Impact of perineural invasion on survival in node negative colon cancer

Perineural invasion (PNI) has been implicated as a poor prognostic indicator in many cancers. The National Comprehensive Cancer Network recommends consideration of observation or adjuvant therapy in the presence of PNI in early colon cancer. These recommendations are based on single institutional studies that fail to evaluate PNI within the context of adjuvant chemotherapy. The US National Cancer Database (2004–2012) was reviewed for patients with node negative colon cancer, and stratified by PNI and receipt of chemotherapy.

Of 21,488 patients evaluated, 55.2% had T3 disease (n = 11,852), 23.1% had T2 (n = 4,971), 14.4% had T1 (n = 3,088), and 7.3% had T4 disease (n = 1,577); 4.6% (n = 987) had PNI. Most patients (86.8%, n = 18,641) did not have PNI and did not receive chemotherapy; 8.7% (n = 1,860) did not have PNI but received chemotherapy; 3.7% (n = 785) had PNI and did not receive chemotherapy, and 0.9% (n = 202) had PNI and received chemotherapy. Among those with PNI, patients who received chemotherapy tended to be younger (P<0.001), covered by private insurance (P<0.001), with fewer comorbidities (P<0.001), and greater T stage disease (P<0.001). Those with PNI who received chemotherapy had significantly improved survival over those who did not in T3–4 disease (P<0.001), but not in T1–2 disease. On multivariate analysis, those with PNI had a 38% greater hazard of mortality (HR 1.38, P<0.001). Additionally, chemotherapy decreased the hazard of mortality by 43% (HR 0.57, P<0.001). PNI appears to be an independent poor prognostic indicator in stage T3–4 node negative colon cancer. Chemotherapy administered to this patient population is associated with improved survival.     

Contradictory KRAS mutation test results in a patient with metastatic colon cancer: A clinical dilemma in the era of personalized medicine

The KRAS oncogene is mutated in 40‒50% of colorectal cancers and confers resistance to EGFR-targeted therapy. In the clinic, agents such as cetuximab or panitumumab target the EGFR receptor for therapeutic benefit. Cetuximab was approved by the FDA in 2012 as first-line therapy for KRAS mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer, in combination with FOLFIRI (5-fluorouracil, irinotecan, leucovorin). Herein we report a case of metastatic colon cancer with conflicting testing results for the KRAS oncogene from two different reference laboratories. The discordant reports complicated the decision-making process regarding the administration of targeted anti-EGFR personalized therapy. As the second test result was wild-type from the same original pathological specimen, the patient was treated with cetuximab-containing combination chemotherapy and appeared to have a response after prior disease progression. It is unclear whether the observed response was fully due to regression of wild-type KRAS-containing tumor or any component of antibody-dependent cellular cytotoxicity to a heterogeneous tumor in this patient.     

Hypofractionated conformal radiotherapy for pediatric diffuse intrinsic pontine glioma (DIPG): A randomized controlled trial

Background

The pediatric diffuse intrinsic pontine glioma (DIPG) outcome remains dismal despite multiple therapeutic attempts.

Purpose

To compare the results of treatment of pediatric diffuse intrinsic pontine glioma (DIPG) using hypofractionated versus conventional radiotherapy.

Patients and methods

Seventy-one newly diagnosed DIPG children were randomized into hypofractionated (HF) (39 Gy/13 fractions in 2.6 weeks) and conventional (CF) arm (54 Gy/30 fractions in 6 weeks).

Results

The median and one-year overall survival (OS) was 7.8 months and 36.4 ± 8.2% for the hypofractionated arm, and 9.5 and 26.2 ± 7.4% for the conventional arm respectively. The 18-month OS difference was 2.2%. The OS hazard ratio (HR) was 1.14 (95% CI: 0.70–1.89) (p = 0.59).The hypofractionated arm had a median and one-year progression-free survival (PFS) of 6.6 months and 22.5 ± 7.1%, compared to 7.3 and 17.9 ± 7.1% for the conventional arm. The PFS HR was 1.10 (95% CI: 0.67–1.90) (p = 0.71). The 18-month PFS difference was 1.1%. These differences exceed the non-inferiority margin.The immediate and delayed side effects were not different in the 2 arms.

Conclusions

Hypofractionated radiotherapy offers lesser burden on the patients, their families and the treating departments, with nearly comparable results to conventional fractionation, though not fulfilling the non-inferiority assumption.     

Restoration of p53 to limit tumor growth

PURPOSE OF REVIEW: p53 mutation occurs in over half of all human tumors. Among the remaining tumors, although they may process a wild-type p53, the pathways of p53-induced cell-cycle arrest and apoptosis are deficient. Therefore, p53 serves as a unique molecular target for cancer therapy. This review focuses on the current progress regarding restoration of p53 function in human tumors for molecularly targeted therapy. RECENT FINDINGS: Targeting p53 for cancer therapy has been intensively pursued. CP-31398 was the first small molecule identified with the ability to restore the wild-type conformation to mutant p53. Subsequently, PRIMA-1 and ellipticine were found to be able to induce mutant p53-dependent cell death. Nutlin was developed to rescue wild-type p53 from degradation mediated by MDM2. More recently, p53 family members can be activated and therefore serve as substitutes of p53 in tumor cells and induce cell death. SUMMARY: Loss of p53 function is a characteristic of almost all human tumors. Recent advances demonstrate that reconstitution of p53 function is possible and practical as a promising antitumor strategy.     

TRAIL inactivates the mitotic checkpoint and potentiates death induced by microtubule-targeting agents in human cancer cells

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted interest as an anticancer treatment, when used in conjunction with standard chemotherapy. We investigated the mechanistic basis for combining low-dose TRAIL with microtubule-targeting agents that invoke the mitotic checkpoint. Treatment of T98G and HCT116 cells with nocodazole alone resulted in a robust mitotic block with initially little cell death; low levels of cell death were also seen with TRAIL alone at 10 ng/mL final concentration. In contrast, the addition of low-dose TRAIL to nocodazole was associated with maximally increased caspase-3, caspase-8, and caspase-9 activation, which efficiently abrogated the mitotic delay and markedly increased cell death. In contrast, the abrogation of mitotic checkpoint and increased cell death were blocked by inhibitors of caspase-8 and caspase-9 or pan-caspase inhibitor. The addition of TRAIL to either nocodazole or paclitaxel (Taxol) reduced levels of the mitotic checkpoint proteins BubR1 and Bub1. BubR1 mutated for the caspase cleavage sites, but not wild-type BubR1, was resistant to cleavage induced by TRAIL added to nocodazole, and partially blocked the checkpoint abrogation. These results suggest that adding a relatively low concentration of TRAIL to antimicrotubule agents markedly increases complete caspase activation. This in turn accentuates degradation of spindle checkpoint proteins such as BubR1 and Bub1, contributes to abrogation of the mitotic checkpoint, and induces cancer cell death. These results suggest that TRAIL may increase the anticancer efficacy of microtubule-targeting drugs.     

The clinical presentation caused by truncating CHD8 variants

Variants in the chromodomain helicase DNA-binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASDs) and overgrowth and CHD8 is one of the causative genes for OGID (overgrowth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (81%), ASDs (84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate-to-severe ID, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were non-ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex-dependent penetrance of CHD8 PTVs in humans.     

Fate of deoxynivalenol in contaminated wheat grain during preparation of Egyptian 'balila'

Soaking and boiling whole wheat kernels in water are the key steps in the preparation of an Egyptian dish called 'balila'. The effects of washing, soaking and boiling wheat kernels in tap water or in 0.1 M Na2CO3 solution on the deoxynivalenol (DON) content of the wheat kernels were studied. Boiling contaminated wheat kernels in water reduced the DON content of the grain by 70%. The mechanism of decontamination due to boiling is probably a leaching of DON out of the grain into the boiling medium. A combined treatment of soaking in 0.1 M Na2CO3 solution (pH 11) with subsequent boiling reduced the DON content of the grain by 93%. Data suggest that apart from leaching DON out of the kernels into the boiling medium, a degradation of DON occurred in alkaline medium. Modifying the traditional process of 'balila' preparation by using Na2CO3 solution may be useful to reduce the risk of mycotoxin exposure via 'balila'.