Clinical and pathological outcomes of induction chemotherapy before neoadjuvant radiotherapy in locally‐advanced rectal cancer

Background and ObjectivesIn North America, preoperative combination chemoradiation is the most commonly recommended and utilized approach to locally advanced rectal cancer. There is increasing interest in the use of induction chemotherapy (IC) before radiation and surgery in locally advanced rectal cancer. How widely IC is being used and whether it improves pathologic and oncologic outcomes is unknown.MethodsWe evaluated clinical stage 2 or 3 rectal cancer patients in the National Cancer Database between 2006 and 2015. We identified predictors of use of IC with multivariable logistic regression and compared survival between groups using Cox proportional hazards regression.ResultsAmong 36 268 patients, IC use increased significantly over time from 5.5% in 2006 to 15.9% in 2015 (P < 0.001). Treatment at a hospital with a high IC rate was an independent predictor of receipt of IC. IC and traditional therapy yielded similar pathologic complete response rates (32.2% vs 30.5%, P = 0.2) and similar 5‐year survival (82.4% vs 81.4%, 0.71).ConclusionsUse of IC for locally advanced rectal cancer has increased significantly. The choice of IC seems to be driven more by institutional and regional practice patterns than clinical characteristics and is not associated with improved pathologic or oncologic outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150518/1/jso25474.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150518/2/jso25474_am.pd

Surgical management of primary colonic lymphoma: Big data for a rare problem

Background and ObjectivesPrimary colonic lymphoma (PCL) is rare, heterogeneous, and presents a therapeutic challenge for surgeons. Optimal treatment strategies are difficult to standardize, leading to variation in therapy. Our objective was to describe the patient characteristics, short‐term outcomes, and five‐year survival of patients undergoing nonpalliative surgery for PCL.MethodsWe performed a retrospective cohort analysis in the National Cancer Database. Included patients underwent surgery for PCL between 2004 to 2014. Patients with metastases and palliative operations were excluded. Univariate predictors of overall survival were analyzed using multivariable Cox proportional hazard analysis.ResultsWe identified 2153 patients. Median patient age was 68. Diffuse large B‐cell lymphoma accounted for 57% of tumors. 30‐ and 90‐Day mortality were high (5.6% and 11.1%, respectively). Thirty‐nine percent of patients received adjuvant chemotherapy. For patients surviving 90 days, 5‐year survival was 71.8%. Chemotherapy improved survival (surgery+chemo, 75.4% vs surgery, 68.6%; P = .01). Adjuvant chemotherapy was associated with overall survival after controlling for age, comorbidity, and lymphoma subtype (HR 1.27; 95% CI, 1.07‐1.51; P = .01).ConclusionsPatients undergoing surgery for PCL have high rates of margin positivity and high short‐term mortality. Chemotherapy improves survival, but <50% receive it. These data suggest the opportunity for improvement of care in patients with PCL.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150597/1/jso25582_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150597/2/jso25582.pd

HIF-3α1 promotes colorectal tumor cell growth by activation of JAK-STAT3 signaling

Hypoxic environment is critical in colorectal cancer (CRC) development. Most studies have mainly focused on hypoxia-inducible factor (HIF)-1α and HIF-2α as the major hypoxic transcription factors in CRC development and progression. However, the role of HIF-3α in CRC is not clear. Here we found that HIF-3α protein was increased in colorectal tumors from both mouse models and human patients. Moreover, increased HIF-3α expression was correlated with decreased survival. Overexpression of a long isoform of HIF-3α, HIF-3α1, increased cell growth in two CRC cell lines. Surprisingly, overexpressed HIF-3α1 was localized to the cytosol and increased phosphorylated signal transducer and activator of transcription 3 (p-STAT3). STAT3 inhibition effectively reduced p-STAT3 levels and cell growth induced by HIF-3α1. The activation of p-STAT3 was independent of the transcriptional activity of HIF-3α1. However, the inhibition of the upstream regulator Janus kinase (JAK) abolished HIF-3α1-induced p-STAT3 and cell growth. Together, these results demonstrated that HIF-3α1 promotes CRC cell growth by activation of the JAK-STAT3 signaling pathway through non-canonical transcription-independent mechanisms

Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis

Dietary iron intake and systemic iron balance are implicated in colorectal cancer (CRC) development, but the means by which iron contributes to CRC are unclear. Gene expression and functional studies demonstrated that the cellular iron importer, divalent metal transporter 1 (DMT1), is highly expressed in CRC through hypoxia-inducible factor 2alpha-dependent transcription. Colon-specific Dmt1 disruption resulted in a tumor-selective inhibitory effect of proliferation in mouse colon tumor models. Proteomic and genomic analyses identified an iron-regulated signaling axis mediated by cyclin-dependent kinase 1 (CDK1), JAK1, and STAT3 in CRC progression. A pharmacological inhibitor of DMT1 antagonized the ability of iron to promote tumor growth in a CRC mouse model and a patient-derived CRC enteroid orthotopic model. Our studies implicate a growth-promoting signaling network instigated by elevated intracellular iron levels in tumorigenesis, offering molecular insights into how a key dietary component may contribute to CRC

Biology of Nodal Spread in Colon Cancer: Insights from Molecular and Genetic Studies

Colorectal cancer (CRC) lymph node metastases are common but their genetics and the mechanism whereby these metastases occur are not well understood. Here we present recent data regarding genetic heterogeneity in primary CRCs and their metastasis. In addition, we explain the different potential models describing the mechanisms of metastasis and the data supporting them. Multiple studies have also revealed a variety of prognostic molecular markers that are associated with lymph node metastasis in CRC. A better understanding of genetic heterogeneity and the mechanisms of metastasis is critical to predicting clinical response and resistance to targeted therapy

RAP inhibits polyp formation and progression in a mouse model of colon polyposis.

<p>(A–C) <i>CDX2P-CreER^T2 Apc^fl/fl</i> mice were administered TAM to induce <i>Apc</i> mutation-dependent polyposis and were then monitored by video-endoscopy for polyp formation after treatment with vehicle (circle) or RAP (triangle). Scores of polyp severity in RAP- and vehicle-treated mice groups were determined at 2, 6, and 12 weeks for all mice that were alive. Each circle or triangle represents an individual mouse (N = 6 per group). The numbers of mice requiring euthanasia due to illness are represented at the top of each graph. The polyp scores were statistically lower by 12 weeks of treatment using 2-sample Z-tests of the proportions of mice with score 4 or higher (N = 6 per group, at 2 weeks, p = 0.12; at 6 weeks, p = 0.08; at 12 weeks, p = 0.01, * signifies p = 0.01). (D) Representative endoscopic pictures of the mouse colons from a control wild-type mouse and TAM-treated and TAM- plus RAP-treated <i>CDX2P-CreER^T2 Apc^fl/fl</i> mice, with inhibition of polyposis by RAP treatment in the model. Polyps are indicated by black arrows.</p

RAP inhibits mTOR signaling in HCECs in a β-catenin/TCF transcription-independent manner in vitro.

<p>HCEC lines stably transformed with shAPC (HCEC/ptripzshAPC) or shScramble (HCEC/ptripzshSCR) were treated with Doxycycline (DXC) at 1 µg/ml to induce shRNA expression for 48 hr or untreated (-). The cells were then treated with RAP (0.001–1 µM) or vehicle (−) for 24 hr in the presence of Doxycycline under serum starving condition (0.2% serum). Total cell lysates were analyzed by Western blotting for phospho-S6 and phospho-mTOR. β-actin protein levels served as loading control (A). Significant decrease in phospho-S6 and phospho-mTOR levels was observed in cells treated with RAP. Expression of selected β-catenin/TCF-regulated target genes <i>AXIN2</i>, <i>NKD1</i> and <i>IRS1</i> were analyzed in the same cells by real time PCR (B–D). The results represent the mean ± SEM; n = 5 for each treatment group. There were no statistical differences between groups.</p

A brief course of RAP treatment decreases markers of proliferation and increases markers of differentiation.

<p><i>CDX2P-CreER^T2 Apc^fl/fl</i> mice were injected with TAM and monitored until polyposis was seen endoscopically, then the mice were treated with vehicle or RAP at 3 mg/kg concentration for periods of one, three, or five days (N = 5 per timepoint). (A) and (B) Immunostaining of distal colons from these mice or Cre negative <i>Apc^fl/fl</i> mice for phospho-mTOR and phospho-S6. Both phospho-mTOR and phospho-S6 show increased expression in mouse polyps due to <i>Apc</i> inactivation, which is suppressed by 5 days of RAP treatment. (C) Immunostaining of BrdU showed increased incorporation of BrdU in mouse polyps and RAP partially reversed the effect. (D) Alcian blue staining shows loss of most of the differentiated goblet cells in mouse polyps and RAP restore the goblet cell differentiation. (E) Immunostaining shows increased Sox9 (a cell fate marker) expression in polyps and RAP decreased the number of cells expressing Sox9. (F) Immunostaining shows increased nuclear and cytoplastic expression of β-catenin in polyps and RAP treatment for 5 days decreased the expression. Scale bars = 100 µm. The inserts are at two times higher magnification than the original.</p