Geoff Watson

16 T Diffusion microimaging of fixed prostate tissue: Preliminary findings

Diffusion tensor microimaging was used to investigate the water diffusion properties of formalin‐fixed prostate tissue at spatial resolution approaching the cellular scale. Diffusion tensor microimaging was performed at 16.4 T with 40 μm isotropic voxels. Diffusion tensor microimaging clearly demonstrated distinct microscopic diffusion environments and tissue architecture consistent with that seen on light microscopy of the same tissue. The most restricted diffusion environment is the secretory epithelial cell layer (voxel bulk mean diffusivity, D = 0.4 ± 0.1 × 10−3 mm2/sec). Diffusion in the fibromuscular stromal matrix is relatively less restricted (D = 0.7 ± 0.1 × 10−3 mm2/sec). In tumor tissue (Gleason pattern 4+4) distinct glandular and ductal structures are absent in the diffusion‐weighted images and diffusivity is low (D = 0.5 ± 0.1 × 10−3 mm2/sec). Distinct stromal and epithelial diffusion compartments are the most likely origin of biexponential diffusion decay observed in vivo. Magn Reson Med, 2011.

Ipilimumab-induced toxicities and the gastroenterologist

Ipilimumab has been shown to improve overall survival in patients with advanced melanoma. Ipilimumab acts through immune‐modulation, and is recognized to cause potentially severe immune‐related adverse events (irAEs) including dermatitis, colitis, thyroiditis, hypophysitis, and hepatitis. The acceptance of ipilimumab as a treatment for metastatic melanoma means patients will continue to be treated with this agent and gastroenterologists will be increasingly called upon to assist in managing severe autoimmune‐related hepatitis and colitis. To date, the recommendations for managing irAEs secondary to ipilimumab have been steroids at a moderate dose of prednisolone (1 mg/kg) as well as immunosuppressive agents such as mycophenolate mofetil (MMF) for steroid‐refractory hepatitis and infliximab in the management of corticosteroid‐refractory colitis. However, the dosing and the duration of immunosuppressive therapy have not been systematically studied in the setting of treating ipilimumab‐induced irAEs. Therefore, additional immune‐modifying agents and/or a change in dosing may be required to manage severe irAEs unresponsive to existing treatment recommendations. We describe a treatment paradigm illustrated by a series of five patients who experienced irAEs. In three cases of metastatic melanoma, ipilimumab‐induced hepatitis was successfully treated with high‐dose parenteral pulsed methylprednisolone. In two other melanoma patients with ipilimumab‐induced colitis, one patient had satisfactory resolution of his colitis with high‐dose corticosteroid therapy alone and the other patient required infliximab infusion. We have reviewed the current literature and management algorithms for ipilimumab‐induced irAEs. Treatment options and the rationale for their use are discussed, including the use of pulsed high‐dose steroids, MMF, azathioprine and calcineurin inhibitors.

Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer

Haploinsufficient inactivating phosphatase and tensin homolog (Pten) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice. PTENKO induced uterine pathology was significantly reduced by AR inactivation with severe macroscopic uterine pathology present in 21% of PTENARKO vs 46% of PTENKO at a median age of 45 weeks. This could be due to reduced stroma ERα expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P4) is assumed protective in uterine cancers, serum P4 was significantly higher in PTENKO females compared to WT, ARKO, and PTENARKO females consistent with more corpora lutea in PTENKO ovaries. Serum testosterone and ovarian estradiol were similar between all females. Hence, our results demonstrated AR inactivation mediated protection against PTENKO induced uterine pathology and suggests a potential role for antiandrogens in uterine cancer prevention and treatment.

Rhabdomyosarcoma arising in testicular teratoma

Somatic type malignancy arising de novo from testicular germ cell tumours is a rare occurrence, particularly sarcomatous malignancy. This case report is of a late presentation with disseminated rhabdomyosarcoma that had arisen from a large 110 mm diameter left testicular tumour (ignored by the patient for several months). Rhabdomyosarcoma had extensively overgrown background mature teratomatous elements within the primary, while ENA staging from the cervical nodes yielded just rhabdomyosarcoma. The diagnosis of rhabdomyosarcoma was confirmed with immuno-chemistry and electron microscopy. It highlights an unusual differential for a testicular tumour.

TFE3 FISH assessment in renal cell carcinomas

Aims: Xp11 translocation renal cell carcinomas (TRCCs) showing rearrangements of TFE3 are rare, present in <1% of adult RCCs. Though typical histological features have been described, definitive diagnosis rests on demonstration of TFE3 rearrangement. Three RCC cases with histological features suspicious for TRCC were evaluated for TFE3 rearrangements using FISH. Methods: FISH was performed using the ZytoLight SPEC TFE3 Dual Colour Break Apart FISH Probe (ZytoVision). Results: Case 1 was a 51-year-old female with TFE3 rearrangement present, one intact fused FISH signal, one broken apart signal. Case 2 was a 48-year-old male with TFE3 rearrangement present and the single TFE3 locus demonstrating a positive breakapart FISH signal pattern. Case 3 was a 45-year-old male with no evidence of TFE3 breakapart signal, however an atypical pattern was observed with an additional, intact TFE3 locus. X and Y FISH to exclude underlying sex copy number changes showed a normal male XY pattern. Discussion: TFE3 breakapart FISH is useful for identifying TRCC. We also report a case in a male with very suggestive histology, lacking the classic breakapart pattern, instead showing an additional copy of the TFE3 locus. We postulate that this may represent an as yet unrecognised variant FISH pattern.

Cells, Tissues and Disease. Principles of General Pathology

Disease processes are explained in the light of malfunctions at the cellular level, offering a rich understanding of the clinical correlates of all aspects of fundamental cellular physiology and basic biomedicine. The book has been fully revised and updated to present a current but deep understanding of disease states at the cell and tissue levels--cellular pathology, inflammation, immunopathology vascular disturbance, and tumor biology.