Glyn R. Morgan

Management of treatment-emergent peripheral neuropathy in multiple myeloma

Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions.

Identification of hepatocytic and bile ductular cell lineages and candidate stem cells in bipolar ductular reactions in cirrhotic human liver

Hepatocyte function and regeneration are severely compromised in severe liver disease, and a common sequela is cirrhosis. Structural changes caused by cirrhosis create a cellular environment conducive to the formation of ductular reactions (DRs). Ductular reactions are primarily composed of oval cells also known as “intermediate hepatobiliary cells”. We have conducted single, double, and triple staining to study lineages of oval cells present in DRs. Staining with NCAM, CK19, and HepPar1 has revealed a distinctly bipolar structure to DRs that are embedded in cirrhotic tissue. Spatial analysis of cells that are singly HepPar1‐positive, or CK19‐positive, has revealed hepatocytic and biliary poles, respectively, in the DRs. Also, the location of singly NCAM‐positive cells in DRs suggests that they may be bipotent liver stem/progenitor cells. The locations of other intermediate hepatobiliary cells, which have combinations of markers, suggest that CK19+/NCAM+ cells are transitional cells in the biliary lineage and that rare cells that are negative for all three markers are transitional cells in the hepatocytic lineage. A working cell lineage model for DRs is presented. (HEPATOLOGY 2007;45:716–724.)

Dose- and time-dependent oval cell reaction in acetaminophen-induced murine liver injury.

We examined the response of murine oval cells, that is, the putative liver progenitor cells, to acetaminophen. Female C57BL/6J mice were injected intraperitoneally with varying doses of N‐acetyl‐paraaminophen (APAP) (250, 500, 750, and 1,000 mg/kg of weight) and sacrificed at 3, 6, 9, 24, and 48 hours. In preliminary studies, we showed that anticytokeratin antibodies detected A6‐positive cells with a sensitivity and specificity of greater than 99%. The oval cell reaction was quantified, on immunostaining for biliary‐type cytokeratins, as both number and density of oval cells per portal tract, analyzed by size of portal tract. Acetaminophen injury was followed by periportal oval cell accumulation displaying a moderate degree of morphological homogeneity. Oval cell response was biphasic, not temporally correlating with the single wave of injury seen histologically. Increases in oval cells were largely confined to the smallest portal tracts, in keeping with their primary derivation from the canals of Hering, and increased in a dose‐dependent fashion. The timing of the two peaks of the oval cell reaction also changed with increasing dose, the first becoming earlier and the second later. In conclusion, our studies indicate a marked oval cell activation during the height of hepatic injury. Oval cells appear to be resistant to acetaminophen injury. The close fidelity of mechanism and histology of acetaminophen injury between mouse and human livers makes it a useful model for investigating liver regeneration and the participation of stem/progenitor cells in that process. (HEPATOLOGY 2005.)

Assessment of hepatocellular carcinoma using apparent diffusion coefficient and diffusion kurtosis indices: preliminary experience in fresh liver explants.

OBJECTIVES The objective was to perform ex vivo evaluation of non-Gaussian diffusion kurtosis imaging (DKI) for assessment of hepatocellular carcinoma (HCC), including presence of treatment-related necrosis, using fresh liver explants. METHODS Twelve liver explants underwent 1.5-T magnetic resonance imaging using a DKI sequence with maximal b-value of 2000 s/mm(2). A standard monoexponential fit was used to calculate apparent diffusion coefficient (ADC), and a non-Gaussian kurtosis fit was used to calculate K, a measure of excess kurtosis of diffusion, and D, a corrected diffusion coefficient accounting for this non-Gaussian behavior. The mean value of these parameters was measured for 16 HCCs based upon histologic findings. For each metric, HCC-to-liver contrast was calculated, and coefficient of variation (CV) was computed for voxels within the lesion as an indicator of heterogeneity. A single hepatopathologist determined HCC necrosis and cellularity. RESULTS The 16 HCCs demonstrated intermediate-to-substantial excess diffusional kurtosis, and mean corrected diffusion coefficient D was 23% greater than mean ADC (P=.002). HCC-to-liver contrast and CV of HCC were greater for K than ADC or D, although these differences were significant only for CV of HCCs (P≤.046). ADC, D and K all showed significant differences between non-, partially and completely necrotic HCCs (P≤.004). Among seven nonnecrotic HCCs, cellularity showed a strong inverse correlation with ADC (r=-0.80), a weaker inverse correlation with D (-0.24) and a direct correlation with K (r=0.48). CONCLUSIONS We observed non-Gaussian diffusion behavior for HCCs ex vivo; this DKI model may have added value in HCC characterization in comparison with a standard monoexponential model of diffusion-weighted imaging.

Liver transplant donor candidates: Associations between vascular and biliary anatomic variants

Our objective was to investigate the coexistence of vascular and biliary anatomic variants, the latter of which are known to increase the risk of biliary complications in living liver donor transplantation. A total of 108 consecutive liver donor candidates were examined by magnetic resonance (MR) imaging that included 2 MR cholangiography methods, T2‐weighted MR cholangiography and mangofodipir‐enhanced T1‐weighted three‐dimensional (3D) MR cholangiography, as well as gadoliniumenhanced MR angiography and venography of the liver. Images were interpreted by at least 2 investigators in consensus for definition of hepatic arterial, portal venous, and biliary anatomy. A subset of 51 subjects underwent laparotomy for right hepatectomy. Of the 108 subjects examined, 50 (46%) demonstrated normal hepatic artery, portal vein, and biliary anatomy. Variants of the hepatic artery were found in 27 of 108 (25%) subjects, of the portal vein in 12 of 108 (11%) subjects, and of the bile ducts in 30 of 108 (28%) subjects. Of the 27 subjects with hepatic arterial variants, 8 (30%) also had variant biliary anatomy. The association between hepatic arterial variants and biliary variants was not statistically significant (P > .5). However, of the 12 subjects with portal vein variants, 7 (58%) had biliary variants, and in 6 of 7 cases, the right posterior hepatic duct was anomalous. By chi‐square analysis, the association between portal venous and biliary variants was significant (P = .012). In conclusion, over half of subjects with portal vein variants were found to have anomalous biliary anatomy, which always involved the hepatic ducts of the right lobe. The association between portal venous and biliary variants is statistically significant, while there is no significant association between hepatic arterial and biliary variants. (Liver Transpl 2004;10:1049–1054.)

Siderotic nodules at MR imaging: regenerative or dysplastic?

Objective To determine if iron containing “siderotic” nodules detected at magnetic resonance (MR) imaging are regenerative (RN) or dysplastic (DN) and to attempt to identify features that may distinguish them. Material and Methods MR imaging (1.5 T) was performed on 77 cirrhotic patients who underwent orthotopic liver transplantation within 0–117 days (mean 30 days) of MR imaging. Two readers retrospectively evaluated breath-hold gradient-echo pulse sequences (echo time ≥9.0 ms, flip angle ≤45°) for the presence of hypointense nodules, which were classified as micronodular (≤3 mm), macronodular (>3 mm), or mixed. Nodule distribution was classified as focal (<5), scattered (5–20), or diffuse (>20) per slice. Thin section pathologic correlation was available in all cases, and Prussian blue iron stains were performed. Results Of 35 patients with pathologically proven siderotic nodules, 10 (29%) had at least 2 siderotic DN. MR detected siderotic nodules in 10 of 10 (100%) patients with siderotic DN and RN, and in 18 of 25 patients (72%) with siderotic RN only. Conclusion Siderotic RN cannot be reliably distinguished from siderotic DN with MR imaging, and therefore the widely used term “siderotic regenerative nodule” should be avoided and replaced by “siderotic nodule.”

Scirrhous changes in dysplastic nodules do not indicate high‐grade status

Background and Aims: Dysplastic nodules (DN) may be divided into high‐grade and low‐grade, and the former has been known as a precancerous or borderline lesion. Recently many morphological characteristics concerning these types of DN have been reported. In the present study we attempted to evaluate the scirrhous change in DN as an indicative feature of high‐grade DN, based on the morphological and cell‐kinetic analyses using immunohistochemical stains for Ki‐67.

Selection and imaging of the living liver donor

Primum non nocere—First, do no harm: this is one of the basic tenets of medical practice. The very act of living donation violates this age-old edict. The rapidly increasing number of adult recipients and the critical shortage of cadaveric organs have forced transplant surgeons and physicians to search for suitable grafts elsewhere. The use of living liver donors for children has already had a significant impact on the pediatric waiting list. There has been considerable concern, however, regarding the rapidity with which adult-to-adult living donor transplantation has been embraced by transplant centers throughout the country compared with the very cautious and calculated start-up witnessed when living liver donation was first introduced for pediatric recipients. Children needing livers have greatly benefited from living donation and, to a lesser degree, from split-liver transplantation. The splitting of cadaveric livers has become more common, but unfortunately relatively few cadaveric organs are suitable for splitting and the procedure generally benefits an adult and a pediatric recipient and so does nothing extra to reduce the numbers of adults on the waiting list. The number of adults on the waiting list is, however, increasing at a tremendous rate, and thus the demand for solutions is great. Most living donor grafts given to adult recipients are right lobes. Left lobe grafts are not discussed in this review. The risks are considerable. Right hepatic lobectomy is a formidable procedure even in the most skilled hands. Proper donor selection is critical. The donor selection practices of four leading transplant centers are reviewed in the first segment of this review. In the second section, the imaging of potential donors is examined in more detail. Curr Opin Organ Transplant 2001, 6:350–354

Thalidomide (Thal) tolerance in patients treated with transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC)

4255 Background: Most HCCs are hypervascular and appropriate for treatments that target tumor angiogenesis. Tumor vascularity may be mechanically disrupted by TACE yet biologic disruption is preferable. As Thal has anti-angiogenic properties we studied the combination of Thal and TACE in patients with HCC. Thals tolerance in patients (pt) with a variety of illnesses is not well-established. We therefore reviewed Thals tolerability in pts with liver disease and HCC undergoing Adriamycin (Adria) Lipiodol (Lip) TACE. METHODS 56 pts with HCC have been enrolled. All pts had total bili < 3, and transaminases ≤ 5 X nl. Thal was initiated at a dose(ds) of 200 mg/d and ds escalations or decreases were permitted as tolerated. After 28 days Thal was discontinued and pts underwent a Adria Lip collagen TACE after which Thal was restarted. RESULTS The mean pt age was 58.4 yrs. The m/f ratio was 46/10. All pts had hepatitis B or C, or alcoholic liver disease. 15 pts recieved liver transplants. 8 pts were removed from study for Thal toxicity (tox). 4, 1 and 3 of the 8 pts were withdrawn for grade (gr) II-III neurologic (neuro), gr I gastrointestinal (gastro) and gr ≥ III other Thal toxs, respectively. 42 pts have undergone TACE. 24 pts remained on 200 mg/d and 18 pts were ds escalated to 250-500 mg/d prior to TACE. There were 42 Thal ds increases and 32 ds reductions. The first post TACE ds was reduced for TACE related constitutional tox in 8 pts. 13 of 18 pts ds escalated prior to TACE required ds reductions after TACE. There were more ds reductions due to Thal tox after TACE then before it (28 vs 4, p = 0.0002), and more pts were reduced to ≤ 150 mg/d as a result of Thal tox after TACE then prior to it. (19 vs 5 p = 0.0007). 47.1 %, 3.7 % and 18.8 % of ds reductions were prompted by constitutional, gastro and neuro Thal tox, respectively. 41.5%, 45.2% and 13.2% of the ds reductions resulted from gr I, II and III Thal toxs. CONCLUSIONS 1.0 Initial Thal ds of 200 mg/d are tolerable in HCC pts with minimal liver dysfunction. 2.0 Ds escalations > 200 mg often result in subsequent ds reductions. 3.0 Ds reductions are more frequent after TACE when some pts may tolerate only 50-150 mg/d. No significant financial relationships to disclose.