A phase II trial of the effect of perindopril on hand-foot skin reaction (HFSR) incidence and severity in patients receiving regorafenib for refractory mCRC.

PURPOSE: Regorafenib is an oral multi-kinase inhibitor that offers an OS benefit to patients with mCRC refractory to standard therapy (Grothey et al., in Lancet 381:303-312, 2013), but comes with potential significant toxicities including grade 3 hand-foot skin reaction (HFSR). The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. We hypothesized that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, indicated for the treatment of hypertension (Ceconi et al., in Cardiovasc Res 73:237-246, 2007), and which plays a role in preventing endothelial dysfunction, may help to prevent or reduce the severity of regorafenib-induced HFSR. PATIENTS AND METHODS: In this single-center phase II open-label trial, patients with refractory mCRC were treated with both regorafenib (160 mg/day) and perindopril (4 mg/day) for 21 days per 28-day cycle. The primary end point was to assess the proportion of patients with any grade HFSR toxicity. Secondary end points included time to development of worst (grade 3) HFSR, reduction of all grades of hypertension and all grade toxicities, as well as progression-free survival. All toxicities were evaluated using CTCAE v4.03. RESULTS: A planned interim analysis was performed after ten evaluable patients had completed their first cycle of study treatment. As 50% (5/10) experienced grade 3 HFSR, enrolment was stopped as the addition of perindopril did not lead to a reduced level of HFSR compared with regorafenib alone. Other grade 3 toxicities included hypertension (16.7%) and increased AST (16.7%). CONCLUSION: The addition of an ACE inhibitor perindopril to regorafenib did not reduce HFSR incidence or severity in patients with refractory mCRC.

Lean methods to improve operating room elective first case on-time starts in a large, urban, safety net medical center.

BACKGROUND: Delays in first cases contribute to multiple operating room (OR) inefficiencies and decreases in OR productivity. METHODS: Lean process improvement methods were used to redesign the existing workflow for elective first cases of the day in a large, urban, public hospital. First case start times were prospectively recorded from May 2, 2016 through December 29, 2017. RESULTS: Data from 415 operating days were examined, 86 days prior to, 35 days during, and 294 days after implementation of interventions in the pre-operative holding area. During this time, of 23,891 operations performed, 14,981 were elective procedures, 5963 (39.8%) of which were first cases of the day. The mean rate of elective first case on-time starts per week went from 23.5% before and during to 73.0% after implementation of lean interventions (p < 0.0000001). CONCLUSIONS: Implementation of lean interventions in the pre-operative holding area was associated with significantly improved rates of elective first case on-time starts.

Survival Impact of CAPOX Versus FOLFOX in the Adjuvant Treatment of Stage III Colon Cancer.

BACKGROUND: Capecitabine and oxaliplatin (CAPOX) and folinic acid, fluorouracil, and oxaliplatin (FOLFOX) are both used in the adjuvant treatment of colon cancer, and while their efficacy is assumed to be similar, they have not been directly compared. We reviewed the toxicity profiles, relative dose intensity (RDI), and survival associated with these regimens across a multi-institutional cohort. PATIENTS AND METHODS: We identified 394 consecutively treated patients with stage III colon cancer who received an oxaliplatin-containing regimen. RDI was defined as the total dose received divided by the intended total dose if all cycles were received. RESULTS: FOLFOX was associated with increased mucositis (6.2% vs. 0.7%, P = .0069) and neutropenia (25.9% vs. 8.6%, P < .0001), while CAPOX was associated with increased dose-limiting toxicities (DLTs) (90.7% vs. 80.2%, P = .0055), diarrhea (31.8% vs. 9.0%, P < .0001), and hand-foot syndrome (19.9% vs. 2.1%, P < .0001). Higher median RDI of fluoropyrimidine (93.7% vs. 80.0%, P < .0001) and oxaliplatin (87.2% vs. 76.3%, P < .0001) was noted for patients receiving FOLFOX. Reducing the duration from 6 to 3 months would have prevented 28.7% of FOLFOX and 20.5% of CAPOX patients from ever experiencing a DLT (P = .0008). Overall survival did not differ by regimen (hazard ratio = 0.73; 95% confidence interval 0.45-1.22; P = .24). However, CAPOX was associated with improved disease-free survival (3-year disease-free survival 83.8% vs. 73.4%, P = .022), which remained significant in high-risk (T4 or N2) (P = .039) but not low-risk patients (P = .19). CONCLUSION: CAPOX may be associated with improved disease-free survival despite greater toxicities and lower RDI. Reducing adjuvant chemotherapy duration to 3 months would prevent 26% of patients from ever experiencing a DLT.

A case report of posterior reversible encephalopathy syndrome in a patient receiving gemcitabine and cisplatin.

RATIONALE: Posterior reversible encephalopathy syndrome (PRES) is a subacute syndrome causing characteristic neurologic and radiologic findings. PRES is predominantly caused by malignant hypertension though it has been associated with immunosuppressive treatments such as chemotherapy. PATIENT CONCERNS: We describe a case of a 58 year old female who developed fluctuant level of consciousness, agitation. DIAGNOSIS: MRI findings were in keeping with posterior reversible encephalopathy syndrome following cycle 6 of palliative gemcitabine and cisplatin therapy for metastatic cholangiocarcinoma. INTERVENTIONS: The patient was managed with magnesium supplementation for hypomagnesemia and amlodipine. OUTCOMES: The patient's level of consciousness returned to normal though she had residual neurologic deficits impairing her ability to drive and impacting her balance. CONCLUSIONS: Cisplatin is a documented causative agent of PRES though gemcitabine is rarely associated with the syndrome. Combination cisplatin and gemcitabine therapy causing radiologically proven PRES has been documented in only 3 previous case reports. Gemcitabine's poor blood-brain barrier penetration makes it an unlikely culprit of central nervous system (CNS) toxicities. Our case and previous reports suggest higher doses may contribute to CNS toxicities such as PRES. Additionally, an emerging trend of hypomagnesemia associated with PRES has been documented inside and outside the context of malignancy and suggests a possible target for treatment and prevention warranting further investigation.

Eligibility of Metastatic Pancreatic Cancer Patients for First-Line Palliative Intent nab-Paclitaxel Plus Gemcitabine Versus FOLFIRINOX.

OBJECTIVES: The PRODIGE and MPACT trials showed superiority of FOLFIRINOX and nab-paclitaxel plus gemcitabine (NG) over gemcitabine alone, respectively. However, both had strict inclusion criteria. We sought to determine the characteristics of patients with metastatic pancreatic cancer (MPC) which inform the appropriateness of first-line chemotherapy FOLFIRINOX and NG in routine practice. MATERIALS AND METHODS: Patients with MPC who initiated palliative chemotherapy with gemcitabine from 2000 to 2011 at the British Columbia Cancer Agency were identified. Clinicopathologic variables and outcomes were retrospectively collected and compared among groups. Eligibility criteria for each regimen were in accordance with the respective pivotal phase III trials. RESULTS: A total of 473 patients were included: 25% of the patients were eligible for FOLFIRINOX versus 45% for NG. Main reasons for FOLFIRINOX ineligibility were Eastern Cooperative Oncology Group (ECOG) performance status (PS)≥2 (56.5%), age older than 75 years (19.0%), and bilirubin>1.5× upper limit of normal (18.6%), whereas those for NG ineligibility were bilirubin > upper limit of normal (24.5%), ECOG PS≥3 (14.6%), and cardiac dysfunction (13.8%). Univariate analyses revealed that FOLFIRINOX and NG-eligible patients had longer median overall survival than their respective ineligible group (8.6 vs. 4.7 mo, P<0.001; 6.7 vs. 4.9 mo, P=0.008, respectively). After accounting for ECOG PS in the multivariate model, however, eligibility for either FOLFIRINOX or NG no longer predicted for better overall survival. CONCLUSIONS: The majority of patients with MPC are not candidates to either NG or FOLFIRINOX due to restrictive eligibility requirements. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

Defining Eligibility of FOLFIRINOX for First-Line Metastatic Pancreatic Adenocarcinoma (MPC) in the Province of British Columbia: A Population-based Retrospective Study.

BACKGROUND: FOLFIRINOX is a first-line treatment option for patients with metastatic pancreatic cancer (MPC) and is associated with improved survival yet significantly more toxicities than standard gemcitabine. Our aim was to determine the proportion of patients with MPC who would be eligible for FOLFIRINOX based upon the pivotal ACCORD study criteria. METHODS: Patients with confirmed MPC at the time of referral to the BC Cancer Agency between 2004 and 2007 were identified from the Gastrointestinal Cancers Outcomes Unit Database (GICOU). Proportion of patients that met the ACCORD study eligibility criteria was determined by chart review. Criteria for FOLFIRINOX exclusion were assessed using descriptive statistics. RESULTS: A total of 100 consecutive patients with complete chart records and MPC were identified. Fifty-two (52%) were male and the median age was 68 years (range, 42 to 98 y). The most common sites of metastases were liver (63%) and peritoneum (22%). Only 26 patients fulfilled the ACCORD study eligibility criteria. The most common reasons for FOLIFIRINOX exclusion per ACCORD were poor Eastern Cooperative Oncology Group score of ≥2 (64%), age of 76 years or greater (22%), elevated bilirubin (22%), and inadequate renal function (6%). CONCLUSIONS: Despite the proven survival benefit of FOLFIRINOX, only approximately one quarter of patients in the real-world setting with MPC would have been considered eligible for such therapy based upon the ACCORD eligibility criteria. Careful patient selection and more tolerable therapies are required.

Genome-Wide Association Analysis Identifies Dcc as an Essential Factor in the Innervation of the Peripheral Vestibular System in Inbred Mice.

This study aimed to investigate the genetic causes of vestibular dysfunction. We used vestibular sensory-evoked potentials (VsEPs) to characterize the vestibular function of 35 inbred mouse strains selected from the Hybrid Mouse Diversity Panel and demonstrated strain-dependent phenotypic variation in vestibular function. Using these phenotypic data, we performed the first genome-wide association study controlling for population structure that has revealed two highly suggestive loci, one of which lies within a haplotype block containing five genes (Stard6, 4930503L19Rik, Poli, Mbd2, Dcc) on Chr. 18 (peak SNP rs29632020), one gene, deleted in colorectal carcinoma (Dcc) has a well-established role in nervous system development. An in-depth analysis of Dcc-deficient mice demonstrated elevation in mean VsEP threshold for Dcc (+/-) mice (-11.86 dB) compared to wild-type (-9.68 dB) littermates. Synaptic ribbon studies revealed Dcc (-/-) (P0) and Dcc (+/-) (6-week-old) mice showed lower density of the presynaptic marker (CtBP2) as compared to wild-type controls. Vestibular ganglion cell counts of Dcc (-/-) (P0) was lower than controls. Whole-mount preparations showed abnormal innervation of the utricle, saccule, and crista ampullaris at E14.5, E16.5, and E18.5. Postnatal studies were limited by the perinatal lethality in Dcc (-/-) mice. Expression analyses using in situ hybridization and immunohistochemistry showed Dcc expression in the mouse vestibular ganglion (E15.5), and utricle and crista ampullaris (6-week-old), respectively. In summary, we report the first GWAS for vestibular functional variation in inbred mice and provide evidence for the role of Dcc in the normal innervation of the peripheral vestibular system.

Correlation between County-Level Surgeon Density and Mortality from Colorectal Cancer.

PURPOSE: We aimed to explore the effect of county-level general surgeon (GS) and colorectal surgeon (CS) density on colorectal cancer (CRC) mortality and to identify additional county characteristics associated with outcomes. METHODS: Using data from the Area Resource File, US Census, and National Cancer Institute, we developed multivariate regression models to determine the effect of density of GS and CS on CRC death between 2005 and 2009 while controlling for CRC incidence, county demographics, and other socioeconomic factors. RESULTS: In total, we included 1767 counties: Mean CRC incidence and death rates were 64.9 and 19.9 %, respectively. In this cohort, 45 % were metropolitan areas. Mean GS and CS densities were 7.2 and 0.15 per 100,000 people, respectively. Counties with at least 1 GS had a statistically significant decrease in CRC-specific mortality (beta coefficient -0.18, p < 0.001). Increasing GS density beyond 8 per 100,000 people did not result in any further meaningful reductions in mortality. The presence of at least 1 CS at the county-level was not associated with differences in CRC mortality (beta coefficient -0.021, p = 0.37). Metropolitan counties and a larger percentage of individuals who were <65 years old were associated with decreased CRC mortality. Conversely, a higher proportion below the poverty line was correlated with a significant increase in CRC mortality. CONCLUSION: Unlike CS, the presence of GS at the county-level was associated with lower CRC mortality. However, increasing GS density beyond a certain point did not result in further meaningful reductions in mortality. A balanced strategy of distributing the surgical workforce across all counties can result in population-based improvements in CRC outcomes.

A qualitative focus group study to identify the needs of survivors of stage II and III colorectal cancer.

BACKGROUND: Prior survivorship research has largely focused on issues faced by survivors of childhood tumors, breast cancers, or hematologic malignancies. Relatively little is known about the needs of other prevalent survivor groups. Our aim was to identify the specific concerns of colorectal cancer (CRC) survivors in the key domains of physical functioning, psychological wellbeing, and social relationships. METHODS: We conducted focus groups with stage II and III CRC survivors who had completed their primary active anti-cancer treatments. Patients were asked to describe how their diagnosis and treatment impacted their lives, to outline deficiencies in the care that they received, and to suggest ways of addressing any unmet needs. A content analysis was subsequently conducted to identify major themes. RESULTS: Thirty CRC survivors participated in six focus groups. Individuals reported some degree of dissatisfaction with the amount and type of diagnostic and treatment information they received at their initial clinic visit. Distress from toxicities, such as peripheral neuropathy, was also common among the survivors. Similarly, the majority faced challenges adjusting to their lives and daily activities, especially in caring for their colostomy. Having survived CRC, many survivors expressed an interest in advocacy and health promotion of CRC. CONCLUSIONS: CRC survivors face many barriers after their cancer treatment. Issues with colostomy are unique to this survivor group. Interventions to improve CRC survivorship care should also incorporate opportunities for patient advocacy. Copyright © 2015 John Wiley & Sons, Ltd.

Population-Based Cost-Minimization Analysis of CAPOX Versus Modified FOLFOX6 in the Adjuvant Treatment of Stage III Colon Cancer.

BACKGROUND: Evidence suggests that CAPOX (capecitabine and oxaliplatin) has efficacy similar to 5-fluorouracil and oxaliplatin (mFOLFOX6) in the adjuvant treatment of colon cancer. CAPOX is partly administered orally and associated with a 3-week rather than a 2-week treatment cycle. A population-based cost-minimization analysis was conducted from the health care payer and societal perspectives to evaluate the potential cost savings of replacing mFOLFOX6 with CAPOX. METHODS: We applied treatment and toxicity data from phase III trials of CAPOX and FOLFOX-based regimens to the adjuvant colon cancer population in British Columbia, Canada. In this cost-minimization analysis we compared the total costs associated with chemotherapy medications, drug administration and delivery, hospital and clinic visits, treatment-related toxicities, and central venous access devices. Costs to patients in terms of lost time and travel were also considered. It was assumed that patients would receive either 8 cycles of CAPOX or 12 cycles of mFOLFOX6. RESULTS: From the payer perspective, the use of CAPOX resulted in cost savings of $5339 CAD per patient compared with the use of mFOLFOX6. From a societal perspective, CAPOX was also associated with savings of $6080 CAD per patient. The greatest cost savings with CAPOX were attributed to fewer visits for chemotherapy treatment and decreased central venous access device usage. CAPOX was also associated with reduced loss of time and decreased travel for patients because of the requirement of fewer clinic visits. CONCLUSIONS: Replacement of mFOLFOX6 with CAPOX in the adjuvant treatment of colon cancer might be associated with potential cost savings from the payer and societal perspectives.

Genome-wide association study identifies nox3 as a critical gene for susceptibility to noise-induced hearing loss.

In the United States, roughly 10% of the population is exposed daily to hazardous levels of noise in the workplace. Twin studies estimate heritability for noise-induced hearing loss (NIHL) of approximately 36%, and strain specific variation in sensitivity has been demonstrated in mice. Based upon the difficulties inherent to the study of NIHL in humans, we have turned to the study of this complex trait in mice. We exposed 5 week-old mice from the Hybrid Mouse Diversity Panel (HMDP) to a 10 kHz octave band noise at 108 dB for 2 hours and assessed the permanent threshold shift 2 weeks post exposure using frequency specific stimuli. These data were then used in a genome-wide association study (GWAS) using the Efficient Mixed Model Analysis (EMMA) to control for population structure. In this manuscript we describe our GWAS, with an emphasis on a significant peak for susceptibility to NIHL on chromosome 17 within a haplotype block containing NADPH oxidase-3 (Nox3). Our peak was detected after an 8 kHz tone burst stimulus. Nox3 mutants and heterozygotes were then tested to validate our GWAS. The mutants and heterozygotes demonstrated a greater susceptibility to NIHL specifically at 8 kHz both on measures of distortion product otoacoustic emissions (DPOAE) and on auditory brainstem response (ABR). We demonstrate that this sensitivity resides within the synaptic ribbons of the cochlea in the mutant animals specifically at 8 kHz. Our work is the first GWAS for NIHL in mice and elucidates the power of our approach to identify tonotopic genetic susceptibility to NIHL.

Central nervous system cancers, version 2.2014. Featured updates to the NCCN Guidelines.

The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.

The association between county-level surgeon density and esophageal and gastric cancer mortality.

BACKGROUND: Surgical resection plays an integral part in the curative treatment of esophageal (EC) and gastric cancer (GC). The impact of the allocation of surgeons at the county level on these cancer outcomes is unclear. Our aims were to examine the effect of surgeon density on EC and GC mortality and to compare the relative roles of thoracic and general surgeons on outcomes. METHODS: Using county-level data from the Area Resource File, we constructed multivariate regression models to explore the effect of thoracic and general surgeon density on EC and GC mortality, adjusting for cancer incidence rate, county-level, socioeconomic factors and health care resource metrics. RESULTS: In total, 663 and 539 counties were analyzed for EC and GC, respectively: Mean EC and GC mortality rates were 4.95 and 4.07; mean thoracic and general surgeon density were 6 and 50 per 100,000 people, respectively. When compared to counties with no thoracic surgeons, those with at least one thoracic surgeon had reduced EC mortality. For GC, counties with one or more general surgeons also had decreased deaths when compared with those without any general surgeons. While increasing the density of surgeons beyond ten only yielded minimal improvements in EC mortality, this resulted in significant further reductions in GC mortality. CONCLUSIONS: Mortality from GC appears to be more susceptible to the benefits of increased surgeon density. For EC, a strategic policy of allocating health resources and distributing the surgical workforce proportionally across counties will be best able to optimize outcomes at the population-based level.

Prostate cancer early detection, version 1.2014. Featured updates to the NCCN Guidelines.

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for men choosing to participate in an early detection program for prostate cancer. These NCCN Guidelines Insights highlight notable recent updates. Overall, the 2014 update represents a more streamlined and concise set of recommendations. The panel stratified the age ranges at which initiating testing for prostate cancer should be considered. Indications for biopsy include both a cutpoint and the use of multiple risk variables in combination. In addition to other biomarkers of specificity, the Prostate Health Index has been included to aid biopsy decisions in certain men, given recent FDA approvals.

Presentation and management of docetaxel-related adverse effects in patients with breast cancer.

The taxane chemotherapeutic agent docetaxel has been utilized in the management of breast cancer in the adjuvant, neoadjuvant and metastatic setting. Although well tolerated by the majority of patients, docetaxel toxicity may limit the dose which can be administered. Adverse events include infusion reactions, febrile neutropenia, fatigue, fluid retention, pneumonitis, cutaneous and nail toxicity, epiphora and lacrimal duct stenosis, gastrointestinal complications, and neuropathies. In this review, we explore these complications and how they can be effectively managed to improve patient quality of life during and following docetaxel therapy.

Dermatofibrosarcoma protuberans, version 1.2014.

Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft tissue tumor characterized by a relatively high risk of local recurrence and low risk of metastasis. The NCCN Guidelines for DFSP provide multidisciplinary recommendations on the management of patients with this rare disease. These NCCN Guidelines Insights highlight the addition of the Principles of Pathology section, which provides recommendations on the pathologic assessment of DFSP. Because DFSP can mimic other lesions, immunohistochemical studies are often required to establish diagnosis. Cytogenetic testing for the characteristic translocation t(17;22)(q22;q13) can also be valuable in the differential diagnosis of DFSP with other histologically similar tumors.

Melanoma, version 4.2014.

The NCCN Guidelines for Melanoma provide multidisciplinary recommendations for the management of patients with melanoma. These NCCN Guidelines Insights highlight notable recent updates. Dabrafenib and trametinib, either as monotherapy (category 1) or combination therapy, have been added as systemic options for patients with unresectable metastatic melanoma harboring BRAF V600 mutations. Controversy continues regarding the value of adjuvant radiation for patients at high risk of nodal relapse. This is reflected in the category 2B designation to consider adjuvant radiation following lymphadenectomy for stage III melanoma with clinically positive nodes or recurrent disease.

Prostate cancer, version 2.2014.

Prostate cancer has surpassed lung cancer as the most common cancer in men in the United States. The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer based on clinical evidence and expert consensus. NCCN Panel guidance on treatment decisions for patients with localized disease is represented in this version. Significant updates for early disease include distinction between active surveillance and observation, a new section on principles of imaging, and revisions to radiation recommendations. The full version of these guidelines, including treatment of patients with advanced disease, can be found online at the NCCN website.

FVB/NJ mice demonstrate a youthful sensitivity to noise-induced hearing loss and provide a useful genetic model for the study of neural hearing loss.

The hybrid mouse diversity panel (HMDP), a panel of 100 strains, has been employed in genome wide association studies (GWAS) to study complex traits in mice. Hearing is a complex trait and the CBA/CaJ mouse strain is a widely used model for age-related hearing loss (ARHI) and noise induced hearing loss (NIHL). The CBA/CaJ strain's youthful sensitivity to noise and limited age-related loss led us to attempt to identify additional strains segregating a similar phenotype for our panel. FVB/NJ is part of the HMDP and has been previously described as having a similar ARHI phenotype to CBA/CaJ. For these reasons, we have studied the FVB/NJ mouse for ARHI and NIHL phenotypes in hopes of incorporating its phenotype into HMDP studies. We demonstrate that FVB/NJ exhibits ARHI at an earlier age than CBA/CaJ and young FVB/NJ mice are vulnerable to NIHL up until 10 to 12 weeks. This suggests that FVB/NJ may be used as an additional genetic model for neural forms of progressive hearing loss and for the study of youthful sensitivity to noise.