PREMIUM: A French prospective multicenter observational study of factors impacting on efficacy and compliance to cetuximab treatment in first-line KRAS wild-type metastatic colorectal cancer.

BACKGROUND: Cetuximab improves progression-free survival (PFS) and overall survival (OS) in patients with KRAS wild type (wt) metastatic colorectal cancer (mCRC). Few data are available on factors impacting both efficacy and compliance to cetuximab treatment, which is, in combination with chemotherapy, a standard-of-care first-line treatment regimen for patients with KRAS wt mCRC. PATIENTS AND METHODS: PREMIUM is a prospective, French multicenter, observational study that recruited patients with KRAS wt mCRC scheduled to receive cetuximab, with or without first-line chemotherapy, as part of routine clinical practice, between October 28, 2009 and April 5, 2012 (ClinicalTrials.gov Identifier: NCT01756625). The main endpoints were the factors impacting on efficacy and compliance to cetuximab treatment. Predefined efficacy endpoints were PFS and safety. RESULTS: A total of 493 patients were recruited by 94 physicians. Median follow-up was 12.9 months. Median progression-free survival was 11 months [9.6-12]. In univariate analyses, ECOG performance status (PS), smoking status, primary tumor location, number of metastatic organs, metastasis resectability, surgery, folliculitis, xerosis and paronychia maximum grade, and acne preventive treatment were statistically significant. In multivariate analysis (Hazard Ratios of multivariate stepwise Cox models), ECOG PS, surgery, xerosis and folliculitis were positive prognostics factors for longer PFS. Among all patients, 69 (14%) were non-compliant. In multivariate analysis, no variables were statistically significant. The safety profile of cetuximab was consistent with previous studies. CONCLUSIONS: ECOG PS <2, surgical treatment performed, and maximum grade xerosis or folliculitis developed were predictive factors of cetuximab efficacy on KRAS wt mCRC patients. Unfortunately, we failed in identifying predictive factors for compliance in these patients.

Impact of ferric carboxymaltose on the evolution of hemoglobin and ECOG performance status in iron-deficient patients with solid tumors: a 3-month follow-up retrospective study.

BACKGROUND: Anemia is often associated with a lower quality of life and less tolerance to treatments in cancer patients. OBJECTIVE: The aims of this retrospective study were to assess the biological (hemoglobin, Hb) and clinical (ECOG index) impact of ferric carboxymaltose (FCM) and to identify predictive factors of response in cancer patients with iron deficiency. METHODS: We included 133 patients with solid tumors who received at least one dose of FCM in 2015. RESULTS: At baseline, most patients had metastatic cancer (70%), were undergoing chemotherapy (82%), suffered from anemia (90%), and 72% had an ECOG 0-1 index. Mean Hb level was statistically higher at M1 (108.3 g/L ± 13.9), M2 (110.3 g/L ± 16.1), and M3 (111.7 g/L ± 12.6) than M0 (99.2 g/L ± 13.9). Mean ECOG score increased significantly at M1 (1.31 ± 0.80) and M2 (1.31 ± 0.87) compared to M0 (1.13 ± 0.80). Variations of ECOG index between M0 and M1 were independent of levels of Hb and ferritin at inclusion and pretreatment use of transfusion and ESAs. Increase of Hb level was higher in patients with Hb < 100 g/L, ferritinemia < 800 ng/ml, or transfused before inclusion. In multivariate analysis, an ECOG index of 0 was the only predictive factor of an increase of ECOG index and Hb level < 100 g/L and ferritinemia < 800 ng/ml were predictive of an increase in Hb. CONCLUSION: Even though there was no improvement in ECOG index, this study did identify an increase of Hb for patients receiving FCM, indicating its potential benefit in iron-deficient cancer patients.

Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia.

Pure hereditary spastic paraplegia (SPG) type 4 is the most common form of autosomal dominant hereditary SPG, a neurodegenerative disease characterized primarily by hyperreflexia and progressive spasticity of the lower limbs. It is caused by mutations in the gene encoding spastin, a member of the AAA family of ATPases. We have screened the spastin gene for mutations in 15 families consistent with linkage to the spastin gene locus, SPG4, and have identified 11 mutations, 10 of which are novel. Five of the mutations identified are in noninvariant splice-junction sequences. Reverse transcription-PCR analysis of mRNA from patients shows that each of these five mutations results in aberrant splicing. One mutation was found to be "leaky," or partially penetrant; that is, the mutant allele produced both mutant (skipped exon) and wild-type (full-length) transcripts. This phenomenon was reproduced in in vitro splicing experiments, with a minigene splicing-vector construct only in the context of the endogenous splice junctions flanking the splice junctions of the skipped exon. In the absence of endogenous splice junctions, only mutant transcript was detected. The existence of at least one leaky mutation suggests that relatively small differences in the level of wild-type spastin expression can have significant functional consequences. This may account, at least in part, for the wide ranges in age at onset, symptom severity, and rate of symptom progression that have been reported to occur both among and within families with SPG linked to SPG4. In addition, these results suggest caution in the interpretation of data solely obtained with minigene constructs to study the effects of sequence variation on splicing. The lack of full genomic sequence context in these constructs can mask important functional consequences of the mutation.

Novel mutations in spastin gene and absence of correlation with age at onset of symptoms.

Autosomal dominant hereditary spastic paraplegia is genetically heterogeneous, with at least five loci identified by linkage analysis. Recently, mutations in spastin were identified in SPG4, the most common locus for dominant hereditary spastic paraplegia that was previously mapped to chromosome 2p22. We identified five novel mutations in the spastin gene in five families with SPG4 mutations from North America and Tunisia and showed the absence of correlation between the predicted mutant spastin protein and age at onset of symptoms.

A disrupted homologue of the human CLN3 or juvenile neuronal ceroid lipofuscinosis gene in Saccharomyces cerevisiae: a model to study Batten disease.

1. In order to investigate the biological function of the human CLN3 gene that is defective in Batten disease, we created a yeast strain by PCR-targeted disruption of the yeast gene (YHC3), which is a homologue of the human CLN3 gene. 2. The phenotypic characterization revealed that the yhc3 delta mutants are more sensitive to combined heat and alkaline stress than the wild-type strains as determined by inhibition of cell proliferation. 3. This suggests that the yhc3 delta mutant is a good model to investigate the biological function of human CLN3 gene in mammalian cells and to understand the pathophysiology of juvenile Batten disease.

Upregulation of Bcl-2 and elevation of ceramide in Batten disease.

The late infantile and juvenile variants of Batten disease are genetically distinct neurodegenerative disorders. Hallmarks of Batten disease include cognitive and motor decline, seizures and blindness due to retinitis pigmentosa. Recently, the CLN3 gene responsible for the juvenile variant has been cloned. Also, apoptosis was proven to be the mechanism by which neurons and photoreceptors die. This paper provides mechanistic support for the occurrence of apoptosis in this disease: There was marked upregulation of Bcl-2 in brain from the late infantile and juvenile types at the protein and RNA levels both by immunocytochemistry and by Northern blot analysis; there were also a 42% to 197% increase in brain ceramide determinations in brains from three patients with the juvenile type and three patients with the late infantile type. Double immunolabeling of brain sections for apoptosis and Bcl-2 supported a protective role for Bcl-2 in the juvenile form of Batten disease. These results raise the possibility that the intact CLN3 gene is normally antiapoptotic, and that it could be an upstream regulator of ceramide.

Apoptosis in development and disease of the nervous system: II. Apoptosis in childhood neurologic disease.

The loss of cells in the human nervous system has long been known as the hallmark of incurable degenerative disease. Recent studies that began with attempts to understand cell loss during normal development have now begun to contribute to our understanding of the process of pathological cell loss. In many neurodegenerative conditions, it has become clear that apoptosis, or programmed cell death, plays a role in the diminution of cell number. In the cases of human immunodeficiency virus-associated encephalopathy and several of the hereditary neurodegenerative disorders, triggers and mediators of this process have been identified. This identification is not only the first step toward treatment of such disorders, but it also raises the possibility of exploiting this information to design targeted apoptosis-based therapies for tumors of the nervous system.

Torticollis acquired in late infancy due to a cerebellar gangliocytoma.

Torticollis in infancy is a common disorder and is typically benign and self-limiting. However, in some instances it is the presentation of serious disease. A critical distinction is whether the condition is congenital or acquired. We present a case of acquired late infantile torticollis caused by a cerebellar gangliocytoma that underscores the importance of making this determination prior to initiating a treatment plan. A gangliocytoma presenting with torticollis has not been previously described.

Role of subunit-9 of mitochondrial ATP synthase in Batten disease.

The role of subunit-9 of mitochondrial ATP synthase in Batten disease was defined by characterizing the expression of genes encoding this protein in human tissues. Two genetically distinct neuronal ceroid-lipofuscinoses (NCL) comprise Batten disease: the late-infantile (LINCL) and juvenile (JNCL) types. We tested cell lines and tissues from both types of patients, along with normal controls. Differences in expression between diseased and normal samples were found for both mRNA and protein. Antibody staining of subunit-9 protein was detected in LINCL and JNCL tissues, and in 6 LINCL and 4 of 5 JNCL fibroblast lines. No immunoreactivity was seen in fibroblasts from obligate carriers, normal controls, and 6 other storage disease controls, with the exception of faint staining in Niemann-Pick, type C cells. There was an appreciable difference in staining pattern in both tissue sections and fibroblasts between LINCL and JNCL. Three subunit-9 transcripts (Hum1, Hum2, and Hum3) were specifically detected in NCL and normal human tissue from heart, liver, brain, muscle, and pancreas. Transcriptional regulation of subunit-9 genes was found to be altered in Batten disease. Pseudogenes related to each of the subunit-9 genes were isolated. Sequence analysis of cDNAs spanning the protein-coding regions of the Hum1, Hum2, and Hum3 genes showed conclusively that the primary defect(s) causing NCL are not mutations in the protein-coding regions of the 3 known subunit-9 genes.

Ultrastructural findings in skin from patients with Niemann-Pick disease, type C.

Niemann-Pick disease, type C is a lysosomal storage disease characterized by hepatosplenomegaly, the presence of foam cells in the reticuloendothelial system, and gradual motor and cognitive decline leading to death. Over 90% of patients demonstrated a defect of cholesterol esterification in cultured fibroblasts. This finding allows a reliable biochemical diagnosis; however, the test is complex and time-consuming and only available in a few centers. Ultrastructural examination of skin biopsy in 5 patients with Niemann-Pick disease, type C demonstrated lysosomes containing loosely arrayed dark lamellated structures within a clear matrix. Affected cells included macrophages, axons, pericytes, Schwann cells, smooth muscle cells, and fibroblasts with relative sparing of vascular endothelium and melanocytes. These findings demonstrate the usefulness of this simple and readily available morphologic test for the diagnosis of Niemann-Pick disease, type C.

Neurological progress. The neuronal ceroid lipofuscinoses: a review.

Neuronal ceroid lipofuscinosis is a common cause of neurodegenerative disease in children. The disease is characterized by visual failure, seizures and dementia. The presence of cortical atrophy by computerized axial tomography and distinctive ultrastructural findings by skin biopsy, together with a suggestive clinical course and neurophysiologic abnormalities, lead to a diagnosis. Presently four subtypes and rare atypical forms are recognized: the infantile, late infantile, juvenile and adult or Kufs variants and atypical early juvenile and protracted juvenile types. The inheritance pattern is autosomal recessive in all subtypes with some of the adult cases representing autosomal dominant inheritance. The biochemical characterization of this disorder is just beginning. There is some evidence to implicate overglycosylation of proteins as playing a role in pathogenesis. Further biochemical description coupled with linkage analysis techniques using DNA probes are needed to develop a better understanding of this group of disorders.

Clinical classification of neuronal ceroid-lipofuscinosis subtypes.

Neuronal ceroid-lipofuscinosis is the most common class of neurodegenerative disease in children. After decades of study, the biochemical basis for this group of diseases continues to elude scientists. One obstacle has been the difficulty in establishing specific criteria for diagnosis. This paper reviews case material from 65 patients referred to the Shriver Center for study from January, 1984 to December, 1986. The late-infantile type was the most commonly encountered (35%) with a mean age-of-onset of 3.1 +/- 0.5 yr. The juvenile type was slightly less frequent (32%) with a mean age-of-onset of 7.8 +/- 4 yr. The infantile type ranked third (23%); age-of-onset 11 +/- 4 months) and the adult form of the disease was the least common (10%; age-of-onset 25 +/- 4 yr). Consistent clinical findings were a progressive decline in mental faculties and seizures, predominantly of the myoclonic type. Neuroradiological changes of cerebral and cerebellar cortical atrophy were common when studies were obtained more than a year after clinical onset. Ataxia was a frequent manifestation in the late-infantile and juvenile types whereas dystonia was unique to the latter. There was a diversity of ultrastructural findings in skin biopsies between and within types. The absence of findings in a few familial cases necessitated sampling a second tissue such as muscle, particularly when the history was suggestive and urine dolichols were high. Elevated urine dolichol levels was a nonspecific but helpful finding.

Mitochondrial cytochrome deficiency presenting as a myopathy with hypotonia, external ophthalmoplegia, and lactic acidosis in an infant and as fatal hepatopathy in a second cousin.

Fatal infantile mitochondrial myopathy with lactic acidosis, morphologically abnormal mitochondria, deficient cytochromes aa3 and b, and a Fanconi-like aminoaciduria has been described. We report two infants, second cousins, with a similar fatal mitochondrial disorder, the cytochrome deficiency limited to skeletal muscle in one child and to liver in the other. The first child at 3 months of age had weight loss, hypotonia, external ophthalmoplegia, and a severe lactic acidosis with a high lactate/pyruvate ratio. Electron microscopy of muscle showed marked proliferation of enlarged mitochondria, many containing concentric rings of cristae. In skeletal muscle mitochondria, cytochromes aa3 and b were not detectable but cytochrome cc was found to be normal by spectroscopy. Cytochrome c oxidase activity was less than 1% of normal. Mitochondria from kidney, liver, heart, lung, and brain examined postmortem had normal cytochromes and preserved cytochrome c oxidase activity. The second cousin at 5 months of age had weight loss and hepatomegaly but no systemic lactic acidosis. Liver biopsy showed hepatocytes packed with enlarged mitochondria. The liver mitochondria showed deficient cytochromes aa3 and b postmortem, and cytochrome c oxidase activity was less than 10% of normal. Kidney mitochondria had normal cytochromes. Muscles was not studied. The mitochondrial abnormality in the two cousins presumably is related. Unexplained are the mode of genetic transmission or environmental exposure and the apparent involvement of a single different organ in each child.