Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and future therapeutic landscape for clinicians

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor and remains a fatal malignancy in the majority of patients. Approximately 20%–30% of patients are eligible for resection, which is considered the only potentially curative treatment; and, after resection, a median survival of 53 months has been reported when sequenced with adjuvant capecitabine. For the 70%–80% of patients who present with locally unresectable or distant metastatic disease, systemic therapy may delay progression, but survival remains limited to approximately 1 year. For the past decade, doublet chemotherapy with gemcitabine and cisplatin has been considered the most effective first-line regimen, but results from the recent use of triplet regimens and even immunotherapy may shift the paradigm. More effective treatment strategies, including those that combine systemic therapy with locoregional therapies like radioembolization or hepatic artery infusion, have also been developed. Molecular therapies, including those that target fibroblast growth factor receptor and isocitrate dehydrogenase, have recently received US Food and Drug Administration approval for a defined role as second-line treatment for up to 40% of patients harboring these actionable genomic alterations, and whether they should be considered in the first-line setting is under investigation. Furthermore, as the oncology field seeks to expand indications for immunotherapy, recent data demonstrated that combining durvalumab with standard cytotoxic therapy improved survival in patients with ICC. This review focuses on the current and future strategies for ICC treatment, including a summary of the primary literature for each treatment modality and an algorithm that can be used to drive a personalized and multidisciplinary approach for patients with this challenging malignancy.     

Clinical significance and prognostic relevance of KRAS,BRAF, PI3K and TP53 genetic mutation analysis for resectable and unresectable colorectal liver metastases: A systematic review of the current evidence

Background

Hepatic resection is considered the optimal potentially curative treatment for colorectal liver metastases (CRLM). Following resection, up to two-thirds of patients will develop recurrence within 5-years. Genetic mutation analysis of CRLM, especially KRAS status, has been proposed as a means to guide treatment, as well as identifying patients who can derive the most survival benefit from hepatic resection.

Evaluation of the introduction of a standardised protocol for the staging and follow-up of colorectal cancer on resection rates for liver metastases

INTRODUCTION

In 2004, an audit in our unit demonstrated wide variation in liver resection rates for colorectal cancer (CRC) metastases within the cancer network. Subsequently, a network-wide CT-based follow-up and referral policy was introduced for all patients. A second audit was performed to assess the impact of the guidelines on liver resection rates.

SUBJECTS AND METHODS

Analysis of prospective liver resection database between 1997 and 2004 and after the introduction of standardised guidelines between January 2005 and April 2008.

RESULTS

A total of 362 patients underwent liver resection for CRC metastases between 1997 and 2008, 237 prior to the introduction of the referral guidelines and 125 after. Liver resection rates according to referring hospital varied from 0.92 to 2.32 per 100,000 population before guidelines were introduced. After 2005, resection rates from the four district hospitals standardised (1.68–1.84 per 100,000 population), but the central unit rate (Sheffield) remained significantly higher (2.67 per 100,000 population). No significant difference in 1-year disease-free survival between patients from Sheffield and the outlying hospitals was found (P = 0.553).

CONCLUSIONS

Introduction of a referral protocol standardised resection rates from the four district hospitals, but these remain lower compared to the specialist centre. The wide-spread adoption of a policy to discuss all patients with liver metastases at an advanced disease multidisciplinary team meeting, in the presence of hepatobiliary specialists, may further increase resection rates across the UK.     

Early gamma interferon and interleukin-2 responses to vaccination predict the late resting memory in malaria-naïve and malaria-exposed individuals

Two different cell populations respond to potent T-cell-inducing vaccinations. The induction and loss of effector cells can be seen using an ex vivo enzyme-linked immunospot (ELISPOT) assay, but the more durable resting memory response is demonstrable by a cultured ELISPOT assay. The relationship of the early effector response to durable resting memory is incompletely understood. Effector phenotype is usually identified by gamma interferon (IFN-gamma) production, but interleukin-2 (IL-2) has been specifically linked to the differentiation of memory cells. Here, IFN-gamma- and IL-2-secreting effector cells were identified by an ex vivo ELISPOT assay 1 week after vaccination and compared with the resting memory responses detected by a cultured ELISPOT assay 3 months later. The different kinetics and induction of IL-2 by different vaccines and natural exposure are described. Furthermore, both early IFN-gamma and IL-2 production independently predicted subsequent memory responses at 3 months in malaria-na?ve volunteers, but only IFN-gamma predicted memory in malaria-exposed volunteers. However, dual ELISPOT assays were also performed on malaria-exposed volunteers to identify cells producing both cytokines simultaneously. This demonstrated that double-cytokine-producing cells were highly predictive of memory. This assay may be useful in predicting vaccinations most likely to generate stable, long-term memory responses.     

Diabetes remission after bariatric surgery

Over the last decade, obesity rates have continued to rise in the United States as well as worldwide and are showing no signs of slowing down. This rise is in parallel with the increasing rates of type 2 diabetes mellitus (T2DM). Given the association between obesity and T2DM and their strong correlation with increased morbidity and mortality in addition to healthcare expenditure, it is important to recognize the most effective ways to combat them. Thus, we performed a review of literature that focused on assessing the outcomes of T2DM following bariatric surgery. Available evidence suggests that bariatric surgery provides better T2DM resolution in obese patients when compared to best medical management alone. Additionally, Biliopancreatic diversion with duodenal switch as well as Roux-en-Y gastric bypass have demonstrated higher rates of T2DM resolution when compared with other bariatric procedures.     

Application of regulated oxygen-enriched negative pressure-assisted wound therapy in combating anaerobic infections

Regulated negative pressure-assisted wound therapy (RNPT) applies non-pharmaceutical technology for enhanced healing of hard to cure, acute and chronic wounds. Although used for over two decades, wound pO₂ levels, an essential physical parameter inherent in RNPT that follows Henry’s Law of gases, have not been reported. Necrotizing fasciitis (NF), a severe soft tissue infection, necessitates prompt intensive therapeutic response using pharmaceutical, surgical, and hyperbaric oxygen treatment when anaerobes are involved. We report a linear decrease in pO₂ values in direct correlation with sub-atmospheric pressure and concurrent changes in wound atmospheric pO₂ by supplemented oxygen in an in vitro phantom leg simulated wound model treated with RNPT. We designed a system using regulated oxygen-enriched negative pressure therapy (RO-NPT) for controlling wound atmospheric pO_2. A representative patient case report treated for NF with RO-NPT is presented. RNPT follows Henry’s law of gases and leads to a decrease in wound atmospheric pO₂. The application of RNPT in anaerobic wound infections should be contraindicated. Wound pO₂ is enhanced by simultaneous application of oxygen by RO-NPT. We have demonstrated the rationale for the possible use of RO-NPT for prevention of anaerobic wound infections and as a supplemental mode of treatment of NF.     

Defects in mismatch repair occur after APC mutations in the pathogenesis of sporadic colorectal tumours

The roles of the intrinsic mutation rate and genomic instability in tumorigenesis are currently controversial. In most colorectal tumours, it is generally supposed that the first mutations occur at the adenomatous polyposis coli (APC) locus; APC mutations are thought to provide cells with a selective advantage but have no known effect on the mutation rate. It has also been suggested that genomic instability is the initiating event in colorectal tumorigenesis and, if this is true, mutations of DNA mismatch repair (MMR) genes (or at similar loci) are the most likely candidates. If defective MMR precedes APC mutations, the APC mutations of colon tumours with defective MMR and hence replication errors (RER+) should differ from those of RER- tumours, in at least three specific ways: (1) a higher frequency of allele loss at APC in RER- tumours; (2) more frameshift than nonsense mutations in RER+ tumours; and (3) APC mutations in simple repeat sequences [(N)_n, (N₁N₂)_n, or (N₁N₂N₃)_n] in RER+ tumours. We found no evidence that sporadic RER+ and RER- colon cancers (including cell lines) differ in any of these three ways. Although it remains possible that MMR is abnormal in tumours from HNPCC families before APC mutations occur, it is likely that in sporadic colon tumours, APC mutations, rather than genomic instability, are the initiating events in tumorigenesis. Hum Mutat 11:114–120, 1998. © 1998 Wiley-Liss, Inc.