Pancreatic cancer and depression.

Pancreatic cancer is a highly devastating disease with high mortality rates. Even patients who undergo potential curative surgery have a high risk for recurrence. The incidence of depression and anxiety are higher in patients with cancer than the general population. However, patients with pancreatic cancer are at most of risk of both depression and anxiety and there seems to be a biological link. In some patients, depression seems to be a precursor to pancreatic cancer. In this article we discuss the biological link between depression anxiety and hepatobiliary malignancies and discuss treatment strategies.

Safe provision of systemic anti-cancer treatment for urological cancer patients during COVID-19: a tertiary centre experience in the first wave of COVID-19.

BACKGROUND: Safe provision of systemic anti-cancer treatment (SACT) during the COVID-19 pandemic remains an ongoing concern amongst clinicians. METHODS: Retrospective analysis on uro-oncology patients who continued or started SACT between 1st March and 31st May 2020 during the pandemic (with 2019 as a comparator). RESULTS: 441 patients received SACT in 2020 (292 prostate, 101 renal, 38 urothelial, 10 testicular) compared to 518 patients in 2019 (340 prostate, 121 renal, 42 urothelial, 15 testicular). In 2020, there were 75.00% fewer patients with stage 3 cancers receiving SACT (p < 0.0001) and 94.44% fewer patients receiving radical treatment (p = 0.00194). The number of patients started on a new line of SACT was similar between both years (118 in 2019 vs 102 in 2020; p = 0.898) but with 53.45% fewer patients started on chemotherapy in 2020 (p < 0.001). Overall, 5 patients tested positive for COVID-19 (one asymptomatic, one mild, two moderate, one severe resulting in death). Compared to 2019, 30-day mortality was similar (1.69% in 2019 vs 0.98% in 2020; p = 0.649) whereas 6-month mortality was lower (9.32% in 2019 vs 1.96% in 2020; p = 0.0209) in 2020. CONCLUSION: This study suggests that delivery of SACT to uro-oncology patients during COVID-19 pandemic may be safe in high-incidence areas with appropriate risk-reduction strategies.

Cancer staff in an NHS cancer center: infections, vaccination, stress and well-being support during the COVID-19 pandemic.

Aim: To evaluate the impact of the pandemic on the well-being of cancer staff and determine the uptake of opt-in mitigation strategies. Materials & methods: Staff at Guy's Cancer Centre (London, UK) participated in an anonymized survey between May and August 2021. Results: Of 1182 staff, 257 (21.7%) participated. Ethnicity (p = 0.020) and comorbidity burden (p = 0.022) were associated with SARS-CoV-2 infection status. Of 199 respondents, seven (3.6%) were vaccine-hesitant, which was associated with low flu vaccine uptake (p < 0.001). Greater stress was associated with younger age (p = 0.030) and redeployment (p = 0.012). Lack of time and skepticism were barriers to using mental well-being resources. Conclusion: Albeit cautious, numerous trends the authors observed echo those in the published literature. Improved accessibility, awareness and utility of mental well-being resources are required.

COVID-19 is caused by the SARS-CoV-2 virus. The pandemic has applied immense pressure to healthcare workers, putting their physical and mental well-being at risk. However, the impact for cancer staff, specifically, is less known. In a survey of 257 cancer staff at Guy's Cancer Centre (London, UK; May­August 2021), the authors found that staff of particular ethnic groups, or with pre-existing illnesses, appeared more likely to become infected with SARS-CoV-2. Few staff were hesitant about SARS-CoV-2 vaccination, appearing more common among those not receiving the flu vaccine. For many, stress increased over time. However, barriers prevent staff from using mental well-being resources. With findings from larger studies, this work will be useful for strategies protecting cancer staff well-being.

Pancreatic Cancer Exposome Profile to Aid Early Detection and Inform Prevention Strategies.

Pancreatic cancer (PCa) is associated with a poor prognosis and high mortality rate. The causes of PCa are not fully elucidated yet, although certain exposome factors have been identified. The exposome is defined as the sum of all environmental factors influencing the occurrence of a disease during a life span. The development of an exposome approach for PCa has the potential to discover new disease-associated factors to better understand the carcinogenesis of PCa and help with early detection strategies. Our systematic review of the literature identified several exposome factors that have been associated with PCa alone and in combination with other exposures. A potential inflammatory signature has been observed among the interaction of several exposures (i.e., smoking, alcohol consumption, diabetes mellitus, obesity, and inflammatory markers) that further increases the incidence and progression of PCa. A large number of exposures have been identified such as genetic, hormonal, microorganism infections and immune responses that warrant further investigation. Future early detection strategies should utilize this information to assess individuals' risk for PCa.

A phase I study to assess afatinib in combination with carboplatin or with carboplatin plus paclitaxel in patients with advanced solid tumors.

PURPOSE: Afatinib, an irreversible ErbB family blocker, has demonstrated preclinical antitumor activity with chemotherapy. METHODS: As part of a phase I trial in patients with advanced solid tumors (NCT00809133; 3 + 3 dose-escalation design), we determined the maximum tolerated dose (MTD) of afatinib with carboplatin (A/C) or with carboplatin plus paclitaxel (A/C/P). Starting doses: afatinib 20 mg/day, carboplatin AUC6 (A/C) with paclitaxel 175 mg/m2 (A/C/P) (chemotherapy: Day 1 of 21-day cycles). The primary objective was to determine the MTDs; safety, pharmacokinetics and antitumor activity were also evaluated. RESULTS: Thirty-eight patients received A/C (n = 12) or A/C/P (n = 26). No dose-limiting toxicities (DLTs) were reported with A(20 mg)/C(AUC6). One patient experienced DLT in the A(40 mg)/C(AUC6) cohort (grade 3 acneiform rash); A(40 mg)/C(AUC6) was determined as the recommended phase II dose (RP2D) for A/C. Two patients each had DLTs with A(20 mg/day)/C(AUC6)/P(175 mg/m2): fatigue, infection, diarrhea, small intestine hemorrhage, dehydration, renal impairment, neutropenic sepsis (n = 1), mucositis (n = 1); A(40 mg)/C(AUC5)/P(175 mg/m2): febrile neutropenia (n = 1), mucositis, fatigue (n = 1); and A(30 mg)/C(AUC5)/P(175 mg/m2): stomatitis (n = 1), mucositis (n = 1). No DLT was observed with A(20 mg)/C(AUC5)/P(175 mg/m2), determined as the RP2D for A/C/P. The most frequent drug-related adverse events were (A/C; A/C/P): rash (75%; 73%), fatigue (67%; 69%), and diarrhea (58%; 88%). Drug plasma concentrations were similar between cycles, suggesting no drug-drug interactions. Objective response rates in these heavily pretreated patients were A/C, 3/12 (25%); A/C/P, 5/26 (19%). CONCLUSIONS: Afatinib 40 mg/day (approved monotherapy dose) with carboplatin AUC6, and afatinib 20 mg/day with carboplatin AUC5 and paclitaxel 175 mg/m2 demonstrated manageable safety and antitumor activity. Afatinib > 20 mg/day in the triple combination was not well tolerated.

Regorafenib as treatment for patients with advanced hepatocellular cancer.

Hepatocellular carcinoma is one of the fastest growing causes of cancer-related mortality worldwide. Sorafenib was the first and only drug to improve survival for patients with advanced disease, and has been the cornerstone of treatment for nearly a decade. Regorafenib is a multikinase inhibitor that has recently been shown to significantly improve survival in patients who have progressed on first-line sorafenib. In this review, we discuss the pharmacokinetic and pharmacodynamics properties of regorafenib and its efficacy and tolerability in patients with advanced hepatocellular carcinoma.

PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration.

It has been reported that p21-activated kinase 4 (PAK4) is amplified in pancreatic cancer tissue. PAK4 is a member of the PAK family of serine/threonine kinases, which act as effectors for several small GTPases, and has been specifically identified to function downstream of HGF-mediated c-Met activation in a PI3K dependent manner. However, the functionality of PAK4 in pancreatic cancer and the contribution made by HGF signalling to pancreatic cancer cell motility remain to be elucidated. We now find that elevated PAK4 expression is coincident with increased expression levels of c-Met and the p85α subunit of PI3K. Furthermore, we demonstrate that pancreatic cancer cells have a specific motility response to HGF both in 2D and 3D physiomimetic organotypic assays; which can be suppressed by inhibition of PI3K. Significantly, we report a specific interaction between PAK4 and p85α and find that PAK4 deficient cells exhibit a reduction in Akt phosphorylation downstream of HGF signalling. These results implicate a novel role for PAK4 within the PI3K pathway via interaction with p85α. Thus, PAK4 could be an essential player in PDAC progression representing an interesting therapeutic opportunity.

Deciphering the link between PI3K and PAK: An opportunity to target key pathways in pancreatic cancer?

The development of personalised therapies has ushered in a new and exciting era of cancer treatment for a variety of solid malignancies. Yet pancreatic ductal adenocarcinoma (PDAC) has failed to benefit from this paradigm shift, remaining notoriously refractory to targeted therapies. Chemotherapy is the cornerstone of management but can offer only modest survival benefits of a few months with 5-year survival rates rarely exceeding 3%. Despite these disappointing statistics, significant strides have been made towards understanding the complex biology of pancreatic cancer, with deep genomic sequencing identifying novel genetic aberrations and key signalling pathways. The PI3K-PDK1-AKT pathway has received great attention due to its prominence in carcinogenesis. However, efforts to target several components of this network have resulted in only a handful of drugs demonstrating any survival benefit in solid tumors; despite promising pre-clinical results. p-21 activated kinase 4 (PAK4) is a gene that is recurrently amplified or overexpressed in PDAC and both PAK4 and related family member PAK1, have been linked to aberrant RAS activity, a common feature in pancreatic cancer. As regulators of PI3K, PAKs have been highlighted as a potential prognostic marker and therapeutic target. In this review, we discuss the biology of pancreatic cancer and the close interaction between PAKs and the PI3K pathway. We also suggest proposals for future research that may see the development of effective targeted therapies that could finally improve outcomes for this disease.

Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: age is not a problem.

OBJECTIVE: Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC), but data on its use in the elderly are inconclusive. METHODS: All consecutive HCC patients who were treated in our institution with sorafenib since its licensing were included in the analysis. Patients were divided into two groups: (A) up to 75 and (B) older than 75 years old. Our endpoints were overall survival (OS) and time to treatment failure (TTF) because of disease progression or toxicity. Safety parameters and the prognostic effect of HCC characteristics were also investigated. RESULTS: Data from 190 patients (157 men), median age 66 (26-87) years, were studied (A=151 and B=39). No significant difference in OS and TTF was detected between the two groups [7.1 (5.5-8.7) vs. 10.4 (6.5-14.3) months, P=0.360 and 4.2 (2.3-6.2) vs. 5.6 (3.1-8.1) months, P=0.369, respectively]. Incidence of toxicities at all grades and dose reductions were comparable between groups A and B. In a multivariate setting, patients with Child-Pugh B score at baseline were associated with a higher risk of death (adjusted hazard ratio=2.17, 95% confidence interval:1.24-3.79, P=0.007) and treatment failure (adjusted hazard ratio=4.64, 95% confidence interval: 2.55-8.42, P=0.001) and had shorter OS and TTF compared with patients with a Child-Pugh A (P=0.004 and P<0.001, respectively). CONCLUSION: Elderly patients with advanced HCC, when treated with sorafenib, have an equivalent clinical outcome with similar toxicity rates as their younger counterparts. Age alone should not be a discriminating factor for the management of advanced HCC with sorafenib.

Molecularly targeted therapy for advanced hepatocellular carcinoma - a drug development crisis?

Hepatocellular carcinoma is the fastest growing cause of cancer related death globally. Sorafenib, a multi-targeted kinase inhibitor, is the only drug proven to improve outcomes in patients with advanced disease offering modest survival benefit. Although comprehensive genomic mapping has improved understanding of the genetic aberrations in hepatocellular cancer (HCC), this knowledge has not yet impacted clinical care. The last few years have seen the failure of several first and second line phase III clinical trials of novel molecularly targeted therapies, warranting a change in the way new therapies are investigated in HCC. Potential reasons for these failures include clinical and molecular heterogeneity, trial design and a lack of biomarkers. This review discusses the current crisis in HCC drug development and how we should learn from recent trial failures to develop a more effective personalised treatment paradigm for patients with HCC.

A novel role for atypical MAPK kinase ERK3 in regulating breast cancer cell morphology and migration.

ERK3 is an atypical Mitogen-activated protein kinase (MAPK6). Despite the fact that the Erk3 gene was originally identified in 1991, its function is still unknown. MK5 (MAP kinase- activated protein kinase 5) also called PRAK is the only known substrate for ERK3. Recently, it was found that group I p21 protein activated kinases (PAKs) are critical effectors of ERK3. PAKs link Rho family of GTPases to actin cytoskeletal dynamics and are known to be involved in the regulation of cell adhesion and migration. In this study we demonstrate that ERK3 protein levels are elevated as MDA-MB-231 breast cancer cells adhere to collagen I which is concomitant with changes in cellular morphology where cells become less well spread following nascent adhesion formation. During this early cellular adhesion event we observe that the cells retain protrusive activity while reducing overall cellular area. Interestingly exogenous expression of ERK3 delivers a comparable reduction in cell spread area, while depletion of ERK3 expression increases cell spread area. Importantly, we have detected a novel specific endogenous ERK3 localization at the cell periphery. Furthermore we find that ERK3 overexpressing cells exhibit a rounded morphology and increased cell migration speed. Surprisingly, exogenous expression of a kinase inactive mutant of ERK3 phenocopies ERK3 overexpression, suggesting a novel kinase independent function for ERK3. Taken together our data suggest that as cells initiate adhesion to matrix increasing levels of ERK3 at the cell periphery are required to orchestrate cell morphology changes which can then drive migratory behavior.

Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients.

Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.

FOLFIRINOX - a new paradigm in the treatment of pancreatic cancer.

Treatment of metastatic and locally advanced pancreatic cancer has made slow progress during the last decade. Single agent gemcitabine or in combination with capecitabine or erlotinib remained the preferred systemic treatment options until 2010 when the ACCORD study demonstrated significantly improved outcomes achieved with FOFIRINOX compared with gemcitabine monotherapy. Since 2010, use of FOLFIRINOX has increased both in metastatic and locally advanced cancer. Despite its gaining popularity among oncologists, unanswered questions remain. Do the often necessary dose modifications affect its efficacy? Are the toxicities manageable and how applicable are the results of the ACCORD study in the general population of patients with newly diagnosed pancreatic cancer? In the present manuscript, we review the published literature regarding the use of FOLFIRINOX, the challenges associated with its use and how it will be optimally incorporated into the management of patients with different stages of pancreatic cancer and ultimately, in a more biomarker-driven pathway algorithm.

Neoadjuvant and adjuvant treatment of renal cell carcinoma.

Locally advanced renal cell cancers have a significant recurrence rate following radical nephrectomy. Traditional cytotoxic chemotherapy and immunotherapy have failed to demonstrate a benefit in the adjuvant setting. Recent advances in the treatment of metastatic renal cell carcinoma using agents that target VEGF and the mTOR pathways have radically changed the way metastatic renal cell carcinoma is treated. These drugs may be able to reduce the rate of recurrence in high-risk disease, and are now being assessed in the neoadjuvant and adjuvant settings. This review summarizes the evidence for targeted treatment in both the neoadjuvant and adjuvant setting, and its use with cytoreductive nephrectomy.