for treatment individualization in this clinical context.Anti-androgena terapija je temelj liječenja lokaliziranog i uznapredovalog raka prostate. Dolazak nove generacije lijekova koji inhibiraju androgenu osovinu preobrazila je liječenje bolesnika sa uznapredovalim rakom prostate. Temeljem uspjeha u uznapredovaloj bolesti, u tijeku su napori da se nova generacija anti-androgenih lijekova inkorporira u liječenje lokalizirane bolesti. Visokorizičan rak prostate predstavlja najagresivniji oblik lokalizirane bolesti sa značajnim metastatskim potencijalom. Za očekivati je da će u ovom stadiju utjecaj novih terapija biti preobražavajući. Lokalizirani visokorizični rak prostate se liječi multidisciplinarno. Tu su kombinacije lokalnog liječenja i sustavne terapije postepeno popravljale ishode liječenja i omogućavale priliku za izliječenje. Zadnji napor predstavlja usvajanje novih anti-androgenih terapija. U ovom preglednom članku razmatramo kliničke dokaze za upotrebu nove generacije anti-adrogene terapije u bolesnika sa lokaliziranim visokorizičnim rakom prostate i dajemo pregled zadnjih strategija za personalizaciju liječenja

Is the digital rectal exam any good as a prostate cancer screening test?

© The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/There is no shortage of references in popular culture to the prostate examination, with many a laugh built on the punchline of the finger up the bum. Interestingly, while cervical, breast, or bowel screening share barriers to uptake around the intimacy of the examination, ‘ick-factor’, or cultural taboos, they have never become comedy tropes — reflecting the uniquely emasculating perception of the rectal examination.Peer reviewe

Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH)

malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHK alpha). due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [F-18]fluoromethyl-[1,2-H-2(4)]choline ([F-18]D4-FCH). [F-18]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a H-1/D-2 isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [F-18]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [F-18]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [F-18]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12-16 weeks despite predominantly stable radiological appearances. the sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival

Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH)

Malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHKα). Due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [18F]fluoromethyl-[1,2-2H4]choline ([18F]D4-FCH). [18F]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a 1H/2D isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [18F]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [18F]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [18F]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. Treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12–16 weeks despite predominantly stable radiological appearances. The sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival

Spinoglenoid notch syndrome

Spinoglenoid notch syndrome is due compression of suprascapular nerve, due to a cyst, at the spinoglenoid notch causing pain, which is often mistaken for rotator cuff injury or cervical spondylosis. This patient presented with pain on the back of the right shoulder with weakness of external rotation and abduction. On examination, he had wasting, and weakness of the infraspinatus muscle and rest of the neurological examination was normal. His right shoulder magnetic resonance imaging scan revealed a cystic lesion at the spinoglenoid notch. An ultrasound guided aspiration of the cyst was done. He improved well with physiotherapy. One year later, the bulk and power of his infraspinatus muscle was normal

Evaluating the prevalence and predictive factors of vasomotor and psychological symptoms in prostate cancer patients receiving hormonal therapy: Results from a single institution experience

Background & purpose: The impact of vasomotor symptoms (VMS) occurring in prostate cancer (PC) patients whilst on androgen deprivation therapy (ADT) has not been extensively researched. This longitudinal study sought to assess the VMS and identify any predictive factors. Material & methods: Data from 250 PC patients on ADT were prospectively evaluated between January 10 and August 13 using a physician-directed questionnaire, to assess the impact of VMS. Parameters including height, weight, body surface area (BSA), body mass index (BMI), duration/type of ADT, co-morbidities and ethnicity were recorded. Results: Fifty (20%) men reported no toxicity, whilst 171 (68.4%), and 29 (11.6%) reported mild to moderate and severe symptoms, respectively. Drenching sweats and hot flashes were common, and coexisted with sleep disturbances and fatigue. Patients with severe toxicity were younger (73 vs. 77 yrs; p = 0.04), had higher BMI (28 vs. 26; p = 0.02), and higher BSA (1.99 vs. 1.90; p = 0.04), when compared with those experiencing no toxicity. On multivariate analysis, younger age was predictive of sweats and hot flushes, whilst Afro-Caribbean men were twice as likely to experience sweats (OR 2.03, p = 0.05). Conclusions: The short-term side-effect profile of ADT for prostate cancer was favourable, though debilitating VMS can occur in a significant minority of cases. Younger age and higher BMI predicted for severe toxicity but not the duration of ADT. Keywords: Prostate cancer, Hormone therapy, Vasomotor symptoms, Predictive factor