Sean M. Ronnekleiv-Kelly

Hepatocellular carcinoma: From diagnosis to treatment.

Primary liver cancer is the sixth most common cancer overall and the second most common cause of cancer mortality worldwide. Hepatocellular carcinoma accounts for up to 90% of all primary hepatic malignancies and represents a major international health problem. While surgical resection and transplantation are the cornerstone of therapy in early-stage hepatocellular carcinoma, locoregional therapy and sorafenib are beneficial in those with more advanced disease or those who are not surgical candidates. At times, the integration of both surgical and locoregional therapy may be necessary. Hence, hepatocellular carcinoma requires a multidisciplinary approach to determine the most appropriate treatment as well as the timing of various treatments for optimal outcomes.

Management of stage IV rectal cancer: Palliative options

Approximately 30% of patients with rectal cancer present with metastatic disease. Many of these patients have symptoms of bleeding or obstruction. Several treatment options are available to deal with the various complications that may afflict these patients. Endorectal stenting, laser ablation, and operative resection are a few of the options available to the patient with a malignant large bowel obstruction. A thorough understanding of treatment options will ensure the patient is offered the most effective therapy with the least amount of associated morbidity. In this review, we describe various options for palliation of symptoms in patients with metastatic rectal cancer. Additionally, we briefly discuss treatment for asymptomatic patients with metastatic disease.

Aryl hydrocarbon receptor-dependent apoptotic cell death induced by the flavonoid chrysin in human colorectal cancer cells

The polyphenolic flavone chrysin has been evaluated as a natural chemopreventive agent due to its anti-cancer effects in a variety of cancer cell lines. However, the mechanism of the chemopreventive effect has been not well established, especially in human colorectal cancer cells. We evaluated the chemopreventive effect of chrysin in three different human colorectal cancer cell lines. We found that chrysin treatment consequently reduced cell viability via induction of apoptosis. We identified that the involvement of up-regulation of pro-apoptotic cytokines tumor necrosis factor (Tnf) α and β genes and consequent activation of the TNF-mediated transcriptional pathway in chrysin-induced apoptosis. Using our generated AHR siRNA expressing colorectal cancer cells, we demonstrated that the chrysin-induced up-regulation of Tnfα and β gene expression was dependent on the aryl hydrocarbon receptor (AHR), which is a ligand-receptor for chrysin. Subsequently, we found that the AHR siRNA expressing colorectal cancer cells were resistant to chrysin-induced apoptosis. Therefore, we concluded that AHR is required for the chrysin-induced apoptosis and the up-regulation of Tnfα and β gene expression in human colorectal cancer cells.

The Aryl Hydrocarbon Receptor is a Repressor of Inflammation-associated Colorectal Tumorigenesis in Mouse

Objective: To determine the role of the aryl hydrocarbon receptor (AHR) in colitis-associated colorectal tumorigenesis. Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in United States. Chronic intestinal inflammation increases the risk for the development of CRC. We investigated the involvement of AHR, a ligand-activated transcriptional regulator, in colitis-associated colorectal tumorigenesis. Methods: We used a mouse model of colitis-associated colorectal tumorigenesis that employs treatment with azoxymethane and dextran sodium sulfate. We examined the role of AHR using both an Ahr-deletion mouse model (Ahr&Dgr;2/&Dgr;2) and treatment with the AHR pro-agonist indole-3-carbinol (I3C). Incidence, multiplicity, and location of tumors were visually counted. Tumors were defined as neoplasms. Intestinal inflammation was assessed by quantitative PCR for proinflammatory markers and colon length. Data were evaluated and compared using GraphPad Prism software (version 6, La Jolla, CA). Results: Tumor incidence was increased 32% in Ahr null mice and tumor multiplicity was approximately increased 3-fold compared with wild-type mice (2.4 vs 7; P < 0.05). Furthermore, tumor multiplicity was reduced 92% by treatment of I3C in wild-type mice, whereas the suppressor effect of I3C was not observed in Ahr null mice (P < 0.05). Conclusions: We found that AHR plays a protective role in colitis-associated colorectal tumorigenesis. This conclusion is based on the observations that Ahr null mice showed increased number of colorectal tumors, and mice treated with I3C exhibited fewer tumors. This study supports the use of AHR agonists such as I3C as a chemopreventive therapy for IBD-associated CRC in human patients.

Epigenetic therapy and chemosensitization in solid malignancy

Epigenetic modifications result in dynamic shifts between transcriptionally active and suppressed states. The potentially reversible nature of epigenetic changes underlies the concept of epigenetic therapy, which serves to reprogram cancer cells as opposed to inducing cytotoxicity that occurs with standard chemotherapeutics. There are numerous enzymes involved in epigenetic changes and each can be potentially targetable. Although many investigations have evaluated the clinical potential of the various epigenetic therapies, currently only histone deacetylase inhibitors and DNA methyltransferase inhibitors are approved for use in specific hematologic malignancies. Use of epigenetic therapy coincident with cytotoxic or targeted systemic therapy appears to derive a benefit due to chemosensitization. Trials demonstrating efficacy from combination therapy have been performed in various diseases such as NSCLC, ovarian cancer and breast cancer. Furthermore, there are patient subsets in certain solid tumors in which epigenetic therapy provide durable response, such as patients with NSCLC and specific hypermethylation patterns. The encouraging results from combination therapy identified in these trials built upon prior investigations and have provided a foundation for ensuing trials seeking to evaluate epigenetic therapy.

Staging of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) comprises approximately 5-30% of primary liver tumors, however it has been increasing over the last several decades. Up to and including the 6th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) edition staging system, ICC was staged the same as hepatocellular carcinoma. In the 7th edition AJCC/UICC manual, the staging system of ICC was revised such that a distinct classification was proposed. Pathologic features for prognosis included vascular invasion, tumor multiplicity, local extension, periductal infiltration and lymph nodal metastasis. Over the last decade, as the incidence of ICC has increased and surgery for this indication has become more common, more data has been published on the prognostic factors associated with long-term survival.

A Singular Hope: How the Discussion Around Cancer Surgery Sometimes Fails

BackgroundPatients with cancer often have an overly optimistic view of prognosis, as well as potential benefits of treatment. Patient–surgeon communication in the preoperative period has not received as much attention as communicating prognosis or bad news in the postoperative setting.MethodsThe published literature on patient–physician communication in the preoperative setting among patients considering surgery for a malignant indication was reviewed. PubMed was queried for MESH terms including “surgery,” “preoperative,” “discussion,” “treatment goals,” “patient perceptions,” and “cure.” Information on how surgeons and patients may be empowered to improve communication about goals of care was also outlined.ResultsPhysicians tended not to dwell on prognosis in early discussions, instead emphasizing the uniqueness of individuals and the uncertainty of statistics. The treatment plan often became the dominant feature of the conversation and functioned to deflect attention from discussions of prognosis. Surgeons tended to understate possible complications and provided little detail regarding potential severity or long-term consequences. While most patients wished to be informed of their prognosis, only a subset actually received an estimate of life expectancy. Because optimism with respect to prognosis (often simplified as “hope”) has been largely considered essential for positivity and optimism—even a false or inappropriate optimism—many providers have created, tolerated, or enabled it. Several studies have emphasized, however, that hope can be maintained with truthful discussion, even if the topic is a bad prognosis or eventual death.ConclusionsOpen, honest, and patient-driven discussions before surgery will lead to more robust shared decision making and create more engaged and satisfied patients (and caregivers). Enhanced preoperative discussion can also facilitate clarity about the possibility of cancer recurrence, cure, preferences about advance care planning, and formation of advance directives.

Regret in Surgical Decision Making: A Systematic Review of Patient and Physician Perspectives

ObjectiveRegret is a powerful motivating factor in medical decision making among patients and surgeons. Regret can be particularly important for surgical decisions, which often carry significant risk and may have uncertain outcomes. We performed a systematic review of the literature focused on patient and physician regret in the surgical setting.MethodsA search of the English literature between 1986 and 2016 that examined patient and physician self-reported decisional regret was carried out using the MEDLINE/PubMed and Web of Science databases. Clinical studies performed in patients and physicians participating in elective surgical treatment were included.ResultsOf 889 studies identified, 73 patient studies and 6 physician studies met inclusion criteria. Among the 73 patient studies, 57.5% examined patients with a cancer diagnosis, with breast (26.0%) and prostate (28.8%) cancers being most common. Interestingly, self-reported patient regret was relatively uncommon with an average prevalence across studies of 14.4%. Factors most often associated with regret included type of surgery, disease-specific quality of life, and shared decision making. Only 6 studies were identified that focused on physician regret; 2 pertained to surgical decision making. These studies primarily measured regret of omission and commission using hypothetical case scenarios and used the results to develop decision curve analysis tools.ConclusionSelf-reported decisional regret was present in about 1 in 7 surgical patients. Factors associated with regret were both patient- and procedure related. While most studies focused on patient regret, little data exist on how physician regret affects shared decision making.

Management of choledochal cysts.

Purpose of review Historically, surgical treatment of choledochal cyst consisted of cyst enterostomy. However, incomplete cyst excision can result in recurrent symptoms and malignant transformation within the cyst remnant. Accordingly, management of choledochal cyst now includes complete cyst excision whenever possible. We provide a review detailing the up to date management of choledochal cysts. We describe choledochal cyst-type specific surgical approaches, the impact of minimally invasive surgery in choledochal cyst therapy, and long-term sequelae of choledochal cyst management. Recent findings Treatment of choledochal cyst aims to avoid the numerous hepatic, pancreatic, or biliary complications that may occur. More recently, minimally invasive approaches are being used for the treatment of choledochal cyst with acceptable morbidity and mortality. Moreover, long-term follow up of choledochal cyst patients after resection has demonstrated that although the risk of biliary malignancy is significantly decreased after choledochal cyst resection, these patients may remain at a slightly increased risk of biliary malignancy even after excision. Summary Management of choledochal cyst and the operative conduct will depend upon the patient comorbidities and choledochal cyst subtype. However, given the complex nature of choledochal cyst and limited experience of most centers, these patients should be evaluated and treated at high-volume hepatopancreaticobiliary centers familiar with management of choledochal cyst.

From bench to bedside: Clinical implications of KRAS status in patients with colorectal liver metastasis

INTRODUCTION While the role of KRAS in the molecular genetics of colorectal cancer has been studied extensively, its prognostic impact in colorectal liver metastases (CRLM) has only recently been examined. This review aimed to summarize currently reported findings on the clinical implications of KRAS mutant (mut-KRAS) status for patients with CRLM. MATERIALS AND METHODS The Pubmed database was searched for relevant articles published from 01/01/2010 to 02/01/2016. Overall survival (OS) and recurrence free survival (RFS) as well as patterns of recurrence were the primary endpoints, but consideration was given to secondary outcomes when the respective findings were of clinical interest. RESULTS Out of the 266 studies screened, 15 were included in our review. Fourteen studies were retrospective cohorts while one was a systematic review/meta-analysis. Among the 14 retrospective studies, 12 reported OS with 9 detecting a negative association with mut-KRAS status. Similarly, 11 out of 14 retrospective cohorts reported RFS with 6 detecting a negative association with mut-KRAS status. Five studies examined patterns of recurrence, with 4 detecting increased extrahepatic recurrence in the mut-KRAS group. One study examined the different effects of codon-specific KRAS mutations on prognosis. CONCLUSION mut-KRAS status predisposes to worse RFS and OS in patients with CRLM, possibly as a result of aggressive tumor biology. Early unresectable extrahepatic recurrence is more frequent in this patient group and may underlie the unfavorable prognosis. Future research should focus on characterizing the distinct effects of codon-specific KRAS mutations as well their interplay with other less common genetic mutations.