The impact of primary tumor sidedness on survival in early-onset colorectal cancer by stage: A National Veterans Affairs retrospective analysis.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC) is rising. Left-sided colorectal cancer (LCC) is associated with better survival compared to right-sided colon cancer (RCC) in metastatic disease. NCCN guidelines recommend the addition of EGFR inhibitors to KRAS/NRAS WT metastatic CRC originating from the left only. Whether laterality impacts survival in locoregional disease and EOCRC is of interest. METHODS: 65,940 CRC cases from the National VA Cancer Cube Registry (2001-2015) were studied. EOCRC (2096 cases) was defined as CRC diagnosed at <50 years. Using ICD codes, RCC was defined from the cecum to the hepatic flexure (C18.0-C18.3), and LCC from the splenic flexure to the rectum (C18.5-18.7; C19 and C20). RESULTS: EOCRC is more likely to originate from the left side (66.65% LCC in EOCRC vs. 58.77% in CRC). Overall, LCC has better 5-year Overall Survival (OS) than RCC in stages I (61.67% vs. 58.01%) and III (46.1% vs. 42.1%) and better 1-year OS in stage IV (57.79% vs. 49.49%). Stage II RCC has better 5-year OS than LCC (53.39% vs. 49.28%). In EOCRC, there is no statistically significant difference between LCC and RCC in stages I-III. Stage IV EOCRC patients with LCC and RCC have a 1-year OS of 73.23% and 59.84%, respectively. CONCLUSION: In EOCRC, LCC is associated with better OS than RCC only stage IV. In the overall population, LCC is associated with better OS in all stages except stage II. The better prognosis of stage II RCC might be due to the high incidence of mismatch repair deficient tumors in this subpopulation.

Treatment and survival rates of stage IV pancreatic cancer at VA hospitals: a nation-wide study.

BACKGROUND: Metastatic pancreatic cancer (MPC) is associated with an extremely high mortality. Current NCCN guidelines recommend systemic therapy, as it is superior to best supportive care. Undertreatment of MPC continues to be an issue. Recent treatment and survival data of MPC in Veterans' Affairs' (VA) hospitals have not been published. The relationship between MPC treatment and survival and the American College of Surgeons' (ACS) Committee on Cancer (CoC) accreditation in VA hospitals has not been studied. METHODS: Nationwide data from the National Veterans Affairs Cancer Cube Registry was analyzed. In total, 6,775 patients were diagnosed with MPC between 2000 and 2014. CoC accreditation of each VA hospital was obtained using the ACS website. RESULTS: MPC constitutes 52.31% of all pancreatic cancer diagnosed (6,775/12,951 cases). The near totality was men (97.44%). The above 70 years age group and the 60-70 years age group were the most common ages at diagnosis with 39.39% and 38.02% respectively. The proportion of early-onset pancreatic cancer (EOPC) was 2.84%. When compared to all stages of pancreatic cancer, stage IV pancreatic cancer had a lower proportion of cancer originating from the head of the pancreas (39.33% versus 50.63%) and more originating from the tail (17.99% versus 13.39%). Tumors originating from head of the pancreas are more likely to cause biliary symptoms and thus are more likely to be caught at an earlier stage. Overall, treatment rate in the VA at the national level with first-line chemotherapy was 37.61%. The rate of treatment over the years has increased in a linear fashion from 33.01% in 2000 to 41.95% in 2014. This has corresponded with an increase of 1-5 years survival of 9.29% in 2000 to 22.99% in 2014 and 5-10 years survival from 0.96% in 2000 to 6.00% in 2012. Treatment rates in CoC-accredited and non-CoC accredited VA hospitals were similar (38.94% and 38.12%, respectively). Survival rates in CoC-accredited and non-COC accredited VAs were similar with a 1-5 years survival rate of 8.89% and 8.57%, respectively. CONCLUSIONS: Treatment and survival of MPC have risen significantly in the past decade at VA hospitals. CoC accreditation is not associated with a change in treatment or survival rates.

Sunitinib-Induced Acute Interstitial Nephritis in a Thrombocytopenic Renal Cell Cancer Patient.

Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is currently the standard of care for patients with metastatic renal cell carcinoma. Renal adverse events associated with sunitinib include proteinuria, renal insufficiency secondary to focal segmental glomerulosclerosis (FSGS), and thrombotic microangiopathy. We describe the second reported instance of biopsy-proven sunitinib-induced acute interstitial nephritis (AIN), in a challenging case complicated by thrombocytopenia. The case illustrates the importance of early diagnosis and intervention in ensuring long-term recovery from renal complications. Four other cases of AIN reported along with inhibition of the vascular endothelial growth factor (VEGF) by either TKI (sunitinib and sorafenib) or antibodies (bevacizumab) suggest a possible class effect. Given our experience, we recommend monitoring renal function with VEGF inhibition, and in the case of renal failure in the setting of an unclear diagnosis, we recommend prompt biopsy.

Serum neural cell adhesion molecule is hyposialylated in hereditary inclusion body myopathy.

Hereditary inclusion body myopathy (HIBM) is a young-adult onset autosomal recessive disorder caused by a hypomorphic rate limiting enzyme of sialic acid biosynthesis. The enzyme is UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, and is encoded by the GNE gene. HIBM causes slowly progressive muscle weakness and atrophy. Patients are typically diagnosed at 20-30 years of age, and most patients are incapacitated and wheelchair-confined by 30-50 years of age. Some sialic acid containing glycoproteins, including neural cell adhesion molecule (NCAM), are hyposialylated in HIBM muscle biopsy samples. We developed a method to allow detection of serum NCAM sialylation using Western blot, and tested serum samples from several patients and a HIBM mouse model. Preliminary results showed a clear difference in polysialylated and hyposialylated forms of NCAM extracted from serum, and showed NCAM is hyposialylated in HIBM serum samples. This initial finding may prove useful in reducing the need for serial muscle biopsies in HIBM treatment trials. Additional studies are underway to further validate this finding and to evaluate the specificity, reliability, and robustness of this potential serum biomarker for HIBM.

Wolman disease (LIPA p.G87V) genotype frequency in people of Iranian-Jewish ancestry.

Wolman disease (WD) is a rare inherited condition caused by lysosomal acid lipase (LAL) deficiency first described in Iranian-Jewish (IJ) children. Newborns with WD are healthy and active, but soon the infant develops symptoms of severe malnutrition in the first few months of life, and often dies before the age of 1 year. Harmful amounts of lipids accumulate in the spleen, liver, bone marrow, intestine, adrenal glands, and lymph nodes. Although worldwide incidence is estimated at 1/350,000 newborns, WD occurs at higher than expected frequency in the IJ community of the Los Angeles area. As a validation study, we analyzed 162 DNA specimens of IJ origin by automated sequencing. For LIPA p.G87V (ggc>gtc, alternative numbering p.G66V), a heterozygous frequency of 5/162 (3.086%) was discovered. Thus, we estimate that as high as 1 in 4200 newborns of IJ couples may be at risk. Additional studies are required to confirm and further validate the higher frequencies seen in our sample pool, and to determine if people of IJ and even possibly Middle Eastern descent are at a higher risk for WD.

Novel GNE mutations in hereditary inclusion body myopathy patients of non-Middle Eastern descent.

Autosomal recessive hereditary inclusion body myopathy (HIBM or IBM2) is a progressive adult onset muscle wasting disorder characterized by sparing of the quadriceps. IBM2 is also known as distal myopathy with rimmed vacuoles or nonaka myopathy. IBM2 is associated with mutations in the UDP-GlcNAc 2-Epimerase/ManNAc Kinase gene (GNE). GNE is the rate-limiting enzyme of N-Acetylneuraminate (Neu5Ac, Sialic acid) biosynthesis. The GNE coding region of 64 symptomatic patients were sequenced. Twenty-eight patients were found to bear GNE mutations. Ten novel mutations were identified among nine patients, including four nonsense (p.R8X, p.W204X, p.Q436X, and p.S615X) and five missense (p.R71W, p.I142T, p.I298T, p.L556S, and p.E2G) variations spanning both the epimerase and kinase domains of GNE. Additionally, a synonymous variation (p.Y591Y, codon tac > tat) was seen in a patient bearing compound heterozygous nonsynonymous mutations (p.S615X and p.Y675H). Six of the nine are Caucasian, one patient is Taiwanese, one patient is Asian Indian, and one patient is of European descent. These findings further expand the clinical and genetic spectrum of IBM2.

MTHFR C677T genotype frequency in patients of Middle Eastern descent as determined by real-time PCR and melting curve analysis.

The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism produces an elevation in plasma homocysteine concentrations when present in the homozygous state. Increased homocysteine levels have been associated with a greater risk for vascular diseases, including cardiovascular disease and ischemic stroke. In this study, we genotyped 42 nucleic acid samples for the C677T allele from our database of Middle Eastern patients as routine validation of the MTHFR 677C>T assay. Our study is the first to evaluate MTHFR C677T genotype frequency in a population of Middle Eastern patients residing in the United States. Among the patients, 47.6% were wild type, 40.5% were heterozygous, and 11.9% were homozygous for the C677T variant. Although C677T genotype frequency in our patient population is slightly higher than that reported by Golbahar et al. (2005), statistical analysis showed no statistically significant difference beyond chance in genotype profiles (chi(2) = 1.54, df = 2, p = 0.1675). However, our findings implicate the need for a larger sample size to explore the need to implement standard clinical screening of MTHFR 677C>T. We also highlight the robust, reliable, and reproducible assay afforded by the use of anchor and sensor hybridization probes within the LightCycler platform to perform amplification and melting curve analysis protocols. Melting curve profiles that are produced display distinct and robust T(m) peaks based on the degree of anchor and sensor hybridization to amplicons produced from template DNA that is either wild-type, heterozygous, or a homozygous variant at the MTHFR 677C>T locus. A 10 degrees C gap between T(m) peaks allows for rapid and accurate qualitative identification of genotype.

Validation of GNE:p.M712T identification by melting curve analysis.

Hereditary inclusion body myopathy/distal myopathy with rimmed vacuoles is an adult onset autosomal recessive muscle-wasting disease common in people of Iranian-Jewish descent, due to the founder allelic variant GNE:p.M712T. High correlation of disease susceptibility with GNE:p.M712T allows its use as a molecular marker for diagnosis. In this study, we applied and validated the use of melting curve analysis using SimpleProbe technology for detection of this mutation using specimens obtained by mouthwash, buccal swab, and whole blood. The assay was then applied to 43 clinical specimens, and results were validated by additional methods. A probe spanning this mutation in exon 12 accurately discerns two Tm corresponding to its hybridization to wild-type and M712T-derived amplicons. A 10 degrees C divergence in Tm allowed rapid single-tube genotyping of reference and patient samples with 100% accuracy. Distal myopathy constitutes a large heterogeneous group of pathologies with similar physiological manifestations and little molecular markers for distinguishing subtypes. Application of SimpleProbes for detection of GNE:p.M712T on genomic DNA obtained from buccal epithelial cells allows accurate, rapid, and cost-effective identification of this allele in individuals at risk. This procedure is amenable to automated high-throughput applications and can be extended to both clinical and research applications.