Phase II study to evaluate combining gemcitabine with flutamide in advanced pancreatic cancer patients

A phase II study was undertaken to determine the safety of combining flutamide with gemcitabine, with response rate being the primary end point. Twenty-seven patients with histologically proven, previously untreated, unresectable pancreatic adenocarcinoma received gemcitabine, 1 g m−2 intravenously on days 1, 8 and 15 of a 28 day cycle, and flutamide 250 mg given orally three times daily. Treatment was halted if there was unacceptable toxicity, or evidence of disease progression. Toxicity was documented every cycle. Tumour assessment was undertaken after cycles 2 and 4, and thereafter at least every additional four cycles. One hundred and seventeen cycles of treatment were administered, median four cycles per patient (range 1–18). Gemcitabine combined with flutamide was well tolerated, with most toxicities being recorded as grade 1 or 2 and only nine treatment cycles associated with grade 3 toxicity. The most frequent toxicity was myelosuppression. One case of transient jaundice was recorded. The commonest symptomatic toxicity was nausea and vomiting. The response rate was 15% (four partial responses), median survival 6 months and 22% of patients were alive at 1 year. These results suggest antitumour activity of the combination therapy to be equivalent to single agent gemcitabine

Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing

Purpose We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). Methods Two large databases of individuals fulfilling NF2 criteria (n = 1361) and those tested for NF2 variants with criteria short of diagnosis (n = 1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the positive predictive value (PPV) with regard to definite diagnosis. Results There was no evidence for usefulness of old criteria “glioma“ or “neurofibroma.” “Ependymoma” had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged ≥60 years had the lowest confirmation rate (6.6%) and reduced PPV (80%). Siblings as a first-degree relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1-associated schwannomatosis. In this category, seven individuals with unilateral VS plus ≥2 nondermal schwannomas reduced PPV to 67%. Conclusions The present study confirms important deficiencies in NF2 diagnostic criteria. The term “glioma” should be dropped and replaced by “ependymoma.” Similarly “neurofibroma” should be removed. Dropping “sibling” from first-degree relatives should be considered and testing of LZTR1 should be recommended for unilateral VS

New insights into the propagation of fatigue damage in cortical bone using confocal microscopy and chelating fluorochromes

Fatigue damage in bone occurs in the form of microcracks and plays an important role in the initiation of bone remodelling and in the occurrence of stress and fragility fractures. The process by which fatigue microcracks in bone initiate and grow remains poorly understood. The aim of this study was to investigate the microscopic tissue changes associated with microcracks during crack propagation in cortical bone and the influence of bone microstructure on this process. Cracks were mechanically initiated and extended longitudinally in a two-stage process, in six bovine tibial compact tension specimens. The sequential application of chelating fluorochromes, xylenol orange followed by calcein, allowed the nature of microcrack damage at different stages of propagation to be monitored by laser scanning confocal microscopy. Specimens were imaged at a focal plane 20 microm below the samples' surface, or as a series of z-plane images collected to a maximal depth of 200 microm and 35 microm for x 4 and x 40 objectives, respectively. Z-series image stacks were then reconstructed using Amira 3.0 software. Confocal images showed that xylenol orange localised to the crack surface and did not migrate into the crack's extension following further mechanical propagation. Similarly, calcein stained the extended crack's surface and displayed minimal incorporation within the original crack. High resolution confocal images provided a detailed visual description of the crack's 'process zone', and 'process zone wake'. Additionally, an 'interface region' was revealed, displaying a clear distinction between the end of the first crack and the commencement of its extension. Confocal images of the interface region demonstrated that the extended crack forms a continuum with the pre-existing crack and propagates through the former process zone. Upon viewing the three-dimensional reconstructed images, we found evidence suggesting a submicroscopic tissue involvement in fatigue damage, in addition to the potential influence of vascular canals and osteocyte lacunae on its propagation through the bone matrix. This study has provided new insights into the process of fatigue damage growth in bone and factors influencing its progression through the bone matrix. Confocal microscopy in combination with sequential chelating fluorochrome labelling is a valuable technique for monitoring microcrack growth in bone.K.H. Zarrinkalam; Dr J.S. Kuliwaba; R.B. Martin; M.A.B. Wallwork; N.L. Fazzalar

Metabolic response at repeat PET/CT predicts pathological response to neoadjuvant chemotherapy in oesophageal cancer.

OBJECTIVES: Reports have suggested that a reduction in tumour 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) examination during or after neoadjuvant chemotherapy may predict pathological response in oesophageal cancer. Our aim was to determine whether metabolic response predicts pathological response to a standardised neoadjuvant chemotherapy regimen within a prospective clinical trial. METHODS: Consecutive patients staged with potentially curable oesophageal cancer who underwent treatment within a non-randomised clinical trial were included. A standardised chemotherapy regimen (two cycles of oxaliplatin and 5-fluorouracil) was used. PET/CT was performed before chemotherapy and repeated 24-28 days after the start of cycle 2. RESULTS: Forty-eight subjects were included: mean age 65 years; 37 male. Using the median percentage reduction in SUV(max) (42%) to define metabolic response, pathological response was seen in 71% of metabolic responders (17/24) compared with 33% of non-responders (8/24; P = 0.009, sensitivity 68%, specificity 70%). Pathological response was seen in 81% of subjects with a complete metabolic response (13/16) compared with 38% of those with a less than complete response (12/32; P = 0.0042, sensitivity 52%, specificity 87%). There was no significant histology-based effect. CONCLUSIONS: There was a significant association between metabolic response and pathological response; however, accuracy in predicting pathological response was relatively low

Metabolic response at repeat PET/CT predicts pathological response to neoadjuvant chemotherapy in oesophageal cancer

Objectives Reports have suggested that a reduction in tumour 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) examination during or after neoadjuvant chemotherapy may predict pathological response in oesophageal cancer. Our aim was to determine whether metabolic response predicts pathological response to a standardised neoadjuvant chemotherapy regimen within a prospective clinical trial. Methods Consecutive patients staged with potentially curable oesophageal cancer who underwent treatment within a non-randomised clinical trial were included. A standardised chemotherapy regimen (two cycles of oxaliplatin and 5- fluorouracil) was used. PET/CT was performed before chemotherapy and repeated 24-28 days after the start of cycle 2. Results Forty-eight subjects were included: Mean age 65 years; 37 male. Using the median percentage reduction in SUVmax (42%) to define metabolic response, pathological response was seen in 71% of metabolic responders (17/24) compared with 33% of non-responders (8/24; P=0.009, sensitivity 68%, specificity 70%). Pathological response was seen in 81% of subjects with a complete metabolic response (13/16) compared with 38% of those with a less than complete response (12/32; P=0.0042, sensitivity 52%, specificity 87%). There was no significant histology-based effect. Conclusions There was a significant association between metabolic response and pathological response; however, accuracy in predicting pathological response was relatively low. Key Points ̇ PET/CT may predict tumour response to chemotherapy in oesophageal cancer. ̇ This was a prospective study using a standardised chemotherapy regimen. ̇ A significant association between PET/CT findings and disease response was found. ̇ However accuracy in predicting pathological response was relatively low. © European Society of Radiology 2012

Metabolic response at repeat PET/CT predicts pathological response to neoadjuvant chemotherapy in oesophageal cancer

Objectives Reports have suggested that a reduction in tumour 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) examination during or after neoadjuvant chemotherapy may predict pathological response in oesophageal cancer. Our aim was to determine whether metabolic response predicts pathological response to a standardised neoadjuvant chemotherapy regimen within a prospective clinical trial. Methods Consecutive patients staged with potentially curable oesophageal cancer who underwent treatment within a non-randomised clinical trial were included. A standardised chemotherapy regimen (two cycles of oxaliplatin and 5- fluorouracil) was used. PET/CT was performed before chemotherapy and repeated 24-28 days after the start of cycle 2. Results Forty-eight subjects were included: Mean age 65 years; 37 male. Using the median percentage reduction in SUVmax (42%) to define metabolic response, pathological response was seen in 71% of metabolic responders (17/24) compared with 33% of non-responders (8/24; P=0.009, sensitivity 68%, specificity 70%). Pathological response was seen in 81% of subjects with a complete metabolic response (13/16) compared with 38% of those with a less than complete response (12/32; P=0.0042, sensitivity 52%, specificity 87%). There was no significant histology-based effect. Conclusions There was a significant association between metabolic response and pathological response; however, accuracy in predicting pathological response was relatively low. Key Points ̇ PET/CT may predict tumour response to chemotherapy in oesophageal cancer. ̇ This was a prospective study using a standardised chemotherapy regimen. ̇ A significant association between PET/CT findings and disease response was found. ̇ However accuracy in predicting pathological response was relatively low. © European Society of Radiology 2012