Metastatic Profile of Colorectal Cancer: Interplay Between Primary Tumor Location and KRAS Status.

BACKGROUND: Mutant KRAS tumors are purported to metastasize differently than wild-type KRAS tumors. The biological heterogeneity of tumors from different parts of the colon are also reported to affect metastasis. This study aims to characterize the metastatic profile by evaluating these factors in unison. METHODS: Retrospective analysis of 899 patients with metastatic colorectal cancers treated from January 2010 to December 2014 was conducted. KRAS mutation status and primary tumors location were correlated with single-site metastasis (liver, lung, and peritoneum) and dual-site metastases (liver-peritoneum, liver-lung, and lung-peritoneum). Patients without KRAS analyses were excluded. RESULTS: Right-sided tumors had highest frequency of peritoneal metastasis as compared to left-sided or rectal tumors (34.7% versus 15.8% versus 8.8%, P = 0.00) regardless of KRAS status (32.6% versus 38.5%, P = 0.62). Left-sided tumors with wild-type KRAS had greater proportion of liver metastasis (78.6% versus 53.5%, P = 0.00), whereas those with mutant KRAS had greater proportion of lung metastasis (23.3% versus 8.7%, P = 0.02). Rectal tumors with wild-type KRAS tend to spread to the liver (81.4% versus 48.0%, P = 0.00) and not to the peritoneum (2.3% versus 20.0%, P = 0.01). In dual-site metastases, left-sided tumors with wild-type KRAS had more liver-peritoneal metastases (75.0% versus 29.4%, P = 0.00), whereas mutant KRAS had greater lung-liver metastases (64.7% versus 20.8%, P = 0.01). Rectal tumors had the predilection for lung-liver metastases as compared to right-sided and left-sided tumors (92.3% versus 40.0% versus 39.0%, P = 0.00) regardless of KRAS status (100% versus 75%, P = 0.12). CONCLUSIONS: Our results may streamline surveillance programs based on primary tumor location and KRAS mutational status.

Determinants and Outcomes of Vasoplegia Following Left Ventricular Assist Device Implantation.

BACKGROUND: Vasoplegia is associated with adverse outcomes following cardiac surgery; however, its impact following left ventricular assist device implantation is largely unexplored. METHODS AND RESULTS: In 252 consecutive patients receiving a left ventricular assist device, vasoplegia was defined as the occurrence of normal cardiac function and index but with the need for intravenous vasopressors within 48 hours following surgery for >24 hours to maintain a mean arterial pressure >70 mm Hg. We further categorized vasoplegia as none; mild, requiring 1 vasopressor (vasopressin, norepinephrine, or high-dose epinephrine [>5 µg/min]); or moderate to severe, requiring ≥2 vasopressors. Predictors of vasoplegia severity were determined using a cumulative logit (ordinal logistic regression) model, and 1-year mortality was evaluated using competing-risks survival analysis. In total, 67 (26.6%) patients developed mild vasoplegia and 57 (22.6%) developed moderate to severe vasoplegia. The multivariable model for vasoplegia severity utilized preoperative Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile, central venous pressure, systolic blood pressure, and intraoperative cardiopulmonary bypass time, which yielded an area under the curve of 0.76. Although no significant differences were noted in stroke or pump thrombosis rates (P=0.87 and P=0.66, respectively), respiratory failure and major bleeding increased with vasoplegia severity (P<0.01). Those with moderate to severe vasoplegia had a significantly higher risk of mortality than those without vasoplegia (adjusted hazard ratio: 2.12; 95% confidence interval, 1.08-4.18; P=0.03). CONCLUSIONS: Vasoplegia is predictive of unfavorable outcomes, including mortality. Risk factors for future research include preoperative INTERMACS profile, central venous pressure, systolic blood pressure, and intraoperative cardiopulmonary bypass time.

Metastatic prostate adenocarcinoma presenting as a large right supraclavicular and anterior chest wall mass.

Left-sided cervical lymphadenopathy as first presentation of metastatic prostate carcinoma is not a novel observation. Here, we discuss a case of metastatic prostate primary carcinoma with an initial presentation of a right supraclavicular mass with extension into the anterior chest wall, which on radiological investigation was suggestive of a sarcomatous tumour; however, was confirmed to be pervasive metastatic prostatic adenocarcinoma. This is the second case in literature, which reports a prostatic primary cancer presenting as a right-sided supraclavicular and anterior chest wall mass.

Comparative profiles of BRAF inhibitors: the paradox index as a predictor of clinical toxicity.

BRAF inhibitor (BRAFi) therapy is associated with the induction of neoplasia, most commonly cutaneous squamous cell carcinoma (cuSCC). This toxicity is explained in part by "paradoxical ERK activation," or the hyperactivation of ERK signaling by BRAFi in BRAF wild-type cells. However, the rate of cuSCC induction varies widely among BRAFi. To explore this mechanistically, we profiled paradoxical ERK activation by vemurafenib, dabrafenib, encorafenib (LGX818), and PLX8394, demonstrating that vemurafenib induces ERK activation the greatest, while dabrafenib and encorafenib have higher "paradox indices", defined as the pERK activation EC80 divided by the IC80 against A375, corresponding to wider therapeutic windows for achieving tumor inhibition without paradoxical ERK activation. Our results identify differences in the paradox indices of these compounds as a potential mechanism for the differences in cuSCC induction rates and highlight the utility of using ERK activity as a biomarker for maximizing the clinical utility of BRAFi.

Cross-species identification of genomic drivers of squamous cell carcinoma development across preneoplastic intermediates.

Cutaneous squamous cell carcinoma (cuSCC) comprises 15-20% of all skin cancers, accounting for over 700,000 cases in USA annually. Most cuSCC arise in association with a distinct precancerous lesion, the actinic keratosis (AK). To identify potential targets for molecularly targeted chemoprevention, here we perform integrated cross-species genomic analysis of cuSCC development through the preneoplastic AK stage using matched human samples and a solar ultraviolet radiation-driven Hairless mouse model. We identify the major transcriptional drivers of this progression sequence, showing that the key genomic changes in cuSCC development occur in the normal skin to AK transition. Our data validate the use of this ultraviolet radiation-driven mouse cuSCC model for cross-species analysis and demonstrate that cuSCC bears deep molecular similarities to multiple carcinogen-driven SCCs from diverse sites, suggesting that cuSCC may serve as an effective, accessible model for multiple SCC types and that common treatment and prevention strategies may be feasible.

Sorafenib suppresses JNK-dependent apoptosis through inhibition of ZAK.

Sorafenib is U.S. Food and Drug Adminstration-approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal-regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor-induced cSCC. Here, we report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun-NH(2)-kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif-containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis.

BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling.

Vemurafenib and dabrafenib selectively inhibit the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase, resulting in high response rates and increased survival in melanoma. Approximately 22% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) during therapy. The prevailing explanation for this is drug-induced paradoxical ERK activation, resulting in hyperproliferation. Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase (JNK), principally ZAK. JNK signaling is suppressed in multiple contexts, including in cSCC of vemurafenib-treated patients, as well as in mice. Expression of a mutant ZAK that cannot be inhibited reverses the suppression of JNK activation and apoptosis. Our results implicate suppression of JNK-dependent apoptosis as a significant, independent mechanism that cooperates with paradoxical ERK activation to induce cSCC, suggesting broad implications for understanding toxicities associated with BRAF inhibitors and for their use in combination therapies. DOI: http://dx.doi.org/10.7554/eLife.00969.001.