Tumor- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review.

Abstract

Background:Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAbs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1) produce unique toxicity profiles. The objective of this review was to identify patterns and incidence of immune related adverse events (irAE) based on tumor type and ICI class.Methods:MEDLINE, EMBASE and COCHRANE databases were searched to identify prospective monotherapy trials of ICIs from 2003 to November 2015. Paired reviewers selected studies for inclusion and extracted data. Odds ratio (OR), chi-squared tests and multivariable regression models were used to analyze for effect size and associations.Results:We identified 48 trials (6938 patients), including 26 CTLA-4, 17 PD-1, 2 PD-L1 trials, and 3 studies tested both CTLA-4 and PD-1. Grade 3/4 irAE were more common with CTLA-4 mAbs compared with PD-1 (31% vs 10%). All grades colitis (OR 8.7, CI 5.8-12.9), hypophysitis (6.5, 3.0-14.3) and rash (2.0, 1.8-2.3) were more frequent with CTLA-4 mAbs; whereas pneumonitis (6.4, 3.2-12.7), hypothyroidism (4.3, 2.9-6.3), arthralgia (3.5, 2.6-4.8) and vitiligo (3.5, 2.3-5.3) were more common with PD-1 mAbs. Comparison of irAE from the 3 most studied tumor types in PD-1 mAbs trials [melanoma (n = 2048), non-small cell lung cancer (n = 1030) and renal cell carcinoma (n = 573)] showed melanoma patients had a higher frequency of gastrointestinal and skin irAE and lower frequency of pneumonitis.Conclusions:CTLA-4 and PD-1 mAbs have distinct irAE profiles. Different immune microenvironments may drive histology-specific irAE patterns. Other tumor-dependent irAE profiles may be identified as data emerge from ICI trials.

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Identification and Characterization of Cadmium-Related Genes in Liver Carcinoma

Abstract

Evidence indicates that exposure to heavy trace element might be a risk factor for liver carcinoma. Cadmium has been supposed to be a carcinogen that has a correlation with the risk of a number of cancers, including liver cancer. However, the mechanisms underlying Cadmium-induced malignant transformation in liver cells are not fully understood. In the present study, we aimed to screen the differentially expressed genes (DEGs) that might play a role in both the Cadmium-related liver cell transformation and the development of liver cancer. Microarray-based gene expression profiles concerning liver carcinoma vs non-cancerous tissue (GSE64041) and Cadmium-treated liver cells vs controls (GSE8865 and GSE31286), respectively, were retrieved from Gene Expression Omnibus (GEO) database. Then, DEGs of each profile were calculated and screened. The intersection of each DEGs was obtained by Venn analysis. Afterwards, the possible roles of the selected genes in cancer development were evaluated by using Oncomine database and TCGA cohort analysis. Consequently, three DEGs, LRAT, SLC7A11, and ITGA2, were selected for further analysis. SLC7A11 and ITGA2, but not LRAT, were upregulated in liver cancer compared with those in normal tissues, respectively. After using a TCGA cohort analysis, results failed to show a significant correlation between SLC7A11 or ITGA2 expression and clinical parameters. However, the survival analysis showed that patients with high expression levels of SLC7A11 had a shorter overall survival time relative to those of the patients with low levels. In conclusion, SLC7A11 and ITGA2 might play a role in the Cadmium-induced liver cell damage or transformation, and the development of liver carcinoma. SLC7A11 might be a prognostic factor for patients with liver carcinoma. Future validation experiments are needed to verify the results.

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GSK2586184, a JAK1 selective inhibitor, in two patients with ulcerative colitis

Tofacitinib, a non-selective Janus kinase (JAK) inhibitor, is effective in inducing clinical and endoscopic remission in patients with active ulcerative colitis (UC). Tofacitinib inhibits cytokine signalling through blockade of JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Adverse events including neutropenia and anaemia resulting from JAK2 inhibition have been observed in actively treated patients. By selectively targeting JAK1, such adverse events could be expected to be avoided. This open label study was designed to enrol 15 patients with UC, however the trial was discontinued after two inclusions due to safety concerns with the agent in a parallel trial for systemic lupus erythematosus. GSK2586184 was administered in two patients with moderate-to-severe UC. The JAK1 selective inhibitor GSK2586184 was well tolerated and induced clinical and endoscopic response in two patients with moderate-to-severe UC. In addition, treatment with GSK2586184 decreased histology scores and faecal calprotectin levels at early withdrawal.

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Aggressive large-cell neuroendocrine carcinoma of the sigmoid colon in a patient with ulcerative colitis

Colonic inflammation seen in inflammatory bowel disease (IBD) predisposes to the development of colorectal adenocarcinoma. In contrast, colorectal neuroendocrine carcinomas (NECs) have rarely been reported in the setting of IBD, and no definitive relationship between these tumours and IBD has been established. Dysplasia from chronic inflammation leading to neuroendocrine cell differentiation may be responsible for NEC development, though this finding has not been seen consistently. We present a case of large-cell neuroendocrine carcinoma of the sigmoid colon in a 65-year-old woman with long-standing ulcerative colitis. Although she underwent regular endoscopic follow-ups and was receiving the tumour necrosis factor alpha inhibitor infliximab, her tumour was large and aggressive, with metastases to the liver discovered at time of diagnosis. This case highlights the aggressive nature and poor prognosis of NECs and stresses the need to identify patients at high risk of developing NECs and develop improved surveillance guidelines for detecting them.

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Rare combination of left-sided congenital diaphragmatic hernia and omphalocele

We reported a rare case of left-sided posterolateral congenital diaphragmatic hernia (CDH) and omphalocele, which is not associated with chromosomal abnormalities or other syndromes. Omphalocele was detected antenatally (CDH was not detected in antenatal ultrasound). The patient suffered from respiratory failure secondary to severe pulmonary hypertension. As the combination of CDH and omphalocele is rare and with the abdominal content herniating into the omphalocele instead of the thorax, antenatal diagnosis of such condition can be difficult. Unlike other reported cases in the literature, our patient's respiratory condition has been improving with time and is surviving beyond the infancy period. We believe this to be the first such survival case reported in the literature.

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Gallstone ileus of the duodenum: an unexpected presentation of Bouveret's syndrome

This report describes a patient who presented with a large gallstone obstructing the duodenal bulb, with the chief complaint of acute on chronic abdominal pain. Classically, this is known as Bouveret's syndrome or a gallstone ileus of the duodenum. Our patient's current health status presented a challenge, with the presence of several comorbidities, particularly a large abdominal aortic aneurism. We chose an open procedure for this reason. The stone was removed through a laparotomy, and the cholecystoduodenal fistula that the stone used to pass into the small bowel was repaired. With our patient's future medical needs in mind, only the necessary interventions were performed to regain functionality of the bowel. This came in the form of a diverting gastrojejunostomy, with a distal jejunostomy and feeding tube inserted. The patient tolerated the procedure well, only remaining intubated postoperative due to her chronic obstructive pulmonary disease (COPD). She achieved a complete recovery and transitioned home.

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Splenic rupture following synchronised direct current cardioversion

Atraumatic rupture of the normal spleen is a rare entity. Often, a triggering factor or minor physical event can be ascribed as the aetiology for rupture, including coughing, vomiting or minor medical procedures not involving the spleen. A 65-year-old man who was hospitalised for eosinophilic pneumonia developed haemodynamically unstable atrial flutter that necessitated urgent synchronised direct current cardioversion (DCCV). Two hours after successful cardioversion, he developed signs of an acute abdomen with free intraperitoneal fluid identified on bedside ultrasonography. Exploratory laparotomy revealed gross haemoperitoneum and splenic rupture requiring splenectomy. With exception of capsular defects and haemorrhage suggestive of organ rupture, the gross and histological examination of the spleen was otherwise unremarkable. The patient denied recent trauma. The cause of his spleen rupture was attributed to cardioversion and subsequent abdominal muscle contraction. This represents the first known case of splenic rupture associated with DCCV.

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Reduction en masse of inguinal hernia: a review of a rare and potential fatal complication following reduction of inguinal hernia

Reduction en masse is reduction of a hernial sac into the pre-peritoneal space with a loop of bowel remaining incarcerated at the neck of the sac, leading to early strangulation. This is a rare complication, usually encountered with inguinal hernias, with a false reassurance to the patient and the treating physician that complete reduction has been achieved. Unless early intervention is carried out, this condition will typically present with worsening pain and absence of an appreciable hernia bulge at the groin, and intestinal necrosis may be encountered on exploration. The outcome will depend on the severity of peritonitis/sepsis, and mortality remains high for late presentations. A case of early presentation of reduction en masse of an inguinal hernia is reported with a review of the existing literature.

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Orbital multiple myeloma: a diagnostic challenge

Orbital involvement in multiple myeloma is unusual. We describe the case of an 85-year-old woman who presented with right eye proptosis, reduced visual acuity and diplopia. Computed tomography showed a lobulated, enhancing soft tissue mass arising from the right greater wing of the sphenoid with intraconal, lacrimal gland and ocular muscle involvement. Histopathology revealed predominantly atypical plasma cells in a background of reactive lymphocytes, with monoclonality towards kappa light chain protein, suggestive of multiple myeloma. This case illustrates the diagnostic imaging challenge of orbital multiple myeloma.

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Paraneoplastic cerebellar degeneration secondary to ovarian carcinosarcoma: a cerebellar conundrum

We present a case of an elderly female patient who presented with a 6-month history of progressive slurred speech, vertigo, unsteadiness and falls. She underwent an extensive battery of neurological and cardiovascular investigations, none of which demonstrated a diagnostic cause for her symptoms. She was referred to the stroke and neurology teams and was started on treatment for presumed anxiety. As her symptoms continued to progress, she was referred to the falls service. Following a multidisciplinary team discussion, she was reviewed by the consultant geriatrician who felt this may be due to a malignancy so the consultant geriatrician arranged blood testsand CT scan of her chest, abdomen and pelvis. These demonstrated a large left adnexal mass and a raised Ca-125 level. The patient was diagnosed with an ovarian tumour, which was treated surgically. A provisional diagnosis of paraneoplastic cerebellar degeneration, secondary to ovarian carcinosarcoma, was made.

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Missed diaphragmatic injury after blunt trauma presenting with colonic strangulation: a rare scenario

Diaphragmatic rupture occurs in 4%–5% cases of thoracoabdominal injuries. It may present acutely, in a delayed fashion or as a complicated hernia. We are describing the case of a young male presenting in respiratory distress with history of chest trauma 1.5 years back. On investigation, he was found to have left side diaphragmatic hernia containing gangrenous colon with lung collapse. The patient underwent successful operative intervention and discharged after 25 days of hospital stay. Record review suggested that the above mentioned diaphragm injury was missed in his evaluation 1.5 years back. Diaphragmatic injury must always be suspected in thoracoabdominal injuries, as missed injury may cause devastating complications like the one narrated above in due course.

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An uncommon hip pain

Description

A 55-year-old man with a medical history of hypertension and dyslipidaemia, presented to our Hip clinic with non-traumatic left hip pain of five months duration. The pain was  insidious in onset and gradually progressive. The pain  aggravated on , prolonged sitting or squatting, and relieved with rest. There was no history of any constitutional symptoms. The gait of the patient was essentially normal. There was tenderness over the anterior joint line and mild pain on flexion and internal rotation of the hip. There was no limb length discrepancy or wasting of the adjacent muscles. Distal neurovascular examination was normal.

A plain X-ray of the pelvis showed an ill-defined expansile lytic lesion involving the left superior pubic ramus with sclerotic margins and few internal septations (figure 1). Further CT and MRI scans defined the extent of the lesion (figure 2A,B,C and 3A,B,C). Through a Pfannenstiel incision, the lesion in the...

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Abdominal aortic aneurysm in the setting of Clostridium perfringens pancreatitis

We report a case of a 56-year-old woman who presented with worsening abdominal pain located in the left upper quadrant together with abdominal distention, nausea and anorexia. One month prior to this admission, she had presented and had been diagnosed with concurrent acute pancreatitis and rapidly expanding abdominal aortic aneurysm. The aneurysm was prioritised over the pancreatitis and she underwent uncomplicated endovascular repair. Cross-sectional imaging was consistent with infected pancreatic necrosis and also revealed a large collection located in the anterior pararenal space with extensive gas formation. An image-guided fluid aspiration revealed Clostridium perfringens as the causative organism. She was treated by placement of large bore drains along with irrigation and targeted intravenous antibiotic for 6 weeks. The collections resolved completely and at 6 months follow-up she was well and symptom free.

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Cognitive and Occupational Function in Survivors of Adolescent Cancer

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Am I a 6 or a 10? Mate Value Among Young Adult Survivors of Childhood Cancer and Healthy Peers

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Three-year cytohistological correlation of salivary gland FNA cytology at a tertiary center with the application of the Milan system for risk stratification

BACKGROUND

Fine-needle aspiration (FNA) cytology of salivary glands is a well-established technique that plays a critical role in the preoperative diagnosis of lesions. A risk stratification of FNA diagnostic categories has been recently proposed to be useful in reporting. The aims of this study were to evaluate the diagnostic accuracy of salivary gland FNA and to apply the proposed Milan system for reporting salivary gland lesions.

METHODS

A retrospective audit of FNA specimens of salivary gland lesions reported from 2014 to 2016 was performed. A correlation with the follow-up histopathology, wherever it was available, was performed. The aspirates were then categorized according to the Milan system as follows: nondiagnostic, nonneoplastic, atypical, benign neoplasm, neoplasm of uncertain malignant potential (NUMP), suspicious for malignancy, or positive for malignancy. Furthermore, the risk of malignancy and the risk of high-grade malignancy were calculated for all diagnostic categories.

RESULTS

A total of 631 salivary gland aspirates were evaluated: 2.2% were nondiagnostic, 55.8% indicated nonneoplastic lesions, and 40.4% indicated neoplastic lesions. Histopathology was available for 94 cases (14.9%). FNA had a sensitivity of 79.4% and a specificity of 98.3% with an overall diagnostic accuracy of 91.4% for differentiating malignant tumors from benign tumors. The overall risk of malignancy was 17.4% for the nonneoplastic category, 100% for the atypical category, 7.3% for the benign neoplasm category, 50% for the NUMP category, and 96% for the positive-for-malignancy category.

CONCLUSIONS

Salivary gland FNA continues to have high diagnostic accuracy and is thus helpful for guiding management. Neoplasms with classic cytomorphology are easily diagnosed; however, in difficult cases showing overlapping features, the use of the Milan system could be beneficial. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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Double-blind, randomized phase 3 trial of low-dose 13-cis retinoic acid in the prevention of second primaries in head and neck cancer: Long-term follow-up of a trial of the Eastern Cooperative Oncology Group-ACRIN Cancer Research Group (C0590)

BACKGROUND

13-Cis retinoic acid (13-CRA) is a synthetic vitamin A derivative. High-dose 13-CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long-term results from a phase 3 randomized trial that compared treatment with low-dose 13-CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS).

METHODS

In total, 176 patients who received treatment for stage I/II SCCHN were randomized to receive either low-dose 13-CRA (weight-based dose of 7.5 mg or 10 mg) or placebo for 2 years. A competing-risk approach and the log-rank test were used to compare the time to SPT and OS, respectively, between groups.

RESULTS

13-CRA neither significantly reduced the cumulative incidence of SPT (P = .61) nor improved the time to SPT (hazard ratio [HR] for 13-CRA/placebo; 0.86; P = .61). Despite limited power, there was a trend toward improved OS for the 13-CRA arm (HR, 0.75; P = .14), particularly among patients whose index tumor was surgically excised (N = 26; HR, 0.50; P = .057) and among women (N = 39; HR, 0.44; P = .065) and never/former smokers (N = 129; HR, 0.61; P = .055), with a median follow-up of 16 years. The main 13-CRA related toxicities were dry skin and cheilitis.

CONCLUSIONS

Treatment with low-dose 13-CRA for 2 years did not decrease the incidence of SPT; subset analysis indicates a potential survival advantage among patients who are women and never/former smokers. More targeted interventions based on clinical risk factors and molecular characterization of tumors may yield greater success in future prevention trials. Cancer 2017. © 2017 American Cancer Society.

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The novel microtubule targeting agent BAL101553 in combination with radiotherapy in treatment-refractory tumor models

Resistance to microtubule targeting agents (MTA) represents a major drawback in successful cancer therapy with MTAs. Here we investigated the combined treatment modality of the novel MTA BAL101553 in combination with radiotherapy in paclitaxel and epothilone-resistant tumor models.

http://ift.tt/2uk0Srm

4DCT imaging to assess radiomics feature stability: An investigation for thoracic cancers

Quantitative tissue characteristics derived from medical images, also called radiomics, contain valuable prognostic information in several tumour-sites. The large number of features available increases the risk of overfitting. Typically test–retest CT-scans are used to reduce dimensionality and select robust features. However, these scans are not always available. We propose to use different phases of respiratory-correlated 4D CT-scans (4DCT) as alternative.

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Gallbladder Adenocarcinoma as the First Manifestation of Germline BRCA1 Mutation

http://ift.tt/2wC0ocN

Six-Year Results From a Phase I/II Trial for Hypofractionated Accelerated Partial Breast Irradiation Using a 2-Day Dose Schedule.

Background: To report 6-year outcomes from a phase I/II trial using balloon-based brachytherapy to deliver APBI in 2 days. Methods: A total of 45 patients with early-stage breast cancer received adjuvant APBI in 2 days with high-dose rate (HDR) brachytherapy totaling 2800 cGy in 4 fractions (700 cGy BID) using a balloon-based applicator as part of a prospective phase I/II clinical trial. All patients had negative margins and skin spacing >=8 mm. We evaluated toxicities (CTCAE v3) as well as ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), distant metastasis, disease-free survival, cause-specific survival, and overall survival. Results: Median age and tumor size were 66 years old (48 to 83) and 0.8 cm (0.2 to 2.3 cm), respectively. Four percent of patients were N1 (n=2) and 73% were estrogen receptor (ER) positive (n=32). Median follow-up was 6.2 years (2.4 to 8.0 y). Nearly all toxicities at 6 years were grade 1 to 2 except 1 instance of grade 3 telangiectasia (2%). Eleven percent (n=5) of patients had chronic asymptomatic fat necrosis whereas asymptomatic seromas were noted on mammogram in 13% of cases (n=6). Cosmesis at last follow-up was good or excellent in 91% of cases (n=40) and fair in 9% (n=4). Two of the previously reported rib fractures healed with conservative measures. There were no IBTR or RNF (6 y IBTR/RNF rate 0%); however, 2 patients experienced distant metastasis (4% at 6 y). The 6-year actuarial disease-free survival, cause-specific survival, and overall survival were 96%, 100%, and 93%, respectively. Conclusions: Hypofractionated 2-day APBI using brachytherapy resulted in excellent clinical outcomes with acceptable chronic toxicities. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Journal Club.

No abstract available

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Brain Monitoring and the Depth of Anesthesia: Another Goldilocks Dilemma.

No abstract available

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Perioperative Acute Kidney Injury: An Under-recognized Problem.

The incidence of perioperative acute kidney injury (AKI) is more common than previously recognized, especially in high-risk patients undergoing higher risk procedures. The growing number of patients who develop perioperative AKI is related, in part, to the aging population and increase in the number of individuals with chronic comorbidities, particularly those with premorbid chronic kidney disease. Despite the acceptance of standardization in the definition of AKI, clinicians routinely underdiagnose it and fail to appreciate that it is associated with considerable morbidity and mortality. Unfortunately, few, if any, preemptive therapies have proven effective in preventing AKI. Timely diagnostic methods using evolving biomarkers raises the prospect of detection of kidney damage before the onset of irreversible loss of function, but remain under investigation. Clear evidence supporting any therapeutic intervention except renal replacement therapy remains elusive. Renal replacement therapy is indicated for select patients with progressive AKI; however, the ideal timing, method, and application of it remain under debate. It is fundamental to identify patients at risk for AKI. The Kidney Disease: Improving Global Outcomes guidelines suggest preventive strategies that include avoidance of nephrotoxic agents and hyperglycemia, optimization of hemodynamics, restoration of the circulating volume, and institution of functional hemodynamic monitoring. Clear evidence in support of this approach, however, is lacking. Recently, the perioperative administration of dexmedetomidine and the provision of remote ischemic preconditioning have been studied to potentially limit the development of perioperative AKI. This review discusses accepted standard definitions of AKI, highlights associated risk factors for its development, and provides an overview of its epidemiology and pathology. It emphasizes potential preventive strategies, the possible role of emerging biomarkers in defining its presence more expeditiously before irreversible injury, and current recommended guidelines and therapeutic approaches. The ultimate goal of this article is to bring to the attention of clinicians the seriousness of this potentially preventable or modifiable perioperative complication. (C) 2017 International Anesthesia Research Society

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Optimization of Endotracheal Tube Cuff Pressure by Monitoring CO2 Levels in the Subglottic Space in Mechanically Ventilated Patients: A Randomized Controlled Trial.

BACKGROUND: Many of the complications of mechanical ventilation are related to inappropriate endotracheal tube (ETT) cuff pressure. The aim of the current study was to evaluate the effectiveness of automatic cuff pressure closed-loop control in patients under prolonged intubation, where presence of carbon dioxide (CO2) in the subglottic space is used as an indicator for leaks. The primary outcome of the study is leakage around the cuff quantified using the area under the curve (AUC) of CO2 leakage over time. METHODS: This was a multicenter, prospective, randomized controlled, noninferiority trial including intensive care unit patients. All patients were intubated with the AnapnoGuard ETT, which has an extra lumen used to monitor CO2 levels in the subglottic space. The study group was connected to the AnapnoGuard system operating with cuff control adjusted automatically based on subglottic CO2 (automatic group). The control group was connected to the AnapnoGuard system, while cuff pressure was managed manually using a manometer 3 times/d (manual group). The system recorded around cuff CO2 leakage in both groups. RESULTS: Seventy-two patients were recruited and 64 included in the final analysis. The mean hourly around cuff CO2 leak (mm Hg AUC/h) was 0.22 +/- 0.32 in the manual group and 0.09 +/- 0.04 in the automatic group (P = .01) where the lower bound of the 1-sided 95% confidence interval was 0.05, demonstrating noninferiority (>-0.033). Additionally, the 2-sided 95% confidence interval was 0.010 to 0.196, showing superiority (>0.0) as well. Significant CO2 leakage (CO2 >2 mm Hg) was 0.027 +/- 0.057 (mm Hg AUC/h) in the automatic group versus 0.296 +/- 0.784 (mm Hg AUC/h) in the manual group (P = .025). In addition, cuff pressures were in the predefined safety range 97.6% of the time in the automatic group compared to 48.2% in the automatic group (P

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Fundamentals of Research Data and Variables: The Devil Is in the Details.

Designing, conducting, analyzing, reporting, and interpreting the findings of a research study require an understanding of the types and characteristics of data and variables. Descriptive statistics are typically used simply to calculate, describe, and summarize the collected research data in a logical, meaningful, and efficient way. Inferential statistics allow researchers to make a valid estimate of the association between an intervention and the treatment effect in a specific population, based upon their randomly collected, representative sample data. Categorical data can be either dichotomous or polytomous. Dichotomous data have only 2 categories, and thus are considered binary. Polytomous data have more than 2 categories. Unlike dichotomous and polytomous data, ordinal data are rank ordered, typically based on a numerical scale that is comprised of a small set of discrete classes or integers. Continuous data are measured on a continuum and can have any numeric value over this continuous range. Continuous data can be meaningfully divided into smaller and smaller or finer and finer increments, depending upon the precision of the measurement instrument. Interval data are a form of continuous data in which equal intervals represent equal differences in the property being measured. Ratio data are another form of continuous data, which have the same properties as interval data, plus a true definition of an absolute zero point, and the ratios of the values on the measurement scale make sense. The normal (Gaussian) distribution ("bell-shaped curve") is of the most common statistical distributions. Many applied inferential statistical tests are predicated on the assumption that the analyzed data follow a normal distribution. The histogram and the Q-Q plot are 2 graphical methods to assess if a set of data have a normal distribution (display "normality"). The Shapiro-Wilk test and the Kolmogorov-Smirnov test are 2 well-known and historically widely applied quantitative methods to assess for data normality. Parametric statistical tests make certain assumptions about the characteristics and/or parameters of the underlying population distribution upon which the test is based, whereas nonparametric tests make fewer or less rigorous assumptions. If the normality test concludes that the study data deviate significantly from a Gaussian distribution, rather than applying a less robust nonparametric test, the problem can potentially be remedied by judiciously and openly: (1) performing a data transformation of all the data values; or (2) eliminating any obvious data outlier(s). (C) 2017 International Anesthesia Research Society

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The Placement of Syringe Labels May Reduce Medication Errors and Cognitive Load.

No abstract available

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Microparticle Release During Normal Cesarean Delivery.

Coagulation increases during pregnancy and peaks during parturition. We hypothesized that an increase in microparticle (MP) levels in plasma occurs around the time of placental separation and subsides over several hours. We performed a prospective observational pilot study to investigate plasma MP levels in healthy parturients immediately before and after cesarean delivery. The primary outcome was MP levels at postdelivery time points compared to baseline levels. Samples underwent flow cytometry and staining to determine MP levels. Placental-derived MPs were further characterized for the presence of procoagulant proteins. Placental-derived MPs increased immediately after delivery before returning to baseline in healthy parturients. (C) 2017 International Anesthesia Research Society

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In Response.

No abstract available

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Repeated Administration of Amitriptyline in Neuropathic Pain: Modulation of the Noradrenergic Descending Inhibitory System.

BACKGROUND: The tricyclic antidepressant amitriptyline, the serotonin and noradrenaline reuptake inhibitor duloxetine, and gabapentinoids are first-line drugs for treatment of neuropathic pain. The analgesic effect of these drugs relates to brainstem-spinal descending noradrenergic systems. However, amitriptyline utilizes a variety of mechanisms for analgesia in neuropathic pain, and it is unclear which mechanism is most important. In the present study, we investigated the role of descending noradrenergic systems in the analgesic effect of these drugs for treatment of neuropathic pain. We also examined whether amitriptyline modifies the descending noradrenergic systems. METHODS: Seven days after L5 spinal nerve ligation (SNL), rats received N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg) to degenerate noradrenergic fibers. The rats then received 5 daily intraperitoneal injections of amitriptyline (10 mg/kg), duloxetine (10 mg/kg), pregabalin (10 mg/kg), or gabapentin (50 mg/kg) from 21 days after SNL surgery. Paw withdrawal thresholds were determined to assess the effect of the drugs on hyperalgesia after SNL. To determine whether 5 daily injections of amitriptyline activated noradrenergic neurons in the locus coeruleus (LC) and spinal cord with or without DSP-4 treatment, we performed immunohistochemistry using antibodies for c-Fos and dopamine beta-hydroxylase (D[beta]H). RESULTS: Five daily injections of amitriptyline, duloxetine, pregabalin, and gabapentin exerted antihyperalgesic effects in SNL rats (P

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Antiallodynic Effects of Endomorphin-1 and Endomorphin-2 in the Spared Nerve Injury Model of Neuropathic Pain in Mice.

BACKGROUND: The spared nerve injury (SNI) model is a new animal model that can mimic several characteristics of clinical neuropathic pain. Opioids are recommended as treatment of neuropathic pain. Therefore, the present study was conducted to investigate the antinociceptive effects of endomorphin-1 (EM-1) and endomorphin-2 (EM-2) given centrally and peripherally in the SNI model of neuropathic pain in mice. METHODS: The SNI model was made in mice by sparing the sural nerve intact, when the other 2 of 3 terminal branches of the sciatic nerve (common peroneal and tibial nerves) were tightly ligated and cut. Von Frey monofilaments were used to measure the SNI-induced mechanical allodynia-like behavior. The antiallodynic effects of EM-1 and EM-2 were determined after central and peripheral administration in the SNI model of neuropathic pain. Also, the specific opioid receptor antagonists were used to determine the opioid mechanisms of EMs involved in neuropathic pain. Values were expressed as the mean +/- standard deviation. RESULTS: Our results showed that the SNI mice developed prolonged mechanical allodynia-like behavior in ipsilateral paw after surgery, with the withdrawal threshold value being 0.061 +/- 0.02 g after 14 days. EM-1 and EM-2 produced significant antiallodynic effects in ipsilateral paw after intracerebroventricular (i.c.v.) administration, more effective than that of morphine. The peak withdrawal thresholds of 10 nmol EM-1 and EM-2 determined at 5 minutes after injection were 0.92 +/- 0.36 and 0.87 +/- 0.33 g, respectively, higher than that of morphine (0.46 +/- 0.20 g). Moreover, both EMs (10 nmol, i.c.v.) exerted significant antiallodynic effects in the contralateral paw, whereas no significant antinociceptive activity was seen after i.c.v. administration of morphine with equimolar dose. It was noteworthy that EM-1 and EM-2 produced antinociception through distinct [mu]1- and [mu]2-opioid receptor subtypes, and the EM-2-induced antiallodynia contained an additional component that was mediated by the release of endogenous dynorphin A, acting on [kappa]-opioid receptor. In addition, the antiallodynic activities of peripheral administration of EM-1, EM-2, and morphine were also investigated. Intraplantar, but not subcutaneous administration of EM-1 and EM-2 also exhibited potent antinociception, establishing the peripheral and local effects. Both [mu]1- and [mu]2-opioid receptor subtypes, but not the [delta]- or [kappa]-opioid receptors were involved in the peripheral antiallodynia of EMs. CONCLUSIONS: The present investigation demonstrated that both EM-1 and EM-2 given centrally and peripherally produced potent antiallodynic activities in SNI mice, and differential opioid mechanisms were involved. (C) 2017 International Anesthesia Research Society

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Repeated Administration of Duloxetine Suppresses Neuropathic Pain by Accumulating Effects of Noradrenaline in the Spinal Cord.

BACKGROUND: Antidepressants are used to treat neuropathic pain and although the detailed mechanisms of their effects are unclear, the descending noradrenergic inhibitory system might play an important role. We tested our hypothesis that repeated administration of duloxetine suppresses neuropathic pain by restoring the descending noradrenergic inhibitory system in rats 6 weeks after spinal nerve ligation (SNL). METHODS: We subcutaneously injected SNL rats with duloxetine (10 mg kg-1 day-1) daily for 3 consecutive days and assessed behavioral hypersensitivity and noxious stimulus-induced analgesia (NSIA) activated by subcutaneous injection of capsaicin. We also performed microdialysis studies of the spinal cord, noradrenaline measurements of homogenized lumbar spinal tissue, and immunohistochemistry of the locus coeruleus. RESULTS: Three daily injections of duloxetine attenuated the mechanical hyperalgesia induced by SNL (SNL treated with vehicle: 88 +/- 9.4 g versus SNL treated with duloxetine: 148 +/- 13 g, P

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Low dose arsenite confers resistance to UV induced apoptosis via p53-MDM2 pathway in ketatinocytes

Low dose arsenite confers resistance to UV induced apoptosis via p53-MDM2 pathway in ketatinocytes

Oncogenesis 6, e370 (August 2017). doi:10.1038/oncsis.2017.67

Authors: Y Zhou, W Zeng, M Qi, Y Duan, J Su, S Zhao, W Zhong, M Gao, F Li, Y He, X Hu, X Xu, X Chen, C Peng & J Zhang

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Lysine demethylase KDM2A inhibits TET2 to promote DNA methylation and silencing of tumor suppressor genes in breast cancer

Lysine demethylase KDM2A inhibits TET2 to promote DNA methylation and silencing of tumor suppressor genes in breast cancer

Oncogenesis 6, e369 (August 2017). doi:10.1038/oncsis.2017.71

Authors: J-Y Chen, C-W Luo, Y-S Lai, C-C Wu & W-C Hung

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Inadequately Staged Endometrial Cancer: a Clinical Dilemma

Abstract

Incidental diagnosis of carcinoma endometrium following hysterectomy requires clinical expertise from a gynecologic oncologist, with regard to subsequent management. We report our experience with completion staging in endometrial cancer, to determine the benefits and risks of completion staging in women with posthysterectomy diagnosis of endometrial cancer. Design: A retrospective case series of 20 women with postoperative diagnosis of endometrial cancer, who had undergone completion staging. Setting: A gynaecologic oncology unit in a tertiary level hospital in Tamil Nadu, India. Patients: Electronic medical records of patients who underwent completion staging between January 2011 and December 2014 for endometrial cancer were reviewed. Two hundred and sixty four women with endometrial cancer were evaluated during this period. Twenty women with carcinoma endometrium, with a mean age of 53 (range 31–67) who were previously inadequately staged, were found to be at risk of extrauterine disease, following histopathological review, consented to undergo completion staging over an average of 57 days (range 30–91) following the initial surgery. Forty-five percent (9/20) had a BMI of more than 30, and 40% (8/20) had metabolic syndrome. The most common indications for the initial surgery were perimenopausal abnormal uterine bleeding and postmenopausal bleeding. Only eight patients had a pre-hysterectomy endometrial sampling/biopsy (40%) of whom, one had a pre-operative diagnosis of carcinoma endometrium. Sixteen (80%) had pathological risk factors for lymph nodal involvement and in the others, besides histological grading, surgicopathological details for risk assessment were unavailable. Adnexae were retained in 11, and uterus was bisected/cored during surgery in three women. Following completion staging, 5/20 (25%) patients were upstaged, 9 (45%) required no adjuvant treatment, 5 required vaginal brachytherapy therapy alone and 5 were advised chemotherapy and radiation. Two patients during the study period of 48 months had disease recurrence, and two women died of disease progression. Complications of surgery included the following: iliac vein injury (1) and bladder injury (1). Patients with incidental diagnosis of endometrial cancer following hysterectomy after clinical and radiological assessment and histopathological review, should be offered completion staging, if at risk for extrauterine disease. Completion staging permits appropriate prognostication of disease and thereby allows tailoring of adjuvant treatment, avoiding risks of overtreatment and undertreatment.

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Congress Report ESMO 2017

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“First in Human” Documentary Highlights NCI Immunotherapy Research

The Discovery Channel special, First in Human, will feature some of the groundbreaking work on cancer immunotherapy being done at the NIH Clinical Center, including CAR T-cell therapy and TIL therapy.

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Prognosis of Signet Ring Cell Carcinoma of the Colon and Rectum and their Distinction of Mucinous Adenocarcinoma with Signet Ring Cells. A Comparative Study

Abstract

Signet ring cell carcinoma (SRCC) of the colorectum is very rare, comprising between <1% and 2.4% cases of colorectal cancer. Patients' prognoses are poor. Several case reports had described as SRCC cases that are mucinous adenocarcinomas (MAC) with signet ring cells (SRC). In order to clearly delineate between MAC with SRC and SRCC, we performed a retrospective study at a national cancer referral center in which survival and clinicopathological characteristics between these two forms were compared and also SRCC were characterized by immunohistochemistry. We retrieved 32 cases that had been classified as either SRCC or MAC with SRC subtypes. It was noted that SRCC patients presented at older ages, demonstrated more advanced clinical stages, lymphovascular invasion, lymph node metastases, and higher carcinoembrionic levels than MAC with SRC patients. Regarding SRCC immunophenotype, 50% showed loss of CDX2 expression, 33% were CK20 negative, 41.7% were CK7 positive, and 25% were negative for both CK7 and CK20. For the MAC with SRC and SRCC groups, the median disease-specific survival (DSS) was 46.1 months (95% CI 36.9–55.25) and 22.4 months (95% CI 5.1–39.7 [p = 0.039]), respectively. The 3-year DSS was 80.7% and 28.6% (p = 0.017) for the MAC and SRCC patients, respectively. Univariate and multivariate analyses showed that SRCC was associated with decreased survival. SRCC had several clinicopathological features that permitted differentiation of MAC with SRC from SRCC patients, who had a poor DSS. A differential diagnosis for metastatic gastric cancer is only possible with a good clinicopathological correlation.

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Prognosis of Signet Ring Cell Carcinoma of the Colon and Rectum and their Distinction of Mucinous Adenocarcinoma with Signet Ring Cells. A Comparative Study

Abstract

Signet ring cell carcinoma (SRCC) of the colorectum is very rare, comprising between <1% and 2.4% cases of colorectal cancer. Patients' prognoses are poor. Several case reports had described as SRCC cases that are mucinous adenocarcinomas (MAC) with signet ring cells (SRC). In order to clearly delineate between MAC with SRC and SRCC, we performed a retrospective study at a national cancer referral center in which survival and clinicopathological characteristics between these two forms were compared and also SRCC were characterized by immunohistochemistry. We retrieved 32 cases that had been classified as either SRCC or MAC with SRC subtypes. It was noted that SRCC patients presented at older ages, demonstrated more advanced clinical stages, lymphovascular invasion, lymph node metastases, and higher carcinoembrionic levels than MAC with SRC patients. Regarding SRCC immunophenotype, 50% showed loss of CDX2 expression, 33% were CK20 negative, 41.7% were CK7 positive, and 25% were negative for both CK7 and CK20. For the MAC with SRC and SRCC groups, the median disease-specific survival (DSS) was 46.1 months (95% CI 36.9–55.25) and 22.4 months (95% CI 5.1–39.7 [p = 0.039]), respectively. The 3-year DSS was 80.7% and 28.6% (p = 0.017) for the MAC and SRCC patients, respectively. Univariate and multivariate analyses showed that SRCC was associated with decreased survival. SRCC had several clinicopathological features that permitted differentiation of MAC with SRC from SRCC patients, who had a poor DSS. A differential diagnosis for metastatic gastric cancer is only possible with a good clinicopathological correlation.

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Allicin ameliorates doxorubicin-induced cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis

Abstract

Purpose

Doxorubicin (DOX) is a highly active antineoplastic agent; however, its clinical use is limited due to associated cardiotoxicity. This study was performed to evaluate the beneficial effects of allicin, a dietary garlic active constituent against DOX-induced cardiotoxicity.

Methods

Forty male Swiss albino mice were divided into five groups, which received normal saline, oral allicin (20 mg kg⁻¹ once daily), intraperitoneal DOX (on the 7, 9 and 11th day of the experiment), or DOX plus once daily allicin at 10 or 20 mg kg⁻¹. Sera were collected for evaluation of cardiac injury markers and proinflammatory cytokines. Additionally, heart tissue spacemen were harvested for determination of oxidative stress markers, as well as for histopathological examination and immunohistochemical analysis.

Results

DOX administration induced significant (p < 0.05) reductions in cardiac tissue level of reduced glutathione and activities of antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase). Moreover, it induced significant (p < 0.05) elevations in cardiac tissue concentrations of nitric oxide and malondialdehyde as well as serum levels of cardiac injury biomarkers (lactate dehydrogenase, creatine kinase, and creatine kinase-MB) and proinflammatory cytokines (interleukin-1β, and tumor necrosis factor-alpha). The histopathological examination showed necrotic and degenerative changes in the cardiac tissue, while immunohistochemical analysis revealed marked myocardial expression of activated caspase-3 and cyclooxygenase-2, following DOX adminstration. Allicin pretreatment significantly improved (p < 0.05) all examined parameters, and restored the cardiac architecture.

Conclusion

The current study demonstrated that allicin effectively mitigates cardiac oxidative damage, apoptosis and inflammation, induced by acute DOX intoxication. Therefore, allicin could be a promising cytoprotective agent against DOX cardiotoxicity.

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NCCN News

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Oncology Research Program

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Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology

Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

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When It's Really Good, We Know It!

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Costs and Benefits of Extended Endocrine Strategies for Premenopausal Breast Cancer

Background: After completing 5 years of adjuvant tamoxifen, women with estrogen receptor (ER)–positive breast cancer benefit from 5 more years of endocrine therapy, either with tamoxifen or an aromatase inhibitor (AI). For premenopausal women, ovarian ablation (OA) would be required before starting an AI (OA/AI). According to the SOFT/TEXT studies, OA/AI improves 5-year disease-free survival compared with tamoxifen alone, suggesting that OA/AI could be superior to tamoxifen as extended endocrine therapy. The long-term costs and consequences of premature menopause from OA are unknown, but could be estimated through a cost-effectiveness analysis. Methods: A Markov chain Monte Carlo simulation model estimated the costs and benefits of 3 extended endocrine strategies in a hypothetical cohort of premenopausal women with ER-positive early breast cancer: (1) no further treatment; (2) tamoxifen for 5 years (extended tamoxifen); or (3) OA/AI for 5 years. Effectiveness was measured in years of life expectancy gain. Sensitivity analyses accounted for uncertainty surrounding various parameters. Monte Carlo simulation estimated the number of adverse events and deaths from each strategy in the US population over a 40-year period. Results: Extended tamoxifen yielded a higher average life expectancy gain than OA/AI (17.31 vs 17.06 years) at lower average cost ($3,550 vs $14,312). For 18,000 premenopausal ER-positive women, the simulation estimated 13,236, 12,557, and 11,338 deaths with no further treatment, extended tamoxifen, and OA/AI, respectively, but an additional 1,897 deaths from OA, for a total of 13,235 deaths associated with OA/AI. After 24.6 years of follow-up, more women are expected to die from OA/AI than extended tamoxifen. Conclusions: For premenopausal women with ER-positive cancer who have completed adjuvant tamoxifen, another 5 years of tamoxifen is the preferable extended endocrine strategy. The potential long-term health consequences of OA could affect overall survival when it precedes the use of an AI.

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To the Editor: How Do We Solve This Confusion?

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Trends in Neoadjuvant Approaches in Pancreatic Cancer

Pancreatic cancer (PDAC) is an aggressive tumor type associated with development of micrometastasis at an early stage. In attempt to eradicate disseminated disease, neoadjuvant therapy has been explored in patients with resectable and borderline resectable PDAC. In large retrospective studies, neoadjuvant therapy was associated with better survival compared with upfront surgery. Previously, trials more commonly used radiotherapy (RT) with small doses of chemotherapy as radiosensitizers. Recent studies, however, have incorporated full systemic doses of chemotherapy with or without RT before surgery with the hope of achieving adequate systemic chemotherapy coverage and improving survival. Several phase II trials have shown encouraging clinical benefits using the neoadjuvant approach. Large cooperative group studies are exploring the role of neoadjuvant treatment with newer combination chemotherapy regimens and modern RT techniques, which will provide more evidence regarding the utility of this approach.

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Targeted MAPK Pathway Inhibitors in Patients With Disseminated Pilocytic Astrocytomas

This report presents a series of 5 pediatric patients with disseminated pilocytic astrocytomas and frequent nonfusion activating mutations. Genetic variants in these patients' tumors include BRAF p.Val600Glu, BRAF p.Val600Asp, and KRAS p.Gly60_Gln62ins7. The 2 patients with BRAF-mutated tumors were treated with dabrafenib or a combination of dabrafenib plus trametinib. The patients had either near complete resolution of the primary tumor (BRAF p.Val600Glu) or a stable primary tumor (BRAF p.Val600Asp). Both patients showed improvement in leptomeningeal dissemination without significant toxicity. Genomic testing of disseminated pilocytic astrocytomas, particularly those arising at extracerebellar locations, may result in the identification of mutations associated with ERK/MAPK activation. Patients with these activating mutations may benefit from targeted therapies.

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The Evolution of Metastatic Colorectal Cancer Clinical Trials: Application of the ASCO Framework for Assessing Value

Background: Phase III trials in metastatic colorectal cancer (mCRC) have collectively led to progressive advancements in patient outcomes over the past decades. This study characterizes the evolution of mCRC phase III trials through assessing the value of cancer therapy, as measured by the ASCO Value Framework. Methods: Phase III trial results of systemic therapy for mCRC published between 1980 and 2015 were identified, and their outcome, statistical significance, journal impact factor, and citation by the 2016 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CRC were recorded. For each trial, the net health benefit (NHB) score was calculated using the June 2015 (original) and May 2016 (revised) ASCO Value Framework: Advanced Disease. Results: There were 114 mCRC phase III trials eligible for calculation of the NHB score. Using the revised framework, the median NHB score was 4.6 (range, –30 to 43.5); 12% of trials received bonus points. Trials with statistically significant results had higher NHB scores compared with nonsignificant trials (median NHB score, 21.6 vs 2.9; P<.0001). Clinical trials cited in the NCCN Guidelines had higher NHB scores than those not cited (median score, 8.0 vs 0.3; P=.02). In multivariate linear regression analysis, the only significant predictor of high NHB score was statistically significant studies. Conclusions: The median NHB score for mCRC phase III trials was 4.6. Higher NHB scores are associated with statistically significant studies and are cited in the NCCN Guidelines, a surrogate for practice-changing trials. The 2016 ASCO Value Framework may not fully capture the benefits on an individual patient level.

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Neoadjuvant Treatment With Trastuzumab and FOLFOX Induces a Complete Pathologic Response in a Metastatic ERBB2 (HER2)-Amplified Duodenal Cancer

Overexpression of HER2 protein and amplification of the ERBB2 gene has been observed in various adenocarcinomas, providing a therapeutic target that can be used to extend the survival of a select cohort of patients. Anti-HER2 therapy has been successfully applied to gastric and colorectal cancers, but its use and potential benefit in small intestinal carcinomas is not well characterized. We applied anti-HER2 therapy to an ERBB2-amplified advanced duodenal adenocarcinoma, adding trastuzumab to FOLFOX in the neoadjuvant setting. A 61-year-old woman with an advanced duodenal cancer harboring an ERBB2 amplification received preoperative trastuzumab and FOLFOX. Restaging revealed significant tumor downstaging with no metastasis. After multidisciplinary assessment, she underwent pancreaticoduodenectomy. Final pathologic analysis revealed no residual invasive adenocarcinoma, consistent with a complete neoadjuvant treatment response. This case report emphasizes the need for further molecular characterization of small bowel cancers; genetic alterations may provide therapeutic targets to improve the prognosis of these rare and aggressive malignancies.

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Short- and Long-Term Survival in Metastatic Pancreatic Adenocarcinoma, 1993-2013

Background: During the past 2 decades, numerous clinical trials have focused on improving outcomes in patients with metastatic pancreatic cancer (mPDAC). The efficacy of new treatments has been demonstrated among highly selected patients in randomized phase III trials; hence, it is not clear to what extent these advances are reflected within the broader mPDAC population. Materials and Methods: Survival statistics were extracted from the SEER database for patients diagnosed with mPDAC between 1993 and 2013. Survival was analyzed using the Kaplan-Meier method and proportional hazard models. Results: The study population consisted of 57,263 patients diagnosed with mPDAC between 1993 and 2013; 52% were male, with a median age of 69 years (range, 15–104). Superior prognosis correlated with younger age, being married, tumor located within the head of the pancreas, lower grade disease, and more recent year of diagnosis. Median overall survival (OS) remained stable at 2 months between 1993 and 2013. Improvements in OS were seen for younger patients (age <50 years) and those with a more recent year of diagnosis (2009–2013). The percentage of patients who died within 2 months of initial diagnosis decreased between 1993 and 2013 (from 63.5% to 50.6%; P<.0001). The percentage of patients surviving ≥12 months improved from 4.9% in 1993 to 12.7% in 2013 (P<.0001). Conclusions: In recent years a modest improvement in OS has been seen among younger patients with mPDAC. The percentage of patients living beyond 1 year has significantly increased over time; however, the percentage of those dying within 2 months remains substantial.

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NCCN Guidelines Insights: Palliative Care, Version 2.2017

The NCCN Guidelines for Palliative Care provide interdisciplinary recommendations on palliative care for patients with cancer. These NCCN Guidelines Insights summarize and provide context for the updated guidelines recommendations regarding hospice and end-of-life (EOL) care. Updates for 2017 include revisions to and restructuring of the algorithms that address important EOL concerns. These recommendations were revised to provide clearer guidance for oncologists as they care for patients with cancer who are approaching the transition to EOL care. Recommendations for interventions and reassessment based on estimated life expectancy were streamlined and reprioritized to promote hospice referrals and improved EOL care.

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DNA Repair Dysfunction in Pancreatic Cancer: A Clinically Relevant Subtype for Drug Development

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a 5-year survival rate of ≤7% across all stages. The limited success of conventional therapies for PDAC is at least partially attributable to its genetic heterogeneity. Precision targeting of known PDAC subtypes may positively affect the outcome of this disease. An important actionable subtype in this cancer is associated with DNA repair dysfunction, including cases with germline BRCA mutations. This subtype can be targeted by inhibitors of poly(ADP-ribose) polymerase (PARP). BRCA mutation–associated PDAC may be the first biomarker-driven subtype in this disease that can be successfully targeted. However, DNA repair defects can extend beyond the narrow spectrum of BRCA1/2 mutations in PDAC and are present in a large proportion of patients with familial PDAC. This review describes the subgroup of patients with PDAC with aberrant DNA repair and discusses diagnostic and therapeutic options.

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Race- and Sex-Based Disparities in the Therapy and Outcomes of Squamous Cell Carcinoma of the Anus

Background: Squamous cell carcinoma of the anus (SCCA) is one of the few cancers with an increasing incidence in the United States. We aimed to characterize race- and sex-based disparities in receipt of therapy and overall survival (OS) of SCCA using the SEER database. Methods: Cases of locoregional SCCA (T2–T4 any N M0) diagnosed between 2000 and 2012 in the SEER database were included. Demographics, tumor characteristics, type of therapy, and outcomes were extracted. Univariable and multivariable Cox proportional hazard models were constructed to test factors associated with OS. Data were reported as hazard ratios (HRs) and 95% CIs. Results: A total of 7,882 cases of locoregional SCCA were identified, with a median age of 58 years, 61.2% of whom were women, and 86.3% were white. Most patients (82.3%) received radiation therapy (RT), with the lowest rate in black men (76.7%) and the highest in white women (86.1%). The median OS was 135 months; OS was lower in elderly patients (age ≥65 years; 68 months), men (108 months), blacks (109 months), and those who did not receive RT (121 months). In multivariable analysis, age (HR, 1.19; 95% CI, 1.17–1.21 per 5 years increase), sex (HR, 1.59; 95% CI, 1.47–1.73, men vs women), race (HR, 1.51; 95% CI, 1.34–1.71, black vs white), and RT (HR, 0.90; 95% CI, 0.82–0.99) were independently associated with OS (P<.05). Conclusions: Significant race- and sex-based disparities exist in survival of patients with locoregional SCCA. Further investigation into the causes of these disparities and methods for elimination are warranted.

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Acting on Rare Driver Alterations: Is Getting a Meaningful Response a Game of Chance or Scientific Rigor?

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Levels of activated platelet-derived microvesicles in patients with soft tissue sarcoma correlate with an increased risk of venous thromboembolism

Abstract

Background

Microvesicles are small vesicles expressing specific antigens from their cells of origin. Elevated levels of microvesicles have been shown to be associated with coagulation disorders as well as with different types of malignancies. This study aims to evaluate a possible correlation of different microvesicle subpopulations with a positive history of venous thromboembolism (VTE) in patients with soft tissue sarcoma.

Methods

Annexin V - positive microvesicles, leukocyte (CD45-positive), platelet (CD61-positive), activated platelet (CD62P-, CD63-positive), endothelium-derived (CD62E-positive) and tissue-factor (CD142-positive) microvesicles were identified in the peripheral blood of patients with soft tissue sarcoma (n = 39) and healthy controls (n = 17) using fluorescence-activated cell sorting (FACS).

Results

Both the total amount of Annexin V-positive microvesicles and levels of endothelium-derived (CD62E-positive) microvesicles were shown to decrease significantly after tumor resection (n = 18, p = 0.0395 and p = 0.0109, respectively). Furthermore, the total amount of Annexin V – positive microvesicles as well as leukocyte (CD45-positive) and endothelium-derived (CD62E-positive) microvesicles were significantly higher in patients with grade 3 (G3) soft tissue sarcoma (n = 9) compared to healthy controls (n = 17) (p = 0.0304, p = 0.0254 and p = 0.0357, respectively). Moreover, patients with G3 soft tissue sarcoma (n = 9) presented higher levels of Annexin V-positive and endothelium-derived (CD62E-positive) microvesicles compared to patients with grade 2 (G2) soft tissue sarcoma (n = 8) (p = 0.0483 and p = 0.0045). Patients with grade 1 (G1) soft tissue sarcoma (n = 3) presented with significantly lower levels of platelet (CD61-positive) microvesicles than patients with G3 soft tissue sarcoma (n = 9) (p = 0.0150).

In patients with a positive history of VTE (n = 11), significantly higher levels of activated platelet (CD62P- and CD63-positive) microvesicles (p = 0.0078 and p = 0.0450, respectively) were found compared to patients without a history of VTE (n = 28).

Conclusion

We found significantly higher levels of Annexin V-positive and endothelium-derived (CD62E-positive) microvesicles to be circulating in the peripheral blood of patients with G3 soft tissue sarcoma compared to patients with G2 soft tissue sarcoma. Furthermore, we showed that high counts of activated platelet-derived microvesicles correlate with the occurrence of VTE. Thus, the detection of these microvesicles might be an interesting new tool for early diagnosis of soft tissue sarcoma patients with increased risk for VTE, possibly facilitating VTE prevention by earlier use of thromboprophylaxis.

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Effects of the body mass index (BMI) on the surgical outcomes of laparoscopic fundoplication for gastro-esophageal reflux disease: a propensity score-matched analysis

Abstract

Purpose

In the present study, we examined how the body mass index (BMI) affected the outcomes of laparoscopic fundoplication for GERD in patients, whose backgrounds were matched in a propensity score-matched analysis.

Methods

We divided the patients into two groups (BMI <25 kg/m² and BMI ≥25 kg/m²). The following background information was matched for the propensity score-matched analysis: sex, age, degree of esophageal hiatal hernia, acid exposure time, and degree of reflux esophagitis. In total, 105 subjects were extracted in each group. The surgical outcomes and postoperative outcomes of patients with BMI <25 kg/m² (Group A) and those with BMI ≥25 kg/m² (Group B) were compared and examined.

Results

There were no differences in the surgical procedure, intraoperative complications, or estimated blood loss (p = 0.876, p = 0.516, p = 0.438, respectively); however, the operative time was significantly prolonged in Group B (p = 0.003). The rate of postoperative recurrence in Group A was 17% (15/87 patients), while that in Group B was 11% (12/91 patients), and did not differ to a statistically significant extent (p = 0.533).

Conclusions

Although the operative time for GERD in obese patients was prolonged in comparison with non-obese patients, there was no difference in the rate of postoperative recurrence.

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Specialized survivor clinic attendance increases adherence to cardiomyopathy screening guidelines in adult survivors of childhood cancer

Abstract

Purpose

To determine if attendance at a specialized clinic for adult survivors of childhood cancer is associated with better rates of adherence to the Children's Oncology Group (COG) Long-term Follow-up (LTFU) guidelines for cardiomyopathy screening.

Methods

We conducted a retrospective population-based study using administrative data in Ontario, Canada of 5-year survivors diagnosed between 1986 and 2005 at risk of therapy-related late cardiomyopathy. Patients were classified into three groups based on the recommended frequency of screening: annual, every 2 years, and every 5 years.

Results

Of 1811 eligible survivors followed for median 7.8 years (range 0–14.0), patients were adherent to screening for only 8.6% of their period of follow-up. Survivor clinic utilization had the strongest association with increased rates of adherence: when compared to no attendance, ≥ 5 clinic visits/10-year period had RR of adherence of 10.6 (95% CI 5.7–19.5) in the annual group, 3.3 (95% CI 2.3–4.8) in the every 2-year group, and 2.3 (95% CI 1.6–3.2) in the every 5-year group. Additional factors associated with increased adherence after adjusting for clinic attendance included annual assessment by a general practioner, female sex, diagnosis prior to 2003, and living in a rural area.

Conclusions

In a model of specialized survivor care, increased clinic utilization is associated with improved patient adherence to COG LTFU cardiomyopathy screening guidelines.

Implications for cancer survivors

Specialized survivor clinics may improve health outcomes in survivors through improved adherence to screening. However, rates of adherence remain suboptimal and further multifacetted strategies need to be explored to improve overall rates of screening in adult survivors of childhood cancer.

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Maternal Resveratrol Treatment Reduces the Risk of Mammary Carcinogenesis in Female Offspring Prenatally Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) presents adverse effects on breast development/carcinogenesis. This study aimed to identify the ability of resveratrol (Res) to modify the adverse effects of TCDD in a female offspring. Pregnant female Wistar rats were allocated into four groups: TCDD, TCDD + Res, Res, and control. TCDD (1 μg/kg) was orally administered as a single dose on gestational day (GD) 15, and Res was orally administered during GD10–21 and lactation at a dose of 20 mg/kg/day. Female offsprings were euthanized on a specific postnatal day (PND) for hormonal analysis (PND 22, 48–51), vaginal opening (PND 30–48), and mammary gland morphology (PND 22). Other females received two doses of N-nitroso-N-methylurea (MNU, 50 mg/kg) on PNDs 22 and 51 and were euthanized on PND 24 (Ki-67, ER-α and apoptosis indexes or molecular analysis) or PND 180 (tumor assay). TCDD exposure altered the development of the mammary structure while these alterations were partially improved by maternal Res. Two days after first MNU administration, some genes associated with apoptosis were altered in the mammary tissue from the TCDD group (Bax and Caspase 3 down- and Bcl-2 upregulated) but were also partially reestablished by maternal Res. Mammary gland bcl-2 and bcl-xl proteins expression was increased while the apoptosis index was reduced by TCDD exposure but restored by maternal Res. An increase in number of mammary tumors was observed in female offspring from the TCDD group compared to the other groups. The results indicate that most mammary changes induced in female offspring through TCDD exposure or after MNU administrations were reduced by maternal resveratrol treatment.

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Low-dose total skin electron beam therapy for cutaneous lymphoma

Abstract

Background

Low-dose total skin electron beam therapy (TSEBT) is attracting increased interest for the effective palliative treatment of primary cutaneous T‑cell lymphoma (pCTCL). In this study, we compared toxicity profiles following various radiation doses.

Patients and methods

We reviewed the records of 60 patients who underwent TSEBT for pCTCL between 2000 and 2016 at the University Hospital of Munster. The treatment characteristics of the radiotherapy (RT) regimens and adverse events (AEs) were then analyzed and compared.

Results

In total, 67 courses of TSEBT were administered to 60 patients. Of these patients, 34 (51%) received a standard dose with a median surface dose of 30 Gy and 33 patients (49%) received a low dose with the median surface dose of 12 Gy (7 salvage low-dose TSEBT courses were administered to 5 patients). After a median follow-up of 15 months, the overall AE rate was 100%, including 38 patients (57%) with grade 2 and 7 (10%) with grade 3 AEs. Patients treated with low-dose TSEBT had significantly fewer grade 2 AEs than those with conventional dose regimens (33 vs. 79%, P < 0.001). A lower grade 3 AE rate was also observed in patients who had received the low-dose regimen compared to those with the conventional dose regimens (6 vs. 15%, P = 0.78). Multiple/salvage low-dose TSEBT courses were not associated with an increased risk of acute AEs.

Conclusion

Low-dose TSEBT regimens are associated with significantly fewer grade 2 acute toxicities compared with conventional doses of TSEBT. Repeated/Salvage low-dose TSEBT, however, appears to be tolerable and can even be applied safely in patients with cutaneous relapses.

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RAS testing of liquid biopsy correlates with the outcome of metastatic colorectal cancer patients treated with first-line FOLFIRI plus cetuximab in the CAPRI-GOIM trial

Abstract

Background. Liquid biopsy is an alternative to tissue for RAS testing in metastatic colorectal carcinoma (mCRC) patients. Little information is available on the predictive role of liquid biopsy RAS testing in patients treated with first-line anti-EGFR monoclonal antibody (MoAb)-based therapy.Patients and Methods. In the CAPRI-GOIM trial, 340 KRAS exon-2 wild-type mCRC patients received first-line cetuximab plus FOLFIRI. Tumor samples were retrospectively assessed by Next Generation Sequencing (NGS). Baseline plasma samples were analyzed for KRAS and NRAS mutations using BEAMing Digital PCR. Discordant cases were solved by droplet digital PCR (ddPCR) or deep-sequencing.Results. A subgroup of 92 patients with available both NGS data on tumor samples and baseline plasma samples were included in this study. Both NGS analysis of tumor tissue and plasma testing with BEAMing identified RAS mutations in 33/92 patients (35.9%). However, 10 cases were RAS tissue mutant and plasma wild-type, and additional 10 cases were tissue wild-type and plasma mutant, resulting in a concordance rate of 78.3%. Analysis of plasma samples with ddPCR detected RAS mutations in 2/10 tissue mutant, plasma wild-type patients. In contrast, in all tissue wild-type and plasma mutant cases, ddPCR or deep-sequencing analysis of tumor tissue confirmed the presence of RAS mutations at allelic frequencies ranging between 0.15% and 1.15%. The median progression free survival (mPFS) of RAS mutant and wild-type patients according to tissue (7.9 vs 12.6 months; p = 0.004) and liquid biopsy testing (7.8 vs 13.8 moths; p < 0.001) were comparable. Similar findings were observed for the median overall survival (mOS) of RAS mutant and wild-type patients based on tissue (22.1 vs 35.8 months; p = 0.016) and plasma (19.9 vs 35.8 months; p = 0.013) analysis.Conclusion. This study indicates that RAS testing of liquid biopsy results in a similar outcome as compared with tissue testing in mCRC patients receiving first-line anti-EGFR MoAbs.

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Urine trouble: genitourinary tuberculosis and subsequent DRESS syndrome

A 40-year-old woman with HIV (CD4 270, viral load undetectable) from Zambia presented with fevers, urinary tract infection symptoms, sterile pyuria and haematuria. She was found to have genitourinary tuberculosis (TB) via mycobacterial culture of urine and ascites, and treated with rifabutin, isoniazid, pyrazinamide and ethambutol. She later had multiple episodes of asymptomatic transaminitis, triggering changes to both TB and HIV regimens. The patient then presented with diffuse rash, fevers, transaminitis and eosinophilia concerning for drug reaction with eosinophilia and systemic symptoms (DRESS). After initial improvement on discontinuation of likely responsible medications and completion of corticosteroid therapy, the patient returned with acute liver failure. This new episode was felt to be severe organ dysfunction due to DRESS, and she was treated with a prolonged corticosteroid taper and changes to her TB regimen. She has since completed therapy for TB, has improving CD4 counts and is without evidence of liver dysfunction.

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Cerebral hyperperfusion syndrome after spontaneous recanalisation of carotid in-stent thrombosis

Description

A 68-year-old man with medical history significant for hypertension and stroke was transferred to our hospital with new onset dysarthria, right face and arm weakness following left carotid stent deployed 24 hours before. The National Institutes of Health Stroke Scale at admission was 7. Head and neck CT angiographies (CTAs) were performed demonstrating in-stent thrombosis of the left carotid artery (figure 1A) and a CT perfusion showed no core infarct but a perfusion defect within the left middle cerebral artery (MCA) territory, as defined by a Tmax greater than 6 s, measuring 78.9 mL (figure 1B).

Figure 1

Initial diagnostic images. (A) CT angiography of the neck demonstrating in-stent thrombosis in the left carotid artery and no contrast filling of the internal carotid artery beyond the stent reconstruction. (B) Initial CT perfusion depicting prolonged time (Tmax) within the territory of the left middle cerebral artery. CBF,...

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Over-the-counter natural products in cardiac surgery: a case of ginseng-related massive perioperative bleeding

We present a case of massive perioperative bleeding due to severe coagulopathy following urgent aortic and mitral valve replacement. Bleeding was persistent despite prolonged and meticulous surgical haemostasis and required high-volume blood products transfusions. No obvious cause was found to justify the severity of the coagulopathy, which was later attributed to high preoperative intake of ginseng.

This case highlights the powerful activity of certain over-the-counter remedies on haemostasis, in this particular case on coagulation status. This also reminds us the paramount importance of a sound and comprehensive drug history for surgical patients.

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Tracheobronchopathia osteochondroplastica: awareness is the key for diagnosis and management

Tracheobronchopathia osteochondroplastica is a rare airway disease of unknown aetiology. Due to overlapping symptomology and lack of awareness, the condition is often missed resulting in unnecessary medical or surgical treatment. A male patient presented with a long-standing history of hoarseness and had earlier received treatment for bronchial asthma and tuberculosis. On evaluation, he had typical submucosal calcified nodules distributed throughout the trachea sparing the posterior membranous part. Although the biopsy confirmed the diagnosis of tracheobronchopathia osteochondroplastica in our case, histopathological examination is not always needed to make this diagnosis. Our patient has been kept under conservative management and is having non-progression of disease at 1-year follow-up. After having reviewed the literature related to pathophysiology and management of tracheobronchopathia osteochondroplastica, we emphasise on the fact that the treating physicians' awareness about this condition is the key to its diagnosis and management.

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The bladder ran dry: bilateral ureteral obstruction

A relatively young healthy man (barring obesity and distant gouty arthritis) was admitted with severe acute kidney injury (serum creatinine, 15.9 mg/dL) following acute gastroenteritis and occasional use of diclofenac. Abdominal ultrasound revealed mild left hydronephrosis due to staghorn stone and normal right kidney. Soon after, complete anuria necessitating haemodialysis developed without pain or evidence of infection. CT imaging revealed stones obstructing the right ureter. Following urological surgery, postobstructive diuresis developed and the serum creatinine came down to near normal. The stones were identified as uric acid stones.

Anuria has a relatively narrow differential and painless (partially non-dilated) bilateral ureteral obstruction is a distinctly unusual cause. A review of the literature to cover all reported causes of bilateral ureteral obstruction is presented. Only a minority of cases were not associated with an underlying malignant disease or its treatment. The multifactorial aetiology of the patient's acute kidney injury (volume depletion, diclofenac and obstructive uropathy) is presented and discussed.

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Reduced dose apixaban resolving dual cardiac chamber thrombi in a patient with ischaemic cardiomyopathy in sinus rhythm

Left atrial (LA) thrombus is a known sequela of atrial fibrillation (AF) but it is less frequently encountered in patients in sinus rhythm. Left ventricular (LV) dysfunction may predispose patients without evidence of atrial tachyarrhythmias to atrial thrombosis. Warfarin is the standard treatment for cardiac chamber thrombosis and prevention of the associated thromboembolic complications. Despite that apixaban was found to be superior to warfarin in prevention of stroke and systemic embolism in patients with AF, evidence for its use in treatment of cardiac chamber thrombi is scarce and is limited to case reports. We report a case of simultaneously occurring LV and LA thrombi successfully treated with reduced dose apixaban in a patient with ischaemic cardiomyopathy and in sinus rhythm. Although apixaban maybe a potential effective treatment for intracardiac thrombi, further studies are needed to demonstrate efficacy and safety of this agent in larger patient populations.

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Treatment of succinate dehydrogenase B-associated renal cancer

Germline mutations in the succinate dehydrogenase B (SDHB) gene are associated with a rare renal cancer with a young age of onset. It is important to raise awareness of this condition as it is dominantly inherited and is associated with other neoplasms. The diagnosis should be considered in patients with renal cancers with distinctive histology. There is little guidance in the literature about how to treat metastatic SDHB renal cancers. We report a confirmed partial response to treatment with a vascular endothelial growth factor receptor tyrosine kinase inhibitor, pazopanib.

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Delirium as presentation of late-onset and relapsing Susac syndrome

A 67-year-old patient, only known for bilateral presbycusis, presented with subacute onset of delirium. Clinical examination showed multifocal neurological deficits, all together suggesting subcortical frontal dysfunction together with cerebellar and corpus callosum involvement.

Cerebral MRI demonstrated supratentorial and infratentorial subcortical and periventricular T2-hyperintense lesions with cerebellar gadolinium enhancement and multiple central lesions of the corpus callosum (snowball lesions). The diagnosis of Susac syndrome was made and the patient treated with intravenous methylprednisolone, followed by a prednisone maintenance dose over 8 weeks. After a clinical improvement, a relapse was noticed during corticosteroid tapering. The patient was again treated with intravenous methylprednisolone followed by a prednisone maintenance therapy with simultaneous introduction of mycophenolate mofetil acid and one cycle of intravenous rituximab. The patient recovered rapidly. At 11-month follow-up, only mild executive dysfunction and persistent right postural tremor was noted, MRI showed partial regression of subcortical and juxtacortical lesions.

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Detecting the presence of leg length discrepancy based on gait deviations and functional measurement of leg length during walking

Leg length discrepancy (LLD) is associated with many musculoskeletal disorders. Its clinical significance is unclear mainly due to limited functional measurement capacity. An integrated approach measuring true LLD, gait deviations and functional leg length during the gait cycle, based on location of joint centre and anatomical landmarks using a three-dimensional motion analysis system was performed on two patients. In one case, strong agreement was found between all measurements thus, leading to the same treatment intervention. However, in another case, true LLD was not correlated with functional LLD or gait deviations, which led to contradictory results. Functional LLD was found to be correlated with gait deviations in both cases. Our results indicate the effectiveness of integrating into the diagnostic regimen, a dynamic method of measuring LLD, together with the functional outcome of gait deviations as a basis for decision-making regarding the presence and clinical significance of LLD in musculoskeletal disorders.

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Pain in the groin: mycotic aneurysm after transcutaneous aortic valve replacement

Description

An 88-year-old man with controlled hypertension, coronary artery disease and atrial fibrillation on warfarin therapy presented to the emergency department for evaluation of a right groin pain and fall. He had undergone a transcatheter aortic valve replacement (TAVR) for severe aortic stenosis a month prior to presentation. The procedure was complicated by a cerebrovascular accident. He was febrile and tachycardic, with a right-sided ptosis, facial droop and a pulsatile mass in the right groin (access site during TAVR). Laboratory evaluation revealed mild leucocytosis (12, 4.23–9.07 x10⁹/L). A new right common femoral mycotic aneurysm was confirmed on abdominal CT (figures 1 and 2) and ultrasound (figure 3). Within 12 hours, blood cultures grew gram-negative rods, later speciated to Pseudomonas aeruginosa. He was started on empiric vancomycin and piperacillin–tazobactam for suspected sepsis. Evaluation for endocarditis with a transoesophageal echocardiogram did not reveal valvular vegetations. He underwent an...

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Rare case of orbital schwannoma with intralesional haemorrhage and fluid-fluid levels

Description

We report a case of a 23-year-old man who presented with a 1-month history of gradually worsening right eye pressure, blurry vision and proptosis, which was not exacerbated with Valsalva or change in position.

MRI of the orbits demonstrated a well-defined, lobulated, cystic, trans-spatial mass with areas of internal haemorrhage (figure 1) and fluid–fluid levels (figure 2) in the superior medial right orbit, which extended posteriorly through the superior orbital fissure to the cavernous sinus (figure 3). The lesion slightly expanded the orbital fissure, mildly deformed the posterior globe and demonstrated peripheral and septal enhancement (figure 4).

Figure 1

Axial T1: increased T1 signal within the lesion located in the right periorbital space indicating haemorrhage.

Figure 2

Axial T2 (superior): multiple fluid–fluid levels.

Figure 3

Axial T2...

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Locoregional recurrence of breast cancer presenting as upper limb venous thromboembolism

Locoregional recurrence of breast cancer is a major concern for both patient and oncologist. Presentation as venous thromboembolism (VTE) carries risk of delayed diagnosis and has a poor prognosis. Here we describe, for the first time in the literature, a delayed diagnosis of local recurrence of infiltrative inflammatory breast cancer presenting as extensive deep venous thrombosis of the upper arm veins. This case demonstrates the need for a high level of vigilance for recurrence of malignancy in patients with no concurrent risk factors for VTE and atypical clinical progression in order to reach a timely diagnosis.

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Cocaine-related subcutaneous emphysema, pneumorrhachis and pneumomediastinum: a rare clinical finding

A young man presented with several days of dyspnoea and delirium due to cocaine use which was confirmed by urine drug screening. Imaging studies confirmed the diagnosis of subcutaneous emphysema, pneumorrhachis and pneumomediastinum. He was managed successfully with conservative therapy.

Although a rare clinical finding, cocaine-related pneumomediastinum, subcutaneous emphysema and pneumorrhachis should be recognised early on presentation. This will certainly help to effectively direct the use of healthcare resources and avoid subjecting the patient to unnecessary investigations.

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Aborted choroidal coloboma: fundus imaging and optical coherence tomography

Choroidal coloboma is characterised by poor embryonic development of chorioretinal structures and is of different types. We present a case of choroidal coloboma where the retinal pigment epithelium was present, clinically and on imaging, but rest of the structures were poorly formed. This observation suggests that in some cases, fusion of the fetal cleft may occur aberrantly, resulting in an aborted choroidal coloboma.

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Undiagnosed acute phase endobronchial tuberculosis with progression to irreversible tracheobronchial stenosis

Description

This case report highlights the challenges in diagnosing the rare endobronchial tuberculosis (EBTB) during the acute phase. The diagnostic dilemma escalated due to the fact that once airway stenosis has developed, it is irreversible and imposes significant morbidity and mortality.

We present a young Chinese woman in her twenties presented to the emergency department (ED) with noisy breathing and breathlessness. She was diagnosed with probable pulmonary tuberculosis (TB) with positive Mantoux and sputum examination for acid-fast bacilli and was started on anti-TB treatment a month prior. In ED, she was breathless, but the oxygen saturation was 95% under room air with normal vital parameters. Auscultations and chest radiograph were unremarkable. Upper airway assessment by the ear, nose and throat surgeon was normal. High-resolution (HR) CT thorax was performed in view of mild occasional stridor observed in the ward (figure 1). The HRCT revealed airway narrowing with bronchiectasis...

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'Trident sign in pelvis: sinister sign with poor prognosis

The perineural spread of the cancer through the lumbosacral plexus gives an appearance of 'trident sign' on contrast-enhanced CT scan and MRI. It is associated with adverse survival rates and carries a poor prognostic value.

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Incomplete cauda equina syndrome secondary to haemorrhage within a Tarlov cyst

Sacral perineural (Tarlov) cysts are benign, cerebrospinal fluid containing lesions of the spinal nerve root sheath. They are usually asymptomatic; however, a small proportion have the potential to cause compression of nerve roots and/or the cauda equina.

We report a case of a 61-year-old man who presented with acute onset back pain associated with bilateral radiculopathy. Between referral and consultation, the patient developed urinary dysfunction which resolved spontaneously.

MRI revealed haemorrhage within a Tarlov cyst, resulting in compression of the cauda equina. Due to the considerable clinical improvement at the time of consultation, surgical decompression of the cyst was not considered to be indicated.

An interval MRI scan 8 weeks later demonstrated that the haemorrhage within the perineural cyst had spontaneously resolved and the patient remained asymptomatic at 5-year follow-up.

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Missed opportunity for anticoagulation in a patient with AL cardiac amyloidosis and rapidly progressive heart failure

A previously healthy 65-year-old woman presented with progressive symptoms of heart failure. Low-voltage ECG and findings on echocardiography were concerning for infiltrative cardiomyopathy. Cardiac MRI showed biventricular late gadolinium enhancement, and endomyocardial biopsy confirmed monoclonal immunoglobulin light-chain (AL) amyloidosis. Bortezomib-based chemotherapy was initiated, but the patient continued to clinically deteriorate. She required hospital readmission after resuscitated out-of-hospital cardiac arrest attributed to progressive conduction disease, and a permanent pacemaker was implanted. Chest CT angiography showed a small subsegmental pulmonary embolism (PE), but anticoagulation was withheld as her lower extremity Doppler was negative. One month later, another pulseless electrical arrest occurred, due to massive PE. Thereafter, she had refractory class IV congestive heart failure with severe right ventricular dysfunction, and was deemed unsuitable for stem-cell or heart transplantation. This case highlights the predilection for thromboembolism in AL cardiac amyloidosis.

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An unusual case of Cushing's syndrome due to bihormonal ACTH-prolactin secreting pituitary macroadenoma with rapid response to cabergoline

A 23-year-old man presenting with florid Cushing's syndrome was found to have high plasma ACTH and very high serum prolactin. Pituitary MRI showed a large invasive macroadenoma. Low-dose cabergoline promptly suppressed both ACTH and prolactin levels within 2 weeks, with unexpected clinical and biochemical hypocortisolism requiring hydrocortisone replacement. Secondary hypogonadism was reversed. Clinical and biochemical remission of his Cushing's syndrome together with significant shrinkage of his macroadenoma has been maintained for 1 year on cabergoline 0.5 mg twice weekly. Reduction in pituitary tumour volume and brisk fall in serum prolactin in response to low-dose cabergoline is regularly observed in patients with macroprolactinomas, but the concurrent fall in the plasma ACTH level and hypocortisolism was a pleasant surprise. We assume that he most likely has a single bihormonal adenoma that is enriched with dopamine-2 receptors.

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Treatment of calmodulinopathy with verapamil

Pathological variants in genes encoding calmodulin are associated with severe clinical presentations, including recurrent ventricular fibrillation and sudden death. Beta-receptor antagonists (beta-blockers) and sodium-channel antagonists have been reported as pharmacotherapies in these disorders; however, recent data have demonstrated the importance of derangements in calcium channel inactivation. We report a sustained attempt to use calcium-channel antagonists to treat calmodulinopathy and review the treatment strategies reported in the literature to date.

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Low-dose total skin electron beam therapy for cutaneous lymphoma

Abstract

Background

Low-dose total skin electron beam therapy (TSEBT) is attracting increased interest for the effective palliative treatment of primary cutaneous T‑cell lymphoma (pCTCL). In this study, we compared toxicity profiles following various radiation doses.

Patients and methods

We reviewed the records of 60 patients who underwent TSEBT for pCTCL between 2000 and 2016 at the University Hospital of Munster. The treatment characteristics of the radiotherapy (RT) regimens and adverse events (AEs) were then analyzed and compared.

Results

In total, 67 courses of TSEBT were administered to 60 patients. Of these patients, 34 (51%) received a standard dose with a median surface dose of 30 Gy and 33 patients (49%) received a low dose with the median surface dose of 12 Gy (7 salvage low-dose TSEBT courses were administered to 5 patients). After a median follow-up of 15 months, the overall AE rate was 100%, including 38 patients (57%) with grade 2 and 7 (10%) with grade 3 AEs. Patients treated with low-dose TSEBT had significantly fewer grade 2 AEs than those with conventional dose regimens (33 vs. 79%, P < 0.001). A lower grade 3 AE rate was also observed in patients who had received the low-dose regimen compared to those with the conventional dose regimens (6 vs. 15%, P = 0.78). Multiple/salvage low-dose TSEBT courses were not associated with an increased risk of acute AEs.

Conclusion

Low-dose TSEBT regimens are associated with significantly fewer grade 2 acute toxicities compared with conventional doses of TSEBT. Repeated/Salvage low-dose TSEBT, however, appears to be tolerable and can even be applied safely in patients with cutaneous relapses.

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Secretory RAB GTPase 3C modulates IL6-STAT3 pathway to promote colon cancer metastasis and is associated with poor prognosis

Abstract

Background

RAB GTPases are important in the regulation of membrane trafficking and cell movement. Recently, exocytic RABs have received increasing attention in cancer research. However, the functional roles of exocytic RABs in colorectal carcinogenesis remain to be elucidated.

Methods

Immunohistochemistry analysis of a microarray containing 215 colorectal adenocarcinoma tissues was used to identify the association between exocytic RABs and patient prognosis. Complementary functional RAB3C overexpression and knockdown experiments were performed. The molecular mechanism of RAB3C in inducing colon cancer cell metastasis was determined.

Results

High RAB3C expression in patients was found to be significantly associated with advanced pathological stage, distant metastasis and poor prognosis. Multivariate analyses showed that high RAB3C expression was an independent prognostic marker in overall (P = 0.001) and disease-free survival (P < 0.001). Furthermore, our experimental results showed an increase in the migration and invasion ability of RAB3C-overexpressing colon cancer cells and increased metastatic nodules in a mouse metastasis model. The effect of RAB3C-overexpressing cell-conditioned medium was found to significantly promote the migration ability of parental colon cancer cells, thus suggesting that the promotion of migration is exocytosis dependent. Upregulation of other exocytic RABs was also seen in RAB3C-overexpressing cells. Through microarray and proteomics analyses, increased production of multiple cytokines was observed in RAB3C-overexpressing cell lines, and the IL-6 pathway was the top pathway whose members exhibited gene expression changes after RAB3C overexpression, according to Ingenuity Pathway Analysis. Blocking IL-6 with IL-6 antibody treatment or IL-6 knockdown significantly inhibited the migration potential of RAB3C-overexpressing colon cancer cells. In addition, IL-6 was found to induce STAT3 phosphorylation in RAB3C-overexpressing colon cancer cells, thus promoting migration. Ruxolitinib, a JAK2 inhibitor, was found to significantly inhibit RAB3C-induced colon cancer cell migration.

Conclusions

Our study revealed that RAB3C overexpression promotes tumor metastasis and is associated with poor prognosis in colorectal cancer, through modulating the ability of cancer cells to release IL-6 through exocytosis and activate the JAK2-STAT3 signaling pathway. These results further suggest that inhibition of STAT3 phosphorylation in the RAB3C-IL-6-STAT3 axis by using Ruxolitinib may be a new therapeutic strategy to combat metastatic colon cancers.

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A pilot evaluation of magnetic resonance imaging characteristics seen with solid papillary carcinomas of the breast in 4 patients

Abstract

Background

Solid papillary carcinoma (SPC) is a rare variant of breast papillary carcinoma with unique pathological morphology and biological behavior. There is only one case report on T₁-MRI of SPC. In this study, we report our findings on this new category of papillary carcinoma to fill the gap in MRI characterization of SPC.

Methods

This retrospective study included four pathology-confirmed in situ SPC patients. Conventional MRI, diffusion weighted imaging (DWI), and magnetic resonance spectroscopy (MRS) were performed with a 1.5 T whole-body MR scanner before surgical operation. The following characteristics of each lesion were recorded: signal intensity on T₂WI/STIR and T₁FSPGR, morphology, maximum lesion size, and time intensity curve (TIC) on dynamic contrast enhancement MRI (DCE-MRI), apparent diffusion coefficient (ADC) value from DWI, and Cho peak from MRS.

Results

Signal intensities of all lesions were heterogenous on T₂WI/STIR and T₁FSPGR. Mass enhancements were observed for all lesions with either oval or irregular shapes on DCE-MRI. The maximum lesion size ranged from 0.8 cm to 3.2 cm. All lesion margins were circumscribed, and internal enhancements were homogeneous or heterogeneous from DCE-MRI. TIC appeared with a rapid increase in initial contrast phases of all lesions. All lesions on DWI (b = 1000s/mm²) were slightly hyperintense with an ADC value range of 1.3 × 10⁻³ mm²/s to 1.9 × 10⁻³ mm²/s. Cho peak was absent at 3.2 ppm for all lesions.

Conclusions

MRI characteristics of SPC include heterogeneous signal intensity within the lesion on T₂WI/STIR and T₁FSPGR, mass enhancement with circumscribed margins, either oval or irregular shapes, and a rapid initial enhancement of TIC on DCE-MRI. ADC values and the absence of Cho peak may provide valuable information to distinguish SPC from other invasive breast carcinomas.

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Impact of comorbid conditions on participation in an organised colorectal cancer screening programme: a cross-sectional study

Abstract

Background

There is controversy regarding how comorbidity impacts on colorectal cancer screening, especially in the context of organised programmes. The aim of this study is to assess the effect of comorbidities on participation in the Barcelona population-based colorectal cancer screening programme (BCCSP).

Methods

Cross-sectional study carried out in ten primary care centres involved in the BCCSP. Individuals aged 50 to 69, at average risk of colorectal cancer, who were invited to participate in the first round of the faecal immunochemical test-based BCCSP were included (2011–2012). The main variable was participation in the BCCSP. Comorbidity was assessed by clinical risk group status. Other adjusting variables were age, sex, socioeconomic deprivation, visits to primary care, smoking, alcohol consumption and body mass index. Logistic regression models were used to test the association between participation in the programme and potential explanatory variables. The results were given as incidence rate ratios (IRR) and their 95% confidence intervals (CI).

Results

Of the 36,208 individuals included, 17,404 (48%) participated in the BCCSP. Participation was statistically significantly higher in women, individuals aged 60 to 64, patients with intermediate socioeconomic deprivation, and patients with more medical visits. There was a higher rate of current smoking, high-risk alcohol intake, obesity and individuals in the highest comorbidity categories in the non-participation group. In the adjusted analysis, only individuals with multiple minor chronic diseases were more likely to participate in the BCCSP (IRR 1.14; 95% CI [1.06 to 1.22]; p < 0.001). In contrast, having three or more dominant chronic diseases was associated with lower participation in the screening programme (IRR 0.76; 95% CI [0.65 to 0.89]; p = 0.001).

Conclusions

Having three or more dominant chronic diseases, was associated with lower participation in a faecal immunochemical test-based colorectal cancer screening programme, whereas individuals with multiple minor chronic diseases were more likely to participate. Further research is needed to explore comorbidity as a cause of non-participation in colorectal cancer screening programmes and which individuals could benefit most from colorectal cancer screening.

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Pirfenidone as salvage treatment for refractory bleomycin-induced lung injury: a case report of seminoma

Abstract

Background

Bleomycin-induced lung injury, a major complication of chemotherapy for germ cell tumors, occasionally fails to respond to the standard treatment with corticosteroids and develops into severe respiratory insufficiency. Little is known about salvage treatment for refractory cases.

Case presentation

A 63-year-old man who had been diagnosed with stage I seminoma and undergone a high orchiectomy 1 year previously developed swelling of his left iliac lymph node and was diagnosed with a recurrence of the seminoma. He was administered a standard chemotherapy regimen of cisplatin, etoposide, and bleomycin. At the end of second cycle, he developed a dry cough and fever that was accompanied by newly-identified bilateral infiltrates on chest X-ray. Despite initiation of oral prednisolone, his exertional dyspnea and decline in pulmonary functions continued to be aggravated. High-dose pulse treatment with methylprednisolone was introduced and improved his symptoms and radiologic findings. However, the maintenance dose of oral prednisolone allowed reactivation of the disease with evidence of newly-developed bilateral lung opacities on high-resolution CT scans. Considering his glucose intolerance and cataracts as complications of corticosteroid treatment, administration of pirfenidone was initiated with the patient's consent. Pirfenidone at 1800 mg/day was well tolerated, and resolved his symptoms and abnormal opacities on a chest CT scan. Subsequently, the dose of prednisolone was gradually tapered without worsening of the disease. At the most recent follow-up, he was still in complete remission of seminoma with a successfully tapered combination dose of prednisolone and pirfenidone.

Conclusions

Pirfenidone, a novel oral agent with anti-inflammatory and -fibrotic properties, should be considered as a salvage drug for refractory cases of bleomycin-induced lung injury.

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Akt/FoxM1 signaling pathway-mediated upregulation of MYBL2 promotes progression of human glioma

Abstract

Background

MYB-related protein B (B-MYB/MYBL2), a member of the myeloblastosis family of transcription factors, has been reported for its role in the genesis and progression of tumors. Forkhead box M1 (FoxM1), another transcriptional factor, is considered to be an independent predictor of poor survival in many solid cancers. The aim of the present study was to investigate the clinical significance of the correlation between MYBL2 and FoxM1 in glioma and the possible mechanism of FoxM1and MYBL2 expression.

Methods

MYBL2 and FoxM1expression in cancerous tissues and cell lines were determined by reverse transcription-PCR (RT-PCR), Western blotting and immunostaining. The co-expression of MYBL2 and FoxM1 was analyzed in low-grade glioma (LGG) and glioblastoma (HGG) cohorts of TCGA using cBioportal and UCSC Xena. And, the role of MYBL2 and FoxM1 in glioma cell progression and the underlying mechanisms were studied by using small interfering RNA (si-RNA) and pcDNA3.1 + HAvectors. Furthermore, the effects of MYBL2 and FoxM1 in cell proliferation, cell cycle progression, apoptosis, migration, invasion, and adhesion were determined by cell proliferation assays, flow cytometry analysis, transwell migration and cell adhesion assay.

Results

MYBL2 and FoxM1 expression are significantly associated with clinical stages and overall survival of glioma patients. In cohorts of TCGA, patients with high MYBL2 but without radio-chemotherapy had the highest hazard ratio (adjusted HR = 5.29, 95% CI = 1.475–18.969, P < 0.05). Meanwhile, MYBL2 closely related to the FoxM1 expression in 79 glioma tissues (r = 0.742, p < 0.05) and LGG (r = 0.83) and HGG (r = 0.74) cohorts of TCGA. Down regulation of FoxM1 and MYBL2 by siRNAs induced the cell cycle arrest, apoptosis and EMT of glioma cells. Furthermore, inactivations of Akt/FoxM1 signaling by Akt inhibitor and siRNA-FoxM1 reduce the expression of MYBL2 in glioma cells.

Conclusions

MYBL2 is a key downstream factor of Akt/FoxM1 signaling to promote progression of human glioma, and could be a new candidate gene for molecular targeting therapy and biomarker for radiotherapy of glioma.

Trial registration

CTXY-1300041-3-2. ChiCTR-COC-15006186. Registered date: 13 September 2013.

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