The effect of aging on short- and long-term results after esophagectomy: an international multicenter retrospective analysis.

The optimal treatment for esophageal cancer in elderly patients is still debated and data on postoperative results are limited. This retrospective international study aims to clarify the impact of age on clinical and oncological outcomes after esophagectomy. All patients that underwent esophagectomy for cancer between 2007 and 2016 at two European high-volume Centers have been included in the study. Patients were divided into three groups according to their age: young-age group (YAG) (18-69), middle-age group (70-74) and old-age group (>74). Primary outcome was 5-year overall survival (OS), while secondary outcomes considered were 5-year disease free survival and disease related survival, 90-day morbidity and mortality, readmission rate and radicality. A total of 575 patients were included. No differences emerged in terms of morbidity and length of stay, while mortality increased with aging from 2% in YAG to 4.8% in old-aged (P = 0.003). Old-age patients had less neoadjuvant treatment (P < 0.001), a less aggressive mediastinal lymphadenectomy and presented a more advanced pathological stage. As expected, OS decreased significantly for older patients compared with the other two age groups (P = 0.044) but, on the other hand, disease free and disease related survival were comparable between the groups. Age itself should not be considered a contraindication to esophagectomy. Although in patients older than 75 years postoperative mortality is significantly increased, esophagectomy could be still an option in selected patients, favoring the use of minimally invasive techniques and enhanced recovery protocols.

Adjuvant therapy following neoadjuvant chemotherapy and surgery for oesophageal adenocarcinoma in patients with clear resection margins.

BACKGROUND: The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy (NAC) and surgery is contentious. In UK practice, surgical resection margin status is often used to classify patients into receiving adjuvant treatment. This study aimed to assess any survival benefit of adjuvant therapy in patients with clear resection margins. METHODS: This was a retrospective collaborative cohort study combining two prospectively collected UK institutional databases of patients with oesophageal adenocarcinoma. Multivariable Cox regression and propensity matched analyses were used to compare overall and recurrence-free survival according to the adjuvant treatment. RESULTS: Of 374 patients with clear resection margins, 221 patients (59%) had no adjuvant treatment, 137 patients (37%) had adjuvant chemotherapy and 16 patients (4%) had adjuvant chemoradiotherapy. For patients who had received NAC (290, 76%), when adjuvant chemotherapy was compared to no adjuvant treatment, hazard ratios (HRs) favoured adjuvant chemotherapy but did not reach independent significance (overall survival [OS] HR 0.65 95% confidence interval [CI] 0.40-1.06; p .0.087). Responders to NAC (Mandard 1-3) were seemingly more likely to demonstrate a survival benefit from adjuvant chemotherapy (HR 0.42 95% CI 0.15-1.11; p .1.081). CONCLUSIONS: Although no independent survival benefit was observed, the point estimates favoured adjuvant treatment, predominantly in patients with chemo-responsive tumours.

Isolated limb perfusion with biochemotherapy and oncolytic virotherapy combines with radiotherapy and surgery to overcome treatment resistance in an animal model of extremity soft tissue sarcoma.

The management of locally advanced or recurrent extremity sarcoma often necessitates multimodal therapy to preserve a limb, of which isolated limb perfusion (ILP) is a key component. However, with standard chemotherapeutic agents used in ILP, the duration of response is limited. Novel agents or treatment combinations are urgently needed to improve outcomes. Previous work in an animal model has demonstrated the efficacy of oncolytic virotherapy when delivered by ILP and, in this study, we report further improvements from combining ILP-delivered oncolytic virotherapy with radiation and surgical resection. In vitro, the combination of radiation with an oncolytic vaccinia virus (GLV-1h68) and melphalan demonstrated increased cytotoxicity in a panel of sarcoma cell lines. The effects were mediated through activation of the intrinsic apoptotic pathway. In vivo, combinations of radiation, oncolytic virotherapy and standard ILP resulted in delayed tumour growth and prolonged survival when compared with standard ILP alone. However, local disease control could only be secured when such treatment was combined with surgical resection, the timing of which was crucial in determining outcome. Combinations of oncolytic virotherapy with surgical resection and radiation have direct clinical relevance in extremity sarcoma and represent an exciting prospect for improving outcomes in this pathology.

BRAF- and MEK-Targeted Small Molecule Inhibitors Exert Enhanced Antimelanoma Effects in Combination With Oncolytic Reovirus Through ER Stress.

Reovirus type 3 (Dearing) (RT3D) infection is selective for cells harboring a mutated/activated RAS pathway. Therefore, in a panel of melanoma cell lines (including RAS mutant, BRAF mutant and RAS/BRAF wild-type), we assessed therapeutic combinations that enhance/suppress ERK1/2 signaling through use of BRAF/MEK inhibitors. In RAS mutant cells, the combination of RT3D with the BRAF inhibitor PLX4720 (paradoxically increasing ERK1/2 signaling in this context) did not enhance reoviral cytotoxicity. Instead, and somewhat surprisingly, RT3D and BRAF inhibition led to enhanced cell kill in BRAF mutated cell lines. Likewise, ERK1/2 inhibition, using the MEK inhibitor PD184352, in combination with RT3D resulted in enhanced cell kill in the entire panel. Interestingly, TCID50 assays showed that BRAF and MEK inhibitors did not affect viral replication. Instead, enhanced efficacy was mediated through ER stress-induced apoptosis, induced by the combination of ERK1/2 inhibition and reovirus infection. In vivo, combined treatments of RT3D and PLX4720 showed significantly increased activity in BRAF mutant tumors in both immune-deficient and immune-competent models. These data provide a strong rationale for clinical translation of strategies in which RT3D is combined with BRAF inhibitors (in BRAF mutant melanoma) and/or MEK inhibitors (in BRAF and RAS mutant melanoma).

Isolated limb perfusion with melphalan, tumour necrosis factor-alpha and oncolytic vaccinia virus improves tumour targeting and prolongs survival in a rat model of advanced extremity sarcoma.

Isolated limb perfusion (ILP) is a treatment for advanced extremity sarcoma and in-transit melanoma. Advancing this procedure by investigating the addition of novel agents, such as cancer-selective oncolytic viruses, may improve both the therapeutic efficacy of ILP and the tumour-targeted delivery of oncolytic virotherapy. Standard in vitro assays were used to characterise single agent and combinatorial activities of melphalan, tumour necrosis factor-alpha (TNF-α) and Lister strain vaccinia virus (GLV-1h68) against BN175 rat sarcoma cells. An orthotopic model of advanced extremity sarcoma was used to evaluate survival of animals after ILP with combinations of TNF-α, melphalan and GLV-1h68. We investigated the efficiency of viral tumour delivery by ILP compared to intravenous therapy, the locoregional and systemic biodistribution of virus after ILP, and the effect of mode of administration on antibody response. The combination of melphalan and GLV-1h68 was synergistic in vitro. The addition of virus to standard ILP regimens was well tolerated and demonstrated superior tumour targeting compared to intravenous administration. Triple therapy (melphalan/TNF-α/GLV-1h68) resulted in increased tumour growth delay and enhanced survival compared to other treatment regimens. Live virus was recovered in large amounts from perfused regions, but in smaller amounts from systemic organs. The addition of oncolytic vaccinia virus to existing TNF-α/melphalan-based ILP strategies results in survival advantage in an immunocompetent rat model of advanced extremity sarcoma. Virus administered by ILP has superior tumour targeting compared to intravenous delivery. Further evaluation and clinical translation of this approach is warranted.

Surgical outcomes following resection for sporadic abdominal wall fibromatosis.

BACKGROUND: Fibromatosis can be classified according to site of origin, namely, extraabdominal, abdominal wall, or intraabdominal. This study reports on the surgical management and long-term outcomes from a single center in the management of sporadic abdominal wall fibromatosis. METHODS: Patients who underwent surgery for abdominal wall fibromatosis between 1998 and 2013 were identified from a prospectively maintained database. A retrospective review of patient demographics, tumor characteristics, surgical outcomes, operative management, and recurrence rates was performed. RESULTS: Fifty patients underwent resection of a primary sporadic abdominal wall fibromatosis; 48 were female, of whom 43 reported previous pregnancy. Twenty-seven patients (54 %) had prior abdominal surgery for other pathologies. Macroscopic clearance was achieved in all cases. The median size of tumors resected was 8 cm (range 3-15 cm). The abdominal wall defect was reconstructed with prosthetic mesh in 47 of 50 cases. No major postoperative complication was encountered. Microscopic margins were reported as clear (R0) in 21 of 50 cases. With a median follow-up of 6 years (range 1-15 years), 46 of 50 patients remain disease free, with a median disease-free survival of 5 years. Of these 46 disease-free patients, 13 had further pregnancies without complications from either the abdominal mesh repair or tumor recurrence. CONCLUSIONS: For asymptomatic sporadic abdominal wall fibromatosis, observation is an accepted first-line strategy. However, in contrast to extraabdominal fibromatosis, the preferred definitive treatment is surgical resection, which is recommended as first-line therapy in symptomatic patients, selected cases when tumors are progressing, and those with tumors >7 cm.

Physician weight recommendations for overweight and obese firefighters, United States, 2011-2012.

INTRODUCTION: National guidelines state that health care professionals (HCPs) should advise patients on the importance of maintaining a healthy weight. Firefighters have high rates of obesity, and cardiovascular events are the leading cause of line-of-duty deaths in firefighters. This study assessed the association of age and body mass index (BMI) with HCP weight recommendations among male firefighters. METHODS: We used data on self-reported HCP weight recommendations and measured BMI from a 2011-2012 national sample of male firefighters (N = 1,002). HCP recommendations were recorded as no advice, maintain, gain, or lose weight, and BMI was categorized as normal (<25.0 kg/m(2)), overweight (25.0-29.9 kg/m(2)), class I obese (30.0-34.9 kg/m(2)), and class II or III obese (≥35.0 kg/m(2)). We used multinomial logistic regression to estimate the odds of receiving weight advice by age and BMI categories. RESULTS: Most firefighters (96%) reported visiting an HCP in the past year. Most (69%) firefighters and 48% of class I to III obese firefighters reported receiving no weight advice. Higher BMI predicted HCP advice to lose weight (odds ratio class I obese vs normal weight: 12.98; 95% confidence interval: 5.38-31.34). Younger firefighters were less likely to receive weight loss advice than older firefighters, except among those who were class II or III obese. CONCLUSIONS: HCPs are important sources of health information for firefighters. Overweight and obese firefighters, particularly those who are younger, do not consistently receive HCP advice to lose weight. This marks a missed opportunity to prevent further weight gain and reduce obesity-related health outcomes.

Low local recurrence rates following marginal surgical resection of non-coelomic Atypical Lipomatous Tumours/Well-differentiated Liposarcomas.

INTRODUCTION: High rates of local recurrence (LR) have been reported following resection of extremity Atypical lipomatous tumours/Well-differentiated liposarcomas (ALTs). This retrospective study of patients who underwent resection of primary deep extremity and trunk ALTs at a specialist sarcoma centre aims to assess morbidity and factors associated with low local recurrence rates (LRR). METHODS: To review a homogeneous cohort of patients with low-grade disease, tumours with known high-risk histological features were excluded. Prognostic variables potentially influencing local recurrence (LR) (age, size, site, margin status, and histological findings) were analysed. Endpoints were LR, distant recurrence (DR) and local disease-free survival (LDFS). RESULTS: 127 patients were identified, with median follow-up of 54 months (0-235). Median tumour size was 17.5 cm (5-36). 85 % occurred in the lower limb. 93.7 % underwent marginal resection. No patients received radiotherapy. Median hospital stay was 3 days (0-16). 7.9 % returned to theatre for evacuation of haematoma or infected seroma and 18.1 % had outpatient seroma aspiration. Surgical margins were R0/R1 in 93.7 % of patients and R2 in 6.3 % with a LR rate of 8.4 % and 75 % respectively at median time of 54 months. One- and 5-year LDFS was 100 % and 88.4 %, respectively. DR rate was 0.8 % (1/127) this patient had pleomorphic liposarcomatous transformation on recurrence and subsequently developed distant metastases. No patients died of disease. CONCLUSION: Function-preserving marginal resection of non-coelomic ALTs has low morbidity, low LR and extremely low rates of distant relapse. Patients with lower limb ALT were found to have significantly lower LR, which may impact follow-up protocols.

Role of thoracotomy and metastatectomy in gestational trophoblastic neoplasia: a single center experience.

Gestational trophoblastic neoplasia (GTN) is a rare collection of malignancies which are usually curable with modern chemotherapy. Lung metastasis is a relatively common feature of these malignancies and is not considered an adverse prognostic feature. Occasionally, however, the management of these patients necessitates adjuvant thoracic surgery, either to establish the diagnosis or to potentially provide a curative resection of drug-resistant foci of disease. This case series highlights 5 such cases in which thoracic surgery has significantly contributed to the management and outcome of complicated GTN patients, and suggests when thoracic surgery should be considered in this rare group of patients.

Regional chemotherapy by isolated limb perfusion prior to surgery compared with surgery and post-operative radiotherapy for primary, locally advanced extremity sarcoma: a comparison of matched cohorts.

BACKGROUND: Induction chemotherapy by isolated limb perfusion (ILP) with melphalan and tumour necrosis factor-α is an effective strategy to facilitate limb-conserving surgery in locally advanced extremity sarcoma. In a comparison of cohorts matched for grade, size and surgical resectability, we compared the outcome of patients undergoing induction ILP prior to limb-conserving surgery and selective post-operative radiotherapy with patients undergoing limb-conserving surgery and routine post-operative radiotherapy. METHODS: Patients with primary, grade 2/3 sarcomas of the lower limbs over 10 cm in size were identified from prospectively maintained databases at 3 centres. Patients treated at a UK centre underwent limb-conserving surgery and post-operative radiotherapy (Standard cohort). Patients at two German centres underwent induction ILP, limb-conserving surgery and selective post-operative radiotherapy (ILP cohort). RESULTS: The Standard cohort comprised 80 patients and the ILP cohort 44 patients. Both cohorts were closely matched in terms of tumour size, grade, histological subtype and surgical resectability. The median age was greater in the Standard vs the ILP cohort (60.5 years vs 56 years, p = 0.033). The median size was 13 cm in both cohorts. 5-year local-recurrence (ILP 12.2%, Standard 20.1%, p = 0.375) and distant metastases-free survival rates (ILP 49.6%, Standard 46.0% p = 0.821) did not differ significantly between cohorts. Fewer patients received post-operative radiotherapy in the ILP cohort compared with the Standard cohort (27% vs 82%, p < 0.001). CONCLUSION: In comparative cohorts, the outcomes of patients undergoing induction ILP prior to surgery did not differ from those undergoing standard management, although induction ILP was associated with a reduced need for adjuvant radiation.

Genetically modified lentiviruses that preserve microvascular function protect against late radiation damage in normal tissues.

Improvements in cancer survival mean that long-term toxicities, which contribute to the morbidity of cancer survivorship, are being increasingly recognized. Late adverse effects (LAEs) in normal tissues after radiotherapy (RT) are characterized by vascular dysfunction and fibrosis causing volume loss and tissue contracture, for example, in the free flaps used for immediate breast reconstruction after mastectomy. We evaluated the efficacy of lentivirally delivered superoxide dismutase 2 (SOD2) overexpression and connective tissue growth factor (CTGF) knockdown by short hairpin RNA in reducing the severity of LAEs in an animal model of free flap LAEs. Vectors were delivered by intra-arterial injection, ex vivo, to target the vascular compartment. LVSOD2 and LVshCTGF monotherapy before irradiation resulted in preservation of flap volume or reduction in skin contracture, respectively. Flaps transduced with combination therapy experienced improvements in both volume loss and skin contracture. Both therapies reduced the fibrotic burden after irradiation. LAEs were associated with impaired vascular perfusion, loss of endothelial permeability, and stromal hypoxia, which were all reversed in the treatment model. Using a tumor recurrence model, we showed that SOD2 overexpression in normal tissues did not compromise the efficacy of RT against tumor cells but appeared to enhance it. LVSOD2 and LVshCTGF combination therapy by targeted, intravascular delivery reduced LAE severities in normal tissues without compromising the efficacy of RT and warrants translational evaluation as a free flap-targeted gene therapy.

Increased haemoglobin A2 percentage in HIV infection: disease or treatment?

An elevated haemoglobin A2 percentage has been reported in HIV-infected patients, possibly attributable to therapy. In cross-sectional and cohort studies we have established that A2 is often elevated in untreated patients; a further rise during treatment is attributable specifically to zidovudine. The haemoglobin A2 may be high enough to lead to a misdiagnosis of beta thalassemia trait if there is a lack of awareness of this unexpected effect of HIV infection and its treatment.

An atypical presentation of small bowel obstruction and perforation secondary to sporadic synchronous intra-abdominal desmoid tumours.

INTRODUCTION: Desmoid tumours (DTs) are rare, soft tissue tumours which account for 0.03% of all neoplasms. They are characteristically locally invasive but do not metastasize. There is frequent association with females of reproductive age, a history of abdominal surgery or trauma and a family history of fibromatoses. Intra-abdominal DTs are infrequently sporadic and more commonly associated with inherited disorders such as familial adenomatous polyposis (FAP), attenuated FAP and Gardener's syndrome. PRESENTATION OF CASE: The authors report a rare case of small bowel obstruction and perforation secondary to sporadic, synchronous intra-abdominal DTs in a 54-year old man with atypical symptoms and no risk factors or family history. DISCUSSION: Intra-abdominal DTs have a worse prognosis as they can cause intestinal bleeding, obstruction and perforation. Due to the rarity of these tumours there are no clear guidelines on their management and this is instead based on small case series from specialist centres. In the non-acute setting patients with sporadic intra-abdominal DTs should be managed in a specialist sarcoma unit by a multidisciplinary team. In the presence of FAP or other polyposis syndromes patients with DTs should be managed at a specialist colorectal unit. Emergent presentations require emergency surgery in suitable candidates. CONCLUSION: In non-emergency presentations of DTs, it is essential to exclude FAP, AFAP and other hereditary polyposis syndromes since this affects treatment and subsequent follow-up.

Enhanced cytotoxicity of reovirus and radiotherapy in melanoma cells is mediated through increased viral replication and mitochondrial apoptotic signalling.

Oncolytic viruses selectively target and replicate in cancer cells, providing us with a unique tool with which to target and kill tumour cells. These viruses come from a diverse range of viral families including reovirus type 3 Dearing (RT3D), a non-pathogenic human double-stranded RNA oncolytic virus, which has been shown to be an effective therapeutic agent, both as a mono-therapy and in combination with traditional chemotherapeutic drugs. This study investigated the interaction between RT3D and radiotherapy in melanoma cell lines with a BRAF mutant, Ras mutant or BRAF/Ras wild type genotype. The data indicates that RT3D combined with radiotherapy significantly increased cytotoxicity relative to either single agent, independent of genotype, both in vitro and in vivo. The mechanism of enhanced cytotoxicity was dependent on an increase in viral replication, mediated by CUG2 up-regulation and subsequent down-regulation of pPKR and p-eIF2α, leading to the activation of mitochondrial apoptotic signalling resulting in increased cell death.

Oncolytic vaccinia virus combined with radiotherapy induces apoptotic cell death in sarcoma cells by down-regulating the inhibitors of apoptosis.

Advanced extremity melanoma and sarcoma present a significant therapeutic challenge, requiring multimodality therapy to treat or even palliate disease. These aggressive tumours are relatively chemo-resistant, therefore new treatment approaches are urgently required. We have previously reported on the efficacy of oncolytic virotherapy (OV) delivered by isolated limb perfusion. In this report, we have improved therapeutic outcomes by combining OV with radiotherapy. In vitro, the combination of oncolytic vaccinia virus (GLV-1h68) and radiotherapy demonstrated synergistic cytotoxicity. This effect was not due to increased viral replication, but mediated through induction of intrinsic apoptosis. GLV-1h68 therapy downregulated the anti-apoptotic BCL-2 proteins (MCL-1 and BCL-XL) and the downstream inhibitors of apoptosis, resulting in cleavage of effector caspases 3 and 7. In an in vivo ILP model, the combination of OV and radiotherapy significantly delayed tumour growth and prolonged survival compared to single agent therapy. These data suggest that the virally-mediated down-regulation of anti-apoptotic proteins may increase the sensitivity of tumour cells to the cytotoxic effects of ionizing radiation. Oncolytic virotherapy represents an exciting candidate for clinical development when delivered by ILP. Its ability to overcome anti-apoptotic signals within tumour cells points the way to further development in combination with conventional anti-cancer therapies.

Prevalence and correlates of cell phone use among Texas drivers.

INTRODUCTION: Cell phone use while driving restricts peripheral awareness and impairs reaction time. This study assessed the 3-year prevalence of cell phone use (CPU) of drivers and characteristics associated with its use in six cities across Texas, 2011-2013. METHODS: CPU and driver characteristics were observed among motor vehicles (n = 1280) stopped at major intersections in medical and academic campuses. A multivariable logistic regression model described the association between driver characteristics and CPU. RESULTS: The overall prevalence of any CPU was 18.7%. Any type of CPU and talking tended to decline, while texting seemed to increase from 2011 to 2013. CPU was more likely among female drivers (OR = 1.63; 95% CI = 1.21, 2.20), drivers < 25 years of age (OR = 4.12; 95% CI = 2.29, 7.39), and drivers without passengers (OR = 4.40; 95% CI = 2.82, 6.88). CONCLUSION: Despite its dangers, CPU remains popular among Texas drivers. CPU and texting bans should target public health campaigns towards female and younger drivers.

Adenovirally delivered enzyme prodrug therapy with herpes simplex virus-thymidine kinase in composite tissue free flaps shows therapeutic efficacy in rat models of glioma.

INTRODUCTION: Free flap gene therapy exploits a novel therapeutic window when viral vectors can be delivered into a flap ex vivo. The authors investigated the therapeutic potential of an adenovirally-delivered thymidine kinase/ganciclovir prodrug system expressed following vector delivery into a free flap. METHODS: The authors demonstrated direct in vitro cytotoxicity by treating a panel of malignant cell lines with the thymidine kinase/ganciclovir system and demonstrated significant cell kill proportional to the multiplicity of infection of adenoviral vector expressing thymidine kinase. Bystander cytotoxicity was demonstrated using conditioned media from producer cells (expressing adenovirally-delivered thymidine kinase and treated with ganciclovir) to demonstrate cytotoxicity in naive tumor cells. The authors investigated the effect of adenoviral vector expressing thymidine kinase/ganciclovir therapy in vivo, using models of microscopic and macroscopic residual disease in a rodent superficial inferior epigastric artery flap model. RESULTS: The authors observed retardation of tumor volume growth in both microscopic (p = 0.0004) and macroscopic (p = 0.0005) residual disease models and prolongation of animal survival. Gene expression studies demonstrated that viral genomic material was found predominantly in flap tissues but declined over time. CONCLUSIONS: The authors describe the utility of virally delivered enzyme/prodrug therapy, using a free flap as a vehicle for delivery. They discuss the merits and limitations of this approach and the unique role of therapeutic free flaps among reconstructive techniques available to the plastic surgeon.

Adiposity predicts self-reported frequency of poor health days among male firefighters.

OBJECTIVE: Quantify the association between adiposity and frequency of self-reported poor health days among male firefighters. METHODS: Measures were taken for body mass index, waist circumference, and percentage of body fat. Firefighters self-reported the outcome of the number of poor health days in the past 30 days. Zero-inflated negative binomial models and fractional polynomial plots were used to determine the impact of adiposity on the frequency of self-reported poor health days. RESULTS: Body mass index (rate ratio [RR]: 1.037; 95% confidence interval [CI]: 1.003 to 1.073), waist circumference (RR: 1.012; 95% CI: 0.999 to 1.030), and percentage of body fat (RR: 1.021; 95% CI: 0.999 to 1.041) were associated with self-reported poor health days. CONCLUSIONS: Adiposity is positively associated with frequency of self-reported poor health days among male firefighters. Future efforts to improve health among firefighters should emphasize reductions in adiposity.