Role of light chain variable region in myeloma with light chain deposition disease: evidence from an experimental model

Light chain deposition disease (LCDD) results from a propensity of some human monoclonal L chains to form tissue deposits. We designed an experimental model for in vivo expression of human kappa L chain sequences in mice and compared a somatically mutated LCDD chain with a closely related control kappa chain, both encoded by the unique V kappa IV gene. Mice secreting the LCDD chain but not those producing the control chain showed deposits with a distribution similar to that observed in patients. These data show that discrete changes in V region sequences can play a major role in tissue deposition of human L chains.     

Failure patterns of combined modality treatment in lung cancer: the impact of staging

BACKGROUND: Patients with locally advanced non-small cell lung cancer (NSCLC) may be treated with induction chemotherapy (IC) followed by surgery with curative intent. The impact of staging inaccuracies on the failure rate of this intensive combined modality treatment approach, i.e. non-curative chemotherapy and thoracotomy, requires further investigation. METHODS: The records of a cohort of 38 consecutive NSCLC IIIA-N2 patients treated with IC followed by surgery were reviewed. RESULTS: The clinical course strongly suggested that the standard diagnostic algorithm failed to demonstrate stage IV disease in 34% of the cases. Surgery instigated by CT-based response criteria at restaging after chemotherapy proved to be irradical in 70% of cases. CONCLUSION: Our data confirm the limitations of the current work-up of patients with apparently locally advanced NSCLC. This applies to the selection of patients to be assigned to combined modality treatment as well as to the post-chemotherapy assessment of resectability. Improved (re)staging of these patients will enhance the efficiency of intervention trials and prevent patients from being exposed to intensive and toxic therapy from which they derive no benefit.     

Studies on regional cerebral haematocrit and blood flow in patients with cerebral tumours using positron emission tomography

Regional cerebral haematocrit has been measured in seven patients with brain tumours, and in one normal subject, using positron emission tomography (PET). Red cell and plasma volumes of distribution were assessed using 11CO and [methyl-11C]albumin, respectively. Haematocrit values were compared with values of regional cerebral blood flow (rCBF) measured using steady-state inhalation of C15O2. Only two of the seven cerebral tumours studied showed any increase in uptake of [methyl-11C]albumin over 45 min. Values of r, the regional ratio of cerebral small-to-large vessel haematocrit, varied from 0.52 to 0.84 for the seven tumours studied. No correlation between r and tumour blood flow was observed. The normal subject yielded an r value of 0.69 for the mean whole brain small-to-large vessel haematocrit ratio. No significant difference between gray and white matter r values was found. The contralateral hemispheres of the seven tumour patients studied yielded an overall mean r value of 0.71 +/- 0.05. We conclude that it is reasonable to assume an r value of 0.7 in tomographic calculations of regional cerebral blood volume (rCBV) from red cell or plasma volumes of distribution in normal brain. Such an assumption for tumours, however, may lead to errors of 35% in estimated rCBV.     

Advancement of multiple myeloma from diagnosis through plateau phase to progression does not involve a new B-cell clone: evidence from the Ig heavy chain gene

The Ig heavy chain (IgH) gene was used as a marker to investigate clonal succession and the origin of the neoplastic cell in multiple myeloma. The polymerase chain reaction (PCR) was used to amplify a section of the rearranged IgH gene at diagnosis and at progression in 21 patients who had exhibited a plateau phase. A monoclonal PCR product was seen for 16 of the patients and the product present at progression was of the same molecular weight as that at diagnosis. This finding suggests that the IgH rearrangement present at diagnosis and progression was the same. This was confirmed by sequencing the IgH gene in 10 patients. The IgH genes were found to be hypermutated at diagnosis, but no further hypermutation occurred during the course of the disease. The results provide evidence that the neoplastic cell in myeloma may originate as a memory B cell, plasmablast, or plasma cell, and suggest that progression beyond the plateau phase is not caused by clonal succession.     

Heterogeneity of breakpoints of 11q23 rearrangements in hematologic malignancies identified with fluorescence in situ hybridization

Twenty-four patients whose cells contained a variety of 11q23 rearrangements, including translocations, insertions, and an inversion, were studied using fluorescence in situ hybridization with cosmid, phage, and plasmid probes mapped to 11q22-24. In 17 patients, the breakpoints of the common 11q23 translocations involving chromosomes 4, 6, 9, and 19 as well as some uncommon translocations involving 3q23, 17q25, 10p11, and an insertion 10;11 were all located in the breakpoint cluster region of the MLL gene, regardless of age, phenotype of disease, or involvement of a third chromosome. The breakpoints in 11q23 in the other 7 patients with a t(7;11)(p15;q23), inv(11)(p11q23), t(4;11)(q23;q23), der(5)t(5;11)(q13;q23), ins(10;11)(p11;q23q24), t(11;14)(q23;q11), or t(11;18;11) (p15;q21;q23) were located either centromeric to CD3D or telomeric to THY1. Thus, although most 11q23 rearrangements, involve the same breakpoint cluster region of MLL, there is heterogeneity in the breakpoint in some of the rare rearrangements.     

Parametric imaging of myocardial viability using 15O-labelled water and PET/CT: comparison with late gadolinium-enhanced CMR

Purpose

The perfusable tissue index (PTI) is a marker of myocardial viability. Recent technological advances have made it possible to generate parametric PTI images from a single [¹⁵O]H₂O PET/CT scan. The purpose of this study was to validate these parametric PTI images.

Methods

The study population comprised 46 patients with documented or suspected coronary artery disease who were studied with [¹⁵O]H₂O PET and late gadolinium-enhanced (LGE) cardiac magnetic resonance imaging (CMR).

Results

Of the 736 myocardial segments included, 364 showed some degree of LGE. PTI and perfusable tissue fraction (PTF) diminished with increasing LGE. The areas under the curve of the PTI and PTF, used to predict (near) transmural LGE on CMR, were 0.86 and 0.87, respectively. Optimal sensitivity and specificity were 91?% and 73?% for PTI and 69?% and 87?% for PTF, respectively.

Conclusion

PTI and PTF assessed with a single [¹⁵O]H₂O scan can be utilized as markers of myocardial viability in patients with coronary artery disease.     

Predictive value of early and late residual 18F-fluorodeoxyglucose and 18F-fluorothymidine uptake using different SUV measurements in patients with non-small-cell lung cancer treated with erlotinib

Purpose

To evaluate the predictive value of early and late residual ¹⁸F-fluorodeoxyglucose (FDG) and ¹⁸F-fluorothymidine (FLT) uptake using different SUV measurements in PET in patients with advanced non-small-cell lung cancer (NSCLC) treated with erlotinib.

Methods

We retrospectively reviewed data from 30 patients with untreated stage IV NSCLC who had undergone a combined FDG PET and FLT PET scan at 1?week (early) and 6?weeks (late) after the start of erlotinib treatment. Early and late residual FDG and FLT uptake were measured in up to five lesions per scan with different quantitative standardized uptake values (SUV_max, SUV_2Dpeak, SUV_3Dpeak, SUV₅₀, SUV_A50, SUV_A41) and compared with short-term outcome (progression vs. nonprogression after 6?weeks of erlotinib treatment). Receiver-operating characteristics (ROC) curve analysis was used to determine the optimal cut-off value for detecting nonprogression after 6?weeks. Kaplan-Meier analysis and the log-rank test were used to evaluate the association between residual uptake and progression-free survival (PFS).

Results

Nonprogression after 6?weeks was associated with a significantly lower early and late residual FDG uptake, measured with different quantitative parameters. In contrast, nonprogression after 6?weeks was not associated with early and late residual FLT uptake. Furthermore, patients with a lower early residual FDG uptake measured in terms of SUV_max and SUV_2Dpeak had a significantly prolonged PFS (282?days vs. 118?days; p?=?0.022) than patients with higher values. Similarly, lower late residual FDG uptake and early residual FLT uptake measured in terms of SUV_3Dpeak, SUV_A50 and SUV_A41, and late FLT uptake measured in terms of SUV_3Dpeak and SUV_A50 was associated with an improved PFS.

Conclusion

Early and late residual FDG uptake, measured using different quantitative SUV parameters, are predictive factors for short-term outcome in patients with advanced NSCLC treated with erlotinib. Additionally, low residual FDG and FLT uptake early and late in the course of erlotinib treatment is associated with improved PFS.     

Digital and conventional chest images: observer performance with Film Digital Radiography System

The Film Digital Radiography System (FilmDRS) is a device with a laser optical film digitizer, 2,000 X 2,000 X 12-bit memory, and a 1,000-line video display. To evaluate the adequacy of this device for general radiography of the chest, four readers independently analyzed both radiographs and the corresponding video display of the digitized chest images of 150 patients, consisting of 100 images of abnormalities and 50 normal images. The overall results indicate equal sensitivity for the two systems. The FilmDRS, with interactive windowing, proved superior in the detection of hilar and mediastinal disease. X-ray film was superior in allowing detection of hyperlucent states. There was equivalent sensitivity for other disease categories. Superior specificity was achieved with conventional radiographs.