Severe hypophosphataemia: a rare cause of postoperative muscle weakness

We report a case of severe generalised muscle weakness in a 66-year-old man who underwent revision of left knee arthroplasty. On postoperative day 1, he developed non-focal muscle weakness and shortness of breath which progressed over a 6-hour period. Serum phosphorus level was severely low at 0.5 mg/dL, along with mild degree of hypokalaemia, hypocalcaemia and hypomagnesaemia. His symptoms completely resolved after emergent phosphorus replacement. The authors believe this case is of educational interest to physicians as generalised muscle weakness is an uncommon presentation of severe hypophosphataemia. In a postoperative setting, hypophosphataemia is often multifactorial, thought to result from combination of perioperative catecholamine surge, administration of saline, diuretics, glucose and antacids, poor oral intake and respiratory alkalosis secondary to pain. We report this case to raise awareness among physicians on severe phosphate imbalance as the primary aetiology for acute generalised muscle weakness and respiratory failure, especially after a surgery.

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A rare case of right pulmonary segmental artery dissection following pacemaker insertion

Description

This paper describes a case of pulmonary segmental artery dissection following pacemaker insertion. The patient was admitted electively and was clinically well prior to admission. The patient had a history of factor V Leiden disease, trifascicular heart block and ischaemic heart disease. The pacemaker was inserted successfully under general anaesthesia.

At day 0 after the operation, the patient was diagnosed with a left leg deep venous thrombosis. Given the high-risk patient factor of developing pulmonary embolism (PE), a CT pulmonary angiogram (CTPA) was performed. No PE was diagnosed; instead, the CTPA discovered a focal dissection flap that originated from the right lower lobe segmental artery, extending into the subsegmental branches craniocaudally for 3 cm (figure 1, figure 2 and figure 3). The CTPA was reviewed by a consultant radiologist. The patient remained asymptomatic. Subsequent discussions with the cardiothoracic surgical team concluded that...

http://ift.tt/2CiiJm3

Role Of Conservative Management In Emphysematous Gastritis

Emphysematous gastritis (EG) is a rare disease of the stomach that is caused by gas-forming bacteria, and it can be lethal. There have been <70 reported cases in the English literature of this disease which carries a mortality rate up to 60%. Early recognition and treatment through conservative management have been a popular and successful choice in today's medicine. Studies have shown that surgical intervention does not confer a statistical benefit on mortality in this condition. We present another case of EG in a 33-year-old woman who was successfully managed conservatively.

http://ift.tt/2CiiHKX

Portomesenteric vein thrombosis following laparoscopic sleeve gastrectomy: are underlying haematological disorders the culprit?

Description

A 51-year-old woman with a medical history of hypothyroidism and deep vein thrombosis (DVT) during pregnancy presented to the emergency department 5 days after laparoscopic sleeve gastrectomy (LSG) complaining of worsening abdominal pain and low-grade fevers. A CT scan and upper  gastrointestional series were performed with no evidence of leak or abscess, and the patient was admitted for observation.

On hospital day 2, the patient had worsening abdominal pain and an episode of emesis. An ultrasound revealed a new moderate amount of intraperitoneal-free fluid. A CT scan was repeated which revealed a segmental non-occlusive thrombus in the splenic vein (figure 1) as well as an occlusive thrombus in the superior mesenteric vein near the portosplenic confluence (figure 2).

Figure 1

(A, B) Segmental non-occlusive thrombus (blue arrow) in the splenic vein. 

Figure 2

(A, B) Occlusive...

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First case of acute granulomatous interstitial nephritis with immune reconstitution inflammatory syndrome in a patient with HIV coinfected with disseminated Mycobacterium kansasii

Restoration of immune response by highly active antiretroviral therapy (HAART) effectively improved the overall prognosis of HIV infection. However, 25%–31.7% of patients experience paradoxical worsening of pre-existing infections or unmasking of subclinical infections after starting HAART therapy, which is termed as immune reconstitution inflammatory syndrome (IRIS). Acute granulomatous interstitial nephritis as a consequence of IRIS has never been reported with Mycobacteriumkansasiicoinfection. Here, we describe an HIV/AIDS patient coinfected with disseminated M. kansasii infection, who presented with acute kidney injury 4.5 months after initiation of HAART. The diagnostic workup revealed IRIS was the cause of acute kidney injury. Short-term course of prednisone (1 mg/kg/day) along with antimycobacterial and HAART regimen achieved significant improvement.

http://ift.tt/2onFmwJ

Nail to the heart: no big deal. A rare case of post-traumatic pericarditis

This is a unique case report of a 32-year-old man who presented with pneumatic nail gun injury to his right chest at work. He removed the nail and continued to work through the day. With continued chest pain, he presented to the emergency room and an echocardiogram revealed moderate-size pericardial effusion. He was managed conservatively as he was haemodynamically stable. Serial echocardiograms revealed slow resolution of the effusion over 3 days. At his 3-month follow-up appointment, there was complete resolution of his effusion. This case highlights the importance of obtaining imaging studies in penetrating chest wall injuries and utilisation of medications to prevent expected complications.

http://ift.tt/2osUzfe

Recurrent postinfectious glomerulonephritis: an unusual evolution compatible with C3 glomerulopathy

Acute endocapillary glomerulonephritis, as its name suggests, is a one-time process, which usually resolves within weeks. However, in a small percentage of patients, the disease becomes chronic. In these cases, a deregulation in the alternative complement pathway, which can be caused by mutations or autoantibodies, has been proposed as a pathophysiological mechanism. As a result, the alternative complement pathway remains active after resolution of infection. We report a patient with two episodes of acute renal failure, both times diagnosed by renal biopsy of acute endocapillary glomerulonephritis, with slow recovery after two episodes of low-serum complement C3, haematuria and proteinuria.

http://ift.tt/2HJdD1G

Stimming behaviour in a 4-year-old girl with autism spectrum disorder

Description

A 4-year-old girl with autism spectrum disorder (ASD) developed a new behaviour of biting hard objects over the previous 6 months. The behaviour has not gotten better over time and she would always explore toys made of hard material (video 1) this way. Fortunately, she has not sustained any injury, choked on or swallowed these objects. She likes hot and spicy foods with textures. Her expressive language has only developed poorly.

Video 1

The child instantly bites and puts hard toys she found in the room into her mouth.

'Stimming' or self-stimulatory behaviours, also known as stereotypic behaviours in ASD, usually come in the form of hand-flapping, body-rocking, pacing or repetition of words. However, chewing or biting non-edible objects is also common. There are a number of possibilities to explain this behaviour. First, stimming acts as a self-regulatory mechanism to help relieve anxiety, anger,...

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Postoperative epidural abscess after spinal anaesthesia for a circumcision necessitated by phimosis

A 70-year-old man was admitted to our hospital for a penile circumcision due to phimosis using continuous dose spinal anaesthesia. On postoperative day 10 he came to the emergency department with a superficial abscess localised at the injection site of the spinal catheter. He was treated with intravenous antibiotics for 10 days, and the superficial abscess was incised and drained. Ten days later, the patient was readmitted to the emergency department with complaints of back pain and fever. A repeat MRI scan of his lumbar sacral area was done and showed epidural abscesses without any compression of the medulla or the myelum. The patient did not have any signs of spinal cord or nerve root compression at that time. He was treated with intravenous antibiotics with resolution of symptoms.

http://ift.tt/2HJFwXw

Incidental presentation of a button battery within a pharyngeal pouch: the first reported case

Description

An 88-year-old woman presented acutely to the ear, nose and throat (ENT) department at a District General Hospital with an unusual foreign body discovered on videofluoroscopy. This investigation had been organised by her general practitioner as the patient was experiencing progressive dysphagia with food regurgitation and weight loss. There was no history of chest or abdominal pain, haemoptysis or known foreign body ingestion. She had a background of polymyalgia rheumatica, ischaemic heart disease, pharyngeal pouch and wore bilateral hearing aids for presbycusis. During videofluoroscopy a circular, radiopaque foreign body was noted within the pharyngeal pouch resembling a button battery (figures 1 and 2). Given these unusual findings, the ENT team was urgently contacted by the speech and language practitioner for further assessment.

Figure 1

Videofluoroscopy image (lateral view) showing a foreign body resembling a button battery within a pharyngeal pouch.

http://ift.tt/2GGSQul

Attenuated form of type II mucopolysaccharidoses (Hunter syndrome): pitfalls and potential clues in diagnosis

Description

A 7-year-old boy, born of a non-consanguineous union, presented with pain over both hips and progressive difficulty in walking for preceding 2 years. He had normal developmental milestones with satisfactory scholastic performances and his family and perinatal histories were unremarkable. Clinical examination revealed short stature (height SD score (SDS): –2.3; midparental height (MPH) SDS: –1.7) with upper segment (US):lower segment (LS) ratio of 0.97, umbilical hernia, apical pansystolic murmur of mitral regurgitation and waddling gait without corneal opacity or organomegaly (figure 1). Complete blood count, baseline biochemistry and thyroid function tests were normal except presence of azurophilic granules within white blood cells seen in peripheral blood smear (figure 2). Transthoracic echocardiography confirmed moderate mitral regurgitation secondary to prolapsed posterior mitral leaflet leading to coaptation failure. Though the difference between his height centile and MPH centile was not striking, his body proportion was suggestive of short trunk dwarfism (US:LS is normally...

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Pioglitazone and bladder cancer risk: a systematic review and meta-analysis

Abstract

Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the use of pioglitazone and identify modifiers that affect the results. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to 25 August 2016 for randomized controlled trials (RCTs) and observational studies that evaluated the association between pioglitazone and bladder cancer risk. Conventional and cumulative meta-analyses were used to calculate the odds ratio (OR) with 95% confidence interval (CI). A restricted spline regression analysis was used to examine the dose–response relationship with a generalized least-squares trend test. We included two RCTs involving 9114 patients and 20 observational studies (n = 4,846,088 individuals). An increased risk of bladder cancer in patients treated with pioglitazone versus placebo was noted from RCTs (OR, 1.84; 95%CI, 0.99 to 3.42). In observational studies, the increased risk of bladder cancer was slight but significant among ever-users of pioglitazone versus never-users (OR, 1.13; 95%CI, 1.03 to 1.25), which appeared to be both time- (P = 0.003) and dose-dependent (P = 0.05). In addition, we observed the association differed by region of studies (Europe, United States, or Asia) or source of funding (sponsored by industry or not). Current evidence suggests that pioglitazone may increase the risk of bladder cancer, possibly in a dose- and time-dependent manner. Patients with long-term and high-dose exposure to pioglitazone should be monitored regularly for signs of bladder cancer.

Current evidence about the association between pioglitazone and bladder cancer risk remains inconsistent. This meta-analysis of two randomized controlled trials and 20 observational studies showed that use of pioglitazone might increase risk of bladder cancer. Our findings suggest a close monitoring of bladder cancer in patients with long-term and high-dose exposure to pioglitazone.

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Pioglitazone and bladder cancer risk: a systematic review and meta-analysis

Abstract

Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the use of pioglitazone and identify modifiers that affect the results. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to 25 August 2016 for randomized controlled trials (RCTs) and observational studies that evaluated the association between pioglitazone and bladder cancer risk. Conventional and cumulative meta-analyses were used to calculate the odds ratio (OR) with 95% confidence interval (CI). A restricted spline regression analysis was used to examine the dose–response relationship with a generalized least-squares trend test. We included two RCTs involving 9114 patients and 20 observational studies (n = 4,846,088 individuals). An increased risk of bladder cancer in patients treated with pioglitazone versus placebo was noted from RCTs (OR, 1.84; 95%CI, 0.99 to 3.42). In observational studies, the increased risk of bladder cancer was slight but significant among ever-users of pioglitazone versus never-users (OR, 1.13; 95%CI, 1.03 to 1.25), which appeared to be both time- (P = 0.003) and dose-dependent (P = 0.05). In addition, we observed the association differed by region of studies (Europe, United States, or Asia) or source of funding (sponsored by industry or not). Current evidence suggests that pioglitazone may increase the risk of bladder cancer, possibly in a dose- and time-dependent manner. Patients with long-term and high-dose exposure to pioglitazone should be monitored regularly for signs of bladder cancer.

Current evidence about the association between pioglitazone and bladder cancer risk remains inconsistent. This meta-analysis of two randomized controlled trials and 20 observational studies showed that use of pioglitazone might increase risk of bladder cancer. Our findings suggest a close monitoring of bladder cancer in patients with long-term and high-dose exposure to pioglitazone.

http://ift.tt/2HJekIk

Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer

Future Oncology, Ahead of Print.


http://ift.tt/2GFutwV

Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer

Future Oncology, Ahead of Print.


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Introducing a New Series: Immunotherapy Facts and Hopes

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FDA Approval: Gemtuzumab ozogamicin for the treatment of adults with newly-diagnosed CD33-positive acute myeloid leukemia

On September 1, 2017, FDA granted approval for gemtuzumab ozogamicin (GO) (Mylotarg; Pfizer, Inc) in combination with daunorubicin and cytarabine (DA) and as a monotherapy for the treatment of adult patients with newly-diagnosed CD33-positive acute myeloid leukemia (AML). GO is a CD33-targeted antibody-drug conjugate joined to calicheamicin. Approval of GO combination treatment was based on a randomized trial of 271 patients with newly-diagnosed AML treated with DA with or without 3 mg/m2 fractionated GO, which resulted in an event-free survival (EFS) of 13.6 months for GO + DA and 8.8 months for DA alone (HR 0.68 [95% CI: 0.51-0.91]). Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with GO + DA. Approval of GO monotherapy was based on a randomized trial of 237 patients with newly-diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with GO versus 3.6 months on best supportive care (HR 0.69, [95% CI 0.53-0.90]). Adverse events were similar on both arms. Post-approval, several studies are required including evaluation of fractionated GO pharmacokinetics, safety of combination GO in the pediatric population, of immunogenicity, and of the effects of GO on platelet function.

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Updated Results of Rituximab Pre- and Post-BEAM with or without 90Yttrium-Ibritumomab Tiuxetan during Autologous Transplant for Diffuse Large B-Cell Lymphoma

Purpose: We evaluated the effect on long-term survival of adding rituximab (R) to BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning with or without yttrium-90 ibritumomab tiuxetan (90YIT) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (ASCT). Experimental Design: Patients were enrolled on three consecutive phase 2 clinical trials. Patients received two doses of rituximab (375 mg/m2 and 1000 mg/m2) during mobilization of stem cells, followed by 1000 mg/m2 on days +1 and +8 after ASCT with R-BEAM or 90YIT-R-BEAM (90YIT dose of 0.4 mCi/kg) conditioning.  Results: One hundred thirteen patients were enrolled, with 73 receiving R-BEAM and 40 receiving 90YIT-R-BEAM. All patients had a prior exposure to rituximab. The median follow-up intervals for survivors were 11.8, 8.1, and 4.2 years in the three trials, respectively. The 5-year disease-free survival (DFS) rates were 62% for R-BEAM and 65% for 90YIT-R-BEAM (P =0.82). The 5-year overall survival rates were 73%, and 77%, respectively (P = 0.65). In patients with de novo DLBCL, survival outcomes of the germinal center/activated b-cell histologic subtypes were similar with 5-year OS rates (P = 0.52) and DFS rates (P = 0.64), irrespective of their time of relapse (< vs. > 1 year) after initial induction chemotherapy (P = 0.97).   Conclusions:Administering ASCT with rituximab during stem cell collection and immediately after transplantation induces long-term disease remission and abolishes the negative prognostic impact of cell-of-origin in patients with relapsed DLBCL. The addition of 90YIT does not confer a further survival benefit.

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Administration of Hypoxia-Activated Prodrug Evofosfamide after Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Colorectal Cancer

Purpose: Cancer-initiating cells (C-ICs) have been described in multiple cancer types, including colorectal cancer (CRC). C-ICs are defined by their capacity to self-renew, thereby driving tumor growth. C-ICs were initially thought to be static entities, however recent studies have determined these cells to be dynamic and influenced by microenvironmental cues such as hypoxia. If hypoxia drives the formation of C-ICs, then targeting hypoxia could represent a novel means to target C-ICs. Experimental Design: Patient-derived CRC xenografts were treated with evofosfamide (Evo), a hypoxia-activated prodrug (HAP), in combination with 5-Fluorouracil (5-FU) or chemoradiotherapy (5-FU and radiation; CRT). Treatment groups included both concurrent and sequential dosing regimens. Effects on the colorectal cancer-initiating cell (CC-IC) fraction were assessed by serial passage in vivo limiting dilution assays. FAZA-PET imaging was utilized as a non-invasive method to assess intratumoral hypoxia. Results: Hypoxia was sufficient to drive the formation of CC-ICs and cells surviving conventional therapy were more hypoxic and C-IC-like. Using a novel approach to combination therapy, we show that sequential treatment with 5-FU or CRT followed by Evo not only inhibits tumor growth of xenografts compared to 5-FU or CRT alone, but also significantly decreases the CC-IC fraction. Furthermore, non-invasive FAZA-PET hypoxia imaging was predictive of a tumor's response to Evo. Conclusions: Our data demonstrate a novel means to target the CC-IC fraction by adding a HAP sequentially after conventional adjuvant therapy, as well as the use of FAZA-PET as a biomarker for hypoxia to identify tumors that will benefit most from this approach.

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Vitamin D-Binding Protein Enhances Epithelial Ovarian Cancer Progression by Regulating the Insulin-like Growth Factor-1/Akt Pathway and Vitamin D Receptor Transcription

Purpose: Malignant ascites of epithelial ovarian cancer (EOC) help identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D-binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC. Experimental Design: We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines. Results: Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. In vivo and in vitro investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP-knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor-1/insulin-like growth factor binding protein-2/Akt axis, and induced suppression of vitamin D-responsive genes. A nuclear factor-kappa B p65-binding site in the VDR promoter was identified as a major determinant of DBP-dependent VDR promoter activation. Conclusions: This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC.

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Focal Irradiation And Systemic Transforming Growth Factor {beta} Blockade in Metastatic Breast Cancer

PURPOSE: This study examined the feasibility, efficacy (abscopal effect) and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients.EXPERIMENTAL DESIGN: Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, with focal radiotherapy to a metastatic site at week 1, (3 doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5 and 15 to isolate PBMCs, plasma and serum.RESULTS: Twenty-three patients were randomized, median age 57 (range 35 to 77). Seven grade 3/4 adverse events occurred in 5/11 patients in the 1mg/kg arm and in 2/12 patients in the 10mg/kg arm, respectively. Response was limited to 3 stable disease. At a median follow up of 12 months, 20/23 patients are deceased. Patients receiving the 10mg/kg had a significantly higher median overall survival than those receiving 1mg/kg fresolimumab dose (hazard ratio: 2.73 with 95% CI: 1.02, 7.30; p=0.039). The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool. CONCLUSIONS: TGFβ blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group.

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Introducing a New Series: Immunotherapy Facts and Hopes

http://ift.tt/2EYtVVZ

FDA Approval: Gemtuzumab ozogamicin for the treatment of adults with newly-diagnosed CD33-positive acute myeloid leukemia

On September 1, 2017, FDA granted approval for gemtuzumab ozogamicin (GO) (Mylotarg; Pfizer, Inc) in combination with daunorubicin and cytarabine (DA) and as a monotherapy for the treatment of adult patients with newly-diagnosed CD33-positive acute myeloid leukemia (AML). GO is a CD33-targeted antibody-drug conjugate joined to calicheamicin. Approval of GO combination treatment was based on a randomized trial of 271 patients with newly-diagnosed AML treated with DA with or without 3 mg/m2 fractionated GO, which resulted in an event-free survival (EFS) of 13.6 months for GO + DA and 8.8 months for DA alone (HR 0.68 [95% CI: 0.51-0.91]). Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with GO + DA. Approval of GO monotherapy was based on a randomized trial of 237 patients with newly-diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with GO versus 3.6 months on best supportive care (HR 0.69, [95% CI 0.53-0.90]). Adverse events were similar on both arms. Post-approval, several studies are required including evaluation of fractionated GO pharmacokinetics, safety of combination GO in the pediatric population, of immunogenicity, and of the effects of GO on platelet function.

http://ift.tt/2sSseEJ

Updated Results of Rituximab Pre- and Post-BEAM with or without 90Yttrium-Ibritumomab Tiuxetan during Autologous Transplant for Diffuse Large B-Cell Lymphoma

Purpose: We evaluated the effect on long-term survival of adding rituximab (R) to BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning with or without yttrium-90 ibritumomab tiuxetan (90YIT) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (ASCT). Experimental Design: Patients were enrolled on three consecutive phase 2 clinical trials. Patients received two doses of rituximab (375 mg/m2 and 1000 mg/m2) during mobilization of stem cells, followed by 1000 mg/m2 on days +1 and +8 after ASCT with R-BEAM or 90YIT-R-BEAM (90YIT dose of 0.4 mCi/kg) conditioning.  Results: One hundred thirteen patients were enrolled, with 73 receiving R-BEAM and 40 receiving 90YIT-R-BEAM. All patients had a prior exposure to rituximab. The median follow-up intervals for survivors were 11.8, 8.1, and 4.2 years in the three trials, respectively. The 5-year disease-free survival (DFS) rates were 62% for R-BEAM and 65% for 90YIT-R-BEAM (P =0.82). The 5-year overall survival rates were 73%, and 77%, respectively (P = 0.65). In patients with de novo DLBCL, survival outcomes of the germinal center/activated b-cell histologic subtypes were similar with 5-year OS rates (P = 0.52) and DFS rates (P = 0.64), irrespective of their time of relapse (< vs. > 1 year) after initial induction chemotherapy (P = 0.97).   Conclusions:Administering ASCT with rituximab during stem cell collection and immediately after transplantation induces long-term disease remission and abolishes the negative prognostic impact of cell-of-origin in patients with relapsed DLBCL. The addition of 90YIT does not confer a further survival benefit.

http://ift.tt/2CeIoMk

Administration of Hypoxia-Activated Prodrug Evofosfamide after Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Colorectal Cancer

Purpose: Cancer-initiating cells (C-ICs) have been described in multiple cancer types, including colorectal cancer (CRC). C-ICs are defined by their capacity to self-renew, thereby driving tumor growth. C-ICs were initially thought to be static entities, however recent studies have determined these cells to be dynamic and influenced by microenvironmental cues such as hypoxia. If hypoxia drives the formation of C-ICs, then targeting hypoxia could represent a novel means to target C-ICs. Experimental Design: Patient-derived CRC xenografts were treated with evofosfamide (Evo), a hypoxia-activated prodrug (HAP), in combination with 5-Fluorouracil (5-FU) or chemoradiotherapy (5-FU and radiation; CRT). Treatment groups included both concurrent and sequential dosing regimens. Effects on the colorectal cancer-initiating cell (CC-IC) fraction were assessed by serial passage in vivo limiting dilution assays. FAZA-PET imaging was utilized as a non-invasive method to assess intratumoral hypoxia. Results: Hypoxia was sufficient to drive the formation of CC-ICs and cells surviving conventional therapy were more hypoxic and C-IC-like. Using a novel approach to combination therapy, we show that sequential treatment with 5-FU or CRT followed by Evo not only inhibits tumor growth of xenografts compared to 5-FU or CRT alone, but also significantly decreases the CC-IC fraction. Furthermore, non-invasive FAZA-PET hypoxia imaging was predictive of a tumor's response to Evo. Conclusions: Our data demonstrate a novel means to target the CC-IC fraction by adding a HAP sequentially after conventional adjuvant therapy, as well as the use of FAZA-PET as a biomarker for hypoxia to identify tumors that will benefit most from this approach.

http://ift.tt/2sQ8OAi

Vitamin D-Binding Protein Enhances Epithelial Ovarian Cancer Progression by Regulating the Insulin-like Growth Factor-1/Akt Pathway and Vitamin D Receptor Transcription

Purpose: Malignant ascites of epithelial ovarian cancer (EOC) help identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D-binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC. Experimental Design: We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines. Results: Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. In vivo and in vitro investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP-knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor-1/insulin-like growth factor binding protein-2/Akt axis, and induced suppression of vitamin D-responsive genes. A nuclear factor-kappa B p65-binding site in the VDR promoter was identified as a major determinant of DBP-dependent VDR promoter activation. Conclusions: This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC.

http://ift.tt/2CfxgPx

Focal Irradiation And Systemic Transforming Growth Factor {beta} Blockade in Metastatic Breast Cancer

PURPOSE: This study examined the feasibility, efficacy (abscopal effect) and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients.EXPERIMENTAL DESIGN: Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, with focal radiotherapy to a metastatic site at week 1, (3 doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5 and 15 to isolate PBMCs, plasma and serum.RESULTS: Twenty-three patients were randomized, median age 57 (range 35 to 77). Seven grade 3/4 adverse events occurred in 5/11 patients in the 1mg/kg arm and in 2/12 patients in the 10mg/kg arm, respectively. Response was limited to 3 stable disease. At a median follow up of 12 months, 20/23 patients are deceased. Patients receiving the 10mg/kg had a significantly higher median overall survival than those receiving 1mg/kg fresolimumab dose (hazard ratio: 2.73 with 95% CI: 1.02, 7.30; p=0.039). The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool. CONCLUSIONS: TGFβ blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group.

http://ift.tt/2sNQO9D

Targeting Epigenetics to Prevent Obesity Promoted Cancers

Epigenetic changes in DNA and associated chromatin proteins are increasingly being considered as important mediators of the linkage between obesity and cancer. Although multiple agents, targeted at epigenetic changes, are being tested for therapy of established cancers, this issue of Cancer Prevention Research carries two articles demonstrating that the bromodomain inhibitor I-BET-762 can attenuate adipose tissue–promoted cancers. Although I-BET-762 significantly delayed, rather than completely prevented, the onset of adiposity-promoted transformation and malignancy, these experiments provide important proof of principle for the strategies of targeting epigenetic changes to disrupt the obesity–cancer linkage. Because bromodomain proteins represent only one of multiple epigenetic mediators, it is probable that targeting other epigenetic processes, alone or in combination, may serve to even more effectively disrupt the obesity promotion of cancer. Given the magnitude of the current obesity pandemic and its impact on cancer, preventive measures to disrupt this linkage are critically important. Cancer Prev Res; 11(3); 1–4. ©2018 AACR.

See related article by Chakraborty et al., p. 129

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TGF{beta} Promotes Immune Evasion to Limit the Efficacy of Anti-PD-1/PD-L1 [Research Watch]

The TGFβ-activated stroma induces T-cell exclusion to suppress antitumor immunity.

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MEK Binding to KSR Promotes Allosteric Activation of BRAF [Research Watch]

KSR–MEK complexes allosterically activate BRAF, which then phosphorylates a second MEK molecule.

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The Oncolytic Adenovirus DNX-2401 Has Antitumor Activity in Glioblastoma [Research Watch]

In a phase I trial, DNX-2401 is safe and achieves durable responses in patients with recurrent glioma.

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Axitinib plus Pembrolizumab Is Effective in Renal Cell Carcinoma [Research Watch]

Axitinib plus pembrolizumab has a 73% response rate in previously untreated advanced renal cell carcinoma.

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Startups Bring AI to Pathology [News in Brief]

Under development: machine-learning algorithms to help diagnose cancer and identify biomarkers from pathology slides.

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SOX2OT variant 7 contributes to the synergistic interaction between EGCG and Doxorubicin to kill osteosarcoma via autophagy and stemness inhibition

Doxorubicin is the preferred chemotherapeuticdrug for osteosarcoma treatment of which clinical efficacy is limited because of its chemo-resistance and cardiac toxicity. It is necessary to develop the combinati...

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Uro-oncology 2018: new horizons, new treatment options, improved patient outcomes

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Targeting angiogenesis in lung cancer

Summary

Angiogenesis inhibition is a promising way to inhibit and eradicate cancer. Many attempts have been made to use this tool for the treatment of lung cancer. Some success has been reported, and antiangiogenic drugs are actively being investigated in combination with other types of anticancer treatments.

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Antiangiogenic therapies in ovarian cancer

Summary

Antiangiogenic compounds were the first active targeted agents implemented in the treatment of ovarian cancer. Bevacizumab and tyrosine kinase inhibitors such as pazopanib, nintedanib and cediranib target the VEGF pathway, while trebananib was developed as an inhibitor of the angiopoietin pathway. All these compounds have been extensively evaluated and, in this review, we provide a structured overview of the randomized trials that have been performed in both primary and relapsed ovarian cancer. From this data, it is evident that antiangiogenic therapy has its place in ovarian cancer. If not during first-line treatment, then at least at some point for the treatment of relapsed disease. In addition, we address and summarize the trials designed to address the remaining issues related to treatment duration, continuation beyond progression and optimal combination. The future clinical development of angiogenesis inhibitors in ovarian cancer indeed looks at combinations with poly (ADP-ribose) polymerase (PARP) inhibitors, immune checkpoint inhibitors and vascular disrupting agents. Finally, an overview is given of the retrospective translational studies that were performed on the samples of the two pivotal first-line trials GOG(Gynecologic Oncology Group)-218 and ICON(International Collaborative Ovarian Neoplasm study)7, with initial evidence for the predictive value of the BRCA status, some molecular subtypes and histological assessment of microvessel density. If confirmed, these biomarkers could further improve the implementation of antiangiogenic therapy in ovarian cancer.

http://ift.tt/2EOMRXZ

Targeting angiogenesis in lung cancer

Summary

Angiogenesis inhibition is a promising way to inhibit and eradicate cancer. Many attempts have been made to use this tool for the treatment of lung cancer. Some success has been reported, and antiangiogenic drugs are actively being investigated in combination with other types of anticancer treatments.

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Uro-oncology 2018: new horizons, new treatment options, improved patient outcomes

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Antiangiogenic therapies in ovarian cancer

Summary

Antiangiogenic compounds were the first active targeted agents implemented in the treatment of ovarian cancer. Bevacizumab and tyrosine kinase inhibitors such as pazopanib, nintedanib and cediranib target the VEGF pathway, while trebananib was developed as an inhibitor of the angiopoietin pathway. All these compounds have been extensively evaluated and, in this review, we provide a structured overview of the randomized trials that have been performed in both primary and relapsed ovarian cancer. From this data, it is evident that antiangiogenic therapy has its place in ovarian cancer. If not during first-line treatment, then at least at some point for the treatment of relapsed disease. In addition, we address and summarize the trials designed to address the remaining issues related to treatment duration, continuation beyond progression and optimal combination. The future clinical development of angiogenesis inhibitors in ovarian cancer indeed looks at combinations with poly (ADP-ribose) polymerase (PARP) inhibitors, immune checkpoint inhibitors and vascular disrupting agents. Finally, an overview is given of the retrospective translational studies that were performed on the samples of the two pivotal first-line trials GOG(Gynecologic Oncology Group)-218 and ICON(International Collaborative Ovarian Neoplasm study)7, with initial evidence for the predictive value of the BRCA status, some molecular subtypes and histological assessment of microvessel density. If confirmed, these biomarkers could further improve the implementation of antiangiogenic therapy in ovarian cancer.

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The arrival of axilla conserving therapy (ACT). Is this the second revolution in locoregional management of breast cancer care?

The locoregional management of breast cancer saw a revolution years ago with the advent of Breast Conserving Therapy (BCT) [1]. This technique, which established the equivalence of mastectomy and breast conservation, typically employed adjuvant radiotherapy after breast conserving surgery (BCS).

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Allostatic load and subsequent all-cause mortality: which biological markers drive the relationship? Findings from a UK birth cohort

Abstract

The concept of allostatic load (AL) refers to the idea of a global physiological 'wear and tear' resulting from the adaptation to the environment through the stress response systems over the life span. The link between socioeconomic position (SEP) and mortality has now been established, and there is evidence that AL may capture the link between SEP and mortality. In order to quantitatively assess the role of AL on mortality, we use data from the 1958 British birth cohort including eleven year mortality in 8,113 adults. Specifically, we interrogate the hypothesis of a cumulative biological risk (allostatic load) reflecting 4 physiological systems potentially predicting future risk of death (N = 132). AL was defined using 14 biomarkers assayed in blood from a biosample collected at 44 years of age. Cox proportional hazard regression analysis revealed that higher allostatic load at 44 years old was a significant predictor of mortality 11 years later [HR = 3.56 (2.3 to 5.53)]. We found that this relationship was not solely related to early-life SEP, adverse childhood experiences and young adulthood health status, behaviours and SEP [HR = 2.57 (1.59 to 4.15)]. Regarding the ability of each physiological system and biomarkers to predict future death, our results suggest that the cumulative measure was advantageous compared to evaluating each physiological system sub-score and biomarker separately. Our findings add some evidence of a biological embodiment in response to stress which ultimately affects mortality.

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Lessons from the sky: an aviation-based framework for maximizing the delivery of quality anesthetic care

Abstract

Though aviation is practiced in airplanes and anesthesiology in operating rooms, the two professions have substantial parallels. Both require readiness to manage a crisis situation, where lives are at stake, at a moment's notice and with incomplete information. The determinants of quality performance in both professions extend far beyond knowledge base and formal training. The science of human factors, a prominent cornerstone of the aviation industry, has not yet found the same place in medicine, but it could change the understanding and execution of medical decision-making in profound ways. This article reviews specific components of crisis management and root cause analysis in aviation that can serve as models for improving those same aspects within anesthesiology.

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A case of anosmia and hypogeusia as a complication of propofol

Abstract

Anesthetics represent an uncommon cause of taste and smell disorders. We describe a case of anosmia and hypogeusia for 6 weeks after recovery from a uterine curettage operation in a 32-year-old woman. The case is unusual because propofol was the only anesthetic used during surgery and anesthesia. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed no abnormality. This case may highly suggest that propofol could induce smell and taste disorders.

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Quality of preoperative pelvic computed tomography (CT) and magnetic resonance imaging (MRI) for rectal cancer in a region in Ontario: A retrospective population-based study

Background and Objectives

Treatment decisions for rectal cancer rely on preoperative staging with CT and MRI scans. We assessed the quality of such scans in a region of Ontario.

Methods

We retrospectively collected data for patients undergoing rectal cancer surgery between July 2011 and December 2014. We measured three aspects of quality: use; comprehensiveness of reporting T-category, N-category, mesorectal fascia (MRF) status; and in non-radiated patients sensitivity and specificity of reports for relevant elements.

Results

A total of 559 patients underwent major rectal cancer surgery. Preoperative staging with CT and MRI was performed in 93% and 50% of patients. CT scan reports provided information on T-category, N-category, and MRF status in 41%, 92%, and 16% of cases. These same elements were reported on MRI in 88%, 93%, and 62% of cases. CT scan sensitivity and specificity was 80% and 80% for T-category, and 85% and 39% for N-category. MRI sensitivity and specificity was 75% and 81% for T-category, 79% and 37% for N-category, and 33% and 89% for MRF status.

Conclusion

In this region of Ontario, pre-operative MRI was underutilized, CT reporting of MRF status was low, and when reported sensitivity and specificity of T- and N-category were similar for CT and MRI.

http://ift.tt/2orTDb6

Postoperative low hepatitis C virus load predicts long-term outcomes after hepatectomy for hepatocellular carcinoma

Background

Preoperative hepatitis C virus (HCV) viral load is known to predict long-term outcomes after hepatectomy for HCV-related hepatocellular carcinoma (HCC). This study sought to examine the hypothesis that postoperative and preoperative HCV viral-load have similar prognostic implications, as well as determine a target viral-load that will improve long-term postoperative outcomes.

Method

One hundred and eighty-one patients who underwent curative hepatectomy for HCV-related HCC were divided into five groups according to time-weighted average viral load. The cumulative-recurrence curves of the five groups were compared to identify prognostic trends. The optimal cut-off viral load value related to recurrence was also investigated.

Results

The five cumulative-recurrence curves were separated into two clusters according to viral load. Patients with a negative viral load had comparable recurrence curves to patients with the lowest viral-load (P = 0.907); both of these patient groups had more favorable outcomes than patients with a viral load categorized in the other groups (all P < 0.050). The optimal cut-off based on maximum HR method (> or ≤4.0 log₁₀IU/mL) was a strong prognostic indicator of recurrence in multivariate analysis (HR 3.09; 95%CI 1.96-5.04; P < 0.001).

Conclusion

Postoperative HCV viral load correlated with long-term surgical outcomes. A low viral load (≤4.0 log₁₀IU/mL) independently predicted better long-term outcomes.

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Can PET/CT help manage ground glass nodules?

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Safety and oncologic outcomes of robotic liver resections: A systematic review

The robotic system has emerged as a new minimally invasive technology with promising results. We sought to systematically review the available literature on the safety and the oncologic outcomes of robotic liver surgery. A systematic review was conducted using Medline (PubMed), Embase and Cochrane library through November 12th, 2017. A robotic approach may be a safe and feasible surgical option for minor and major liver resections.

http://ift.tt/2HHHlnC

HEPATOFLUO: A prospective monocentric study assessing the benefits of indocyanine green (ICG) fluorescence for hepatic surgery

Background and Objectives

Fluorescence imaging using indocyanine green (ICG) is undergoing extensive development. This study aimed to assess the merits of ICG in regard to hepatic surgery.

Methods

Patients with liver lesions that required a resection were eligible. They received an injection of ICG the day before the surgery. Step 1 allowed assessment of use of the medical device under surgical conditions. Steps 2 and 3 assessed the capacity of the MD to detect known tumorous lesions and to spot a predefined area of the liver following injection of ICG into the portal vein (ICGp).

Results

The 1st step allowed for validation of the MD use with three patients. Between 04-2013 and 04-2015, 45 pts were included (40 eligible) in steps 2 and 3. All of the tumorous lesions (95/119) exhibited fluorescence. Four new metastasis were detected in 3 pts, and two missing metastases in 1 pt. False positive were 22%. The maximal depth for detection by fluorescence was 13 mm. Injection of ICGp allowed the corresponding anatomical area to be identified in 16/20 patients.

Conclusion

This study confirmed that intraoperative fluorescence is a helpful and relevant tool for the liver surgeon (NCT 01738217).

http://ift.tt/2EPb9gc

Reconstruction using a constrained-type hip tumor prosthesis after resection of malignant periacetabular tumors: A study by the Japanese Musculoskeletal Oncology Group (JMOG)

Background

We conducted a nationwide survey of prosthetic reconstruction using a constrained-type hip tumor prosthesis (C-THA) following resection of periacetabular tumors.

Methods

Eighty patients with periacetabular tumors underwent wide resection and prosthetic reconstruction using C-THA at JMOG-affiliated institutions (39 males and 41 females; mean age, 46.7 years; mean follow-up period, 65 months). Primary bone or soft tissue sarcoma accounted for 75% of the cases. Adjuvant radiotherapy and chemotherapy were performed for 12 and 37 patients, respectively.

Results

There were 21 local recurrences (26%), necessitating amputation in 2 patients. Other postoperative complications included deep infection in 31 patients (39%), delayed wound healing in 25 (31%), and prosthesis-related complications requiring surgery in 7 (9%). Removal of the prosthesis was required in 23 patients (29%) (deep infection (n = 20), local recurrence resulting in amputation (n = 2), and outer cup displacement (n = 1). Patients whose abductor muscle was conserved or who underwent functional abductor muscle reconstruction showed significantly longer prosthesis survival. No postoperative wound complications occurred in three recent patients undergoing wound management with a RAM flap. The mean MSTS score was 43%.

Conclusions

We analyzed the outcome of 80 patients with periacetabular tumors undergoing C-THA reconstruction. The rates of postoperative complication were still high, but comparable to those in previous studies. Our results suggest wound management using a RAM flap is useful for reducing wound complications.

http://ift.tt/2HHH588

Comparison of two novel staging systems with the TNM system in predicting stage III colon cancer survival

Background and Objectives

Adaptations of the TNM staging system that incorporate the Lymph Node Ratio (LNR) have been proposed for stage III colon cancer. This study compared the concordance of two novel staging systems and the TNM system with observed survival outcomes in stage III patients.

Methods

A review of patients who underwent surgery for stage III colon cancer between January 2002 and April 2015 at a tertiary care centre was performed. The Kaplan-Meier method was used to estimate the 5-year overall (OS) and disease free survival (DFS) rates, and the concordance probability was calculated to evaluate the discriminatory power of the staging systems.

Results

Two hundred and sixty-one patients were identified. For TNM stages IIIA, IIIB, and IIIC, 5-year OS was 83.4%, 67.6%, and 38.3%, respectively (P < 0.001). All three staging systems were independently predictive of OS and DFS (P < 0.001). However, the novel staging system by Sugimoto et al¹⁸ was the most favourable prognostic tool, with a concordance of 0.646 for DFS and 0.659 for OS.

Conclusions

The novel staging system by Sugimoto et al¹⁸ was superior to the TNM system. Incorporating LNR into staging models for node positive colon cancers may improve survival information available to patients and potentially aid treatment decisions.

http://ift.tt/2EMjOQF

Importance of wide re-resection in adult spermatic cord sarcomas: Report on oncologic outcomes at a single institution

Background and Objectives

We evaluated the effect of re-resection with wide margins (undertaken because initial resection performed elsewhere was incomplete) on survival in patients with spermatic cord sarcoma (SCS).

Methods

After excluding those with metastatic disease and those not undergoing surgical intervention, the records of 72 consecutive patients treated for SCS between 1981 and 2011 at Memorial Sloan Kettering Cancer Center were reviewed. Recurrence-free survival (RFS) and cancer-specific survival were calculated using the Kaplan-Meier method for comparing between the 48 patients who underwent wide re-resection (WRR) within 5 months of diagnosis and the 24 who did not. The relationship of age, tumor size, tumor histology, adjuvant radiation, and wide re-resection with recurrence and death was assessed by univariate Cox regression.

Results

WRR significantly improved RFS (hazard ratio [HR] 0.16, 95%CI 0.07-0.37; P < 0.0001), despite the fact that patients receiving WRR had higher-grade disease. Tumor-positive margins upon WRR were strongly associated with both disease recurrence (HR 5.56; 95%CI 1.14-27.11, P = 0.034) and death from cancer (HR 6.16, 95%CI 1.25-30.29; P = 0.025).

Conclusions

A WRR with negative margins is effective in the management of patients with SCS and leads to improved RFS.

http://ift.tt/2HHGMu0

Breast-specific factors determine cosmetic outcome and patient satisfaction after breast-conserving therapy: Results from the randomized COBALT study

Background and Objectives

To identify breast-specific factors and the role of tumor, treatment, and patient-related items in influencing patient opinion on cosmesis and satisfaction after breast-conserving therapy (BCT).

Methods

Data from the randomized COBALT study was used. At 3, 12, and 36 months, 128 patients with T1-T2 breast cancer completed a questionnaire on breast-specific factors and overall cosmetic outcome and patient satisfaction, using a 4-point Likert scale.

Results

There was a strong positive correlation between breast-specific factors, overall cosmetic outcome,and satisfaction at all time-points. Excellent/good cosmetic outcomes and satisfaction decreased during follow-up. A shift was noted in the degree of influence of the various breast-specific factors. At 3 years, symmetry factors such as size, shape, and nipple position largely determined a patient's opinion on the final cosmesis, followed by firmness. The risk of an unacceptable outcome was associated with young age and large excision volumes.

Conclusion

A questionnaire including breast-specific questions provides important information on final cosmetic results and satisfaction after BCT. These outcomes can also be of great value as quality indicators and pre-operative counseling. The major influence of breast-specific factors on asymmetry underlines the importance of achieving an optimal excision volume at the initial procedure.

http://ift.tt/2BMK2E3

Is tissue still the issue? Lobectomy for suspicious lung nodules without confirmation of malignancy

Background

Histologic confirmation of malignancy has been indicated for a suspicious lung nodule prior to resection. The purpose of this study was to determine whether or not foregoing routine tissue biopsy increased the incidence of lobectomy for benign lesions.

Methods

Retrospective cohort of 256 patients who underwent thoracoscopic or open lobectomy for a confirmed or suspected pulmonary malignancy, with or without tissue diagnosis. Clinical, radiographic, and pathologic data were compared.

Results

Among 256 patients, 127 had attempted biopsy (group A) and 129 had no biopsy procedure (group B). There was no significant difference in the incidence of benign resections between the groups (Group A = 4 (3.2%) benign pathology vs group B = 9 (7.0%; P = 0.16). Group B had significantly lower operative time (127.1 vs 112.3 minutes; P = 0.004) and intraoperative complications (23 vs 37 patients; P = 0.03). There was a trend toward longer hospital stay and surgical waiting time in group A (6.6 vs 5.2 days, P = 0.24; 92.4 vs 66.2 days; P = 0.14, respectively).

Conclusion

Foregoing biopsies and proceeding to lobectomy in selected patients with suspicious lung nodules is safe, did not increase the incidence of resected benign pathology, and may decrease surgical wait time. Patients should be carefully evaluated and counseled.

http://ift.tt/2HCvyXH

LETTER TO THE EDITOR

http://ift.tt/2EPoUeY

Cover Image, Volume 117, Number 1, January 1, 2018

The cover image, by Dimitri Tzanis et al., is based on the Review Article Major vascular resections in retroperitoneal sarcoma, DOI 10.1002/jso.24920.

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Issue Information - TOC

http://ift.tt/2EORr4m

Issue Information - Ed Board

http://ift.tt/2HGkdWT

Taste and smell perception and quality of life during and after systemic therapy for breast cancer

Abstract

Purpose

The purpose of the study was to assess self-reported taste and smell perception after chemotherapy in breast cancer patients compared with women without cancer, and to assess whether taste and smell perception is associated with quality of life after the end of chemotherapy.

Methods

We included 135 newly diagnosed breast cancer patients who completed chemotherapy and 114 women without cancer. Questionnaires on taste, smell, and quality of life were completed shortly after and 6 months after chemotherapy (patients) or at two moments with 6 months' time window in between (comparisons).

Results

Self-reported taste and smell perception were significantly lower in patients shortly after chemotherapy compared to the comparison group. Most patients recovered 6 months after chemotherapy, although patients who were still receiving trastuzumab then reported a lower taste and smell perception compared to patients who were not. A lower self-reported taste and smell were statistically significantly associated with a worse quality of life, social, emotional, and role functioning shortly after chemotherapy. Six months after chemotherapy, taste and smell were statistically significantly associated with quality of life, social and role functioning, but only in patients receiving trastuzumab.

Conclusions

Most taste and smell alterations recovered within 6 months after the end of chemotherapy for breast cancer, but not for patients receiving trastuzumab. These results highlight the importance of monitoring taste and smell alterations during and after treatment with chemotherapy and trastuzumab, as they may impact quality of life.

http://ift.tt/2F0arAd

Radiotherapy in soft-tissue sarcoma of the extremities

Abstract

Sarcomas are an infrequent and heterogeneous group of neoplasia. Surgery with or without associated radiotherapy (RT) is the basic treatment for this type of tumour. To increase the therapeutic ratio (the index between cytotoxic effects in tumours and normal tissue complications with a certain dose of radiation), new advances are being investigated to increase local and distant control and to decrease the morbidity of the treatment. The aim of this review was to analyse the different strategies, based on technology and biology, which are being investigated to increase the therapeutic ratio of this disease

http://ift.tt/2EM3VO1

Radiotherapy in soft-tissue sarcoma of the extremities

Abstract

Sarcomas are an infrequent and heterogeneous group of neoplasia. Surgery with or without associated radiotherapy (RT) is the basic treatment for this type of tumour. To increase the therapeutic ratio (the index between cytotoxic effects in tumours and normal tissue complications with a certain dose of radiation), new advances are being investigated to increase local and distant control and to decrease the morbidity of the treatment. The aim of this review was to analyse the different strategies, based on technology and biology, which are being investigated to increase the therapeutic ratio of this disease

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Impact of time-related factors on biologically accurate radiotherapy treatment planning

The incomplete repair (IR) model expresses the cell repair effect from radiation-induced damage over time, which is given little consideration in actual treatment planning. By incorporating the IR model into t...

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Dosimetric impact of tumor treating field (TTField) transducer arrays onto treatment plans for glioblastomas – a planning study

Tumor-Treating Fields (TTFields) are a novel treatment strategy for glioblastoma (GBM) that is approved for the use concomitantly to adjuvant chemotherapy. Preclinical data suggest a synergistic interaction of...

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Impact of time-related factors on biologically accurate radiotherapy treatment planning

The incomplete repair (IR) model expresses the cell repair effect from radiation-induced damage over time, which is given little consideration in actual treatment planning. By incorporating the IR model into t...

http://ift.tt/2oufXAH

Dosimetric impact of tumor treating field (TTField) transducer arrays onto treatment plans for glioblastomas – a planning study

Tumor-Treating Fields (TTFields) are a novel treatment strategy for glioblastoma (GBM) that is approved for the use concomitantly to adjuvant chemotherapy. Preclinical data suggest a synergistic interaction of...

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Asymptomatic thyroiditis presenting as pyrexia of unknown origin: a case report

Pyrexia of unknown origin is a difficult and challenging problem for the physician. Endocrine disorders, such as subacute thyroiditis, rarely present with pyrexia of unknown origin. Subacute thyroiditis can ha...

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The use of Latin terminology in medical case reports: quantitative, structural, and thematic analysis

This paper focuses on the prevalence of Latin terms and terminological collocations in the issues of Journal of Medical Case Reports (February 2007–August 2017) and discusses the role of Latin terminology in the ...

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First-line treatment of apatinib in elderly patient of advanced gastric carcinoma: A case report of NGS-driven targeted therapy

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The predictive value and role of stromal tumor-infiltrating lymphocytes in pancreatic ductal adenocarcinoma (PDAC)

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Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma

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MicroRNA-326 sensitizes human glioblastoma cells to curcumin via the SHH/GLI1 signaling pathway

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First-line treatment of apatinib in elderly patient of advanced gastric carcinoma: A case report of NGS-driven targeted therapy

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http://ift.tt/2orzzFH

The predictive value and role of stromal tumor-infiltrating lymphocytes in pancreatic ductal adenocarcinoma (PDAC)

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http://ift.tt/2CdbXhi

Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma

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http://ift.tt/2orVUTB

MicroRNA-326 sensitizes human glioblastoma cells to curcumin via the SHH/GLI1 signaling pathway

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Post-Ocular Trauma Corneal Staphyloma in a Child Living in an Underdeveloped Region of Eastern Indonesia

Ocular trauma occurring in children often leads to visual impairment or blindness when it is not properly managed. This often occurs in underdeveloped regions with difficult access to professional care at local health facilities. We report a case of post-trauma corneal staphyloma in an underdeveloped region of eastern Indonesia to illustrate the importance of proper management of ocular trauma in areas lacking such expertise and where patients have difficulty accessing even basic health care. During a community health outreach in Southwest Sumba, eastern Indonesia in May 2017, a 7-year-old boy presented with white protrusion of the left eye of 3 years' duration following an event of sharp trauma. The patient lived in an inaccessible and impoverished area. Upon contemporary examination, visual acuity of the left eye was 1/300 while that of the right eye was 6/6. Anterior examination revealed corneal staphyloma of the left eye, and its posterior segment could not be evaluated. The patient was transported to an eye care center in Jakarta, receiving a stock prosthesis implant while awaiting a corneal evisceration procedure with dermofat graft. Ocular trauma is one of the most common causes of visual impairment in children. This case illustrates the consequences of inadequate post-trauma management and the importance of prevention of infection.
Case Rep Ophthalmol 2018;9:24–29

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An intrapancreatic accessory spleen presenting as a rapidly growing pancreatic mass after splenectomy in a patient with hereditary spherocytosis: a case report and literature review

Abstract

The case of a 16-year-old boy with an intrapancreatic accessory spleen presenting as a rapidly growing pancreatic mass after splenectomy for splenomegaly due to hereditary spherocytosis is reported herein. When he was 15 years old, the patient visited at a hospital due to jaundice and radiological examinations showed a huge spleen with a 2-cm mass near or in the pancreatic tail. Sonazoid-enhanced ultrasonography showed hypervascularity in the mass located near the pancreatic tail, which was suspicious for an accessory spleen. During splenectomy by laparotomy, the mass could not be found by inspection or intraoperative ultrasonography. One year after the splenectomy, the mass grew rapidly to 4 cm. Laparoscopic surgery was performed to aid in the differential diagnosis of the mass, and a laparoscopic ultrasonogram revealed that the mass was located in the pancreatic tail. The patient underwent laparoscopic distal pancreatectomy and was discharged uneventfully on the 11th postoperative day.

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Disparity in breast cancer mortality by age and geography in 10 racially diverse US cities

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Dominique Sighoko, Bijou R. Hunt, Bethliz Irizarry, Karriem Watson, David Ansell, Anne Marie Murphy
ObjectivesAssess geographic variation in breast cancer racial mortality disparity by age cohorts in US and ten cities with large African American populations.MethodsNon-Hispanic Black (NHB) and Non-Hispanic White (NHW) female breast cancer mortality rates and NHB:NHW rate ratio (RR) (disparity) were calculated by four age group categories: <40, 40–49, 50–64 and 65+ with time period 1999–2013.ResultsIn all 10 cities and the US, the most pronounced breast cancer disparities, measured by RR, were seen among younger women. In age group <40, the RR ranges from 1.71 in Houston to 5.37 in Washington, DC. For age group 50–64, the disparity was less pronounced, ranging from 1.24 in New York to 1.72 in Chicago. For 65+ age group, there was wide city to city variation in breast cancer mortality disparity. Three cities had higher mortality for NHW compared to NHB; Baltimore 0.78, Washington DC 0.94 and New York 0.98. One city had no statistically significant racial variation in breast cancer mortality in this age group and six cities had increased NHB: NHW mortality disparities.ConclusionsWhile the mortality rate for breast cancer is lower among younger women, the NHB:NHW disparities, as measured by rate ratios, are most pronounced in these age groups. Given the absence of available data regarding incidence, stage and subtypes, further research is necessary and such research is important, given the possible policy implications of these results with respect to screening guidelines and coverage for mammography and breast cancer treatment in particular for younger NHB women.



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Incidence of malignant lymphoma in adolescents and young adults in the 58 counties of California with varying synthetic turf field density

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Archie Bleyer, Theresa Keegan
BackgroundCase reports of cancer among soccer players raised concerns that the crumb rubber infill in synthetic turf fields may cause malignant lymphoma. One prior epidemiologic study on the topic found no association.MethodsAn ecologic evaluation of county-level incidence of lymphomas by race/ethnicity and socioeconomic status for the state of California with data obtained from the National Cancer Institute Surveillance, Epidemiology, and End Results Program. Synthetic turf field density by county was obtained from the Synthetic Turf Council. During 2000–2013, 7214 14- to 30-year-old Californians were diagnosed with malignant lymphoma.ResultsAnnual lymphoma county incidence trends were not associated with the county-level synthetic turf field density. None of 20 sub-analyses by race/ethnicity, sex and county median household income indicated a correlation of lymphoma incidence with synthetic turf field density. In California, there was no evidence at the county-level that synthetic turf fields are associated with an increased incidence of lymphoma in adolescents and young adults.ConclusionOur findings in the state with the greatest number of such fields and a large, diverse patient population are consistent with those of a prior study observing no association between individual-level exposures to turf fields and cancer incidence. Avoidance of synthetic turf fields for fear of increased cancer risk is not warranted.



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Maintenance proton pump inhibition therapy and risk of oesophageal cancer

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Nele Brusselaers, Lars Engstrand, Jesper Lagergren
BackgroundThe association of long-term use of proton pump inhibitors (PPIs) with oesophageal adenocarcinoma has been poorly defined. Our aim was to assess the risk of oesophageal cancer assessing confounding by indication.MethodsThis population-based cohort study included all 796,492 adults exposed to maintenance therapy with PPIs in Sweden in 2005–2012. Standardised incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated to assess the risk of oesophageal adenocarcinoma (and squamous cell carcinoma as a comparison) among long-term PPI users relative to the corresponding background population. The different indications for maintenance PPI therapy were analysed separately.ResultsAmong all individuals using maintenance PPI therapy, the overall SIR of oesophageal adenocarcinoma was 3.93 (95% CI 3.63–4.24). The SIRs of adenocarcinoma were increased also among individuals without gastro-oesophageal reflux disease who used PPIs for indications not associated with any increased risk of oesophageal adenocarcinoma. For example, the SIRs among participants using maintenance PPI therapy because of maintenance treatment with non-steroidal anti-inflammatory drugs and aspirin were 2.74 (95% CI 1.96–3.71) and 2.06 (95% CI 1.60–2.60), respectively. The SIRs of oesophageal squamous cell carcinoma were increased for most investigated indications, but to a lesser degree than for oesophageal adenocarcinoma.ConclusionIn conclusion, the long term use of PPIs is associated with increased risk of oesophageal adenocarcinoma in the absence of other risk factors. Long term use of PPIs should be addressed with caution.



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Evaluation of data quality at the National Cancer Registry of Ukraine

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Anton Ryzhov, Freddie Bray, Jacques Ferlay, Zoya Fedorenko, Liudmyla Goulak, Yevgeniy Gorokh, Olena Soumkina, Ariana Znaor
BackgroundCancer notification has been mandatory in Ukraine since 1953, with the National Cancer Registry of Ukraine (NCRU) established in 1996. The aim of this study was to provide a comprehensive evaluation of the data quality at the NCRU.MethodsQualitative and semi-quantitative methods were used to assess the comparability, completeness, validity and timeliness of cancer incidence data from the NCRU for the period 2002–2012.ResultsCancer registration procedures at the NCRU are in accordance with international standards and recommendations. Semi-quantitative methods suggested the NCRU's data was reasonably complete, although decreases in age-specific incidence and mortality rates in the elderly indicated some missing cases at older ages. The proportion of microscopically-verified cases increased from 73.6% in 2002 to 82.3% in 2012, with death-certificate-only (DCO) proportions stable at around 0.1% and unknown stage recorded in 9.6% of male and 7.5% of female solid tumours. Timeliness was considered acceptable, with reporting >99% complete within a turn-around time of 15 months.ConclusionWhile timely reporting of national data reflects the advantages of a mandatory data collection system, a low DCO% and observed age-specific declines suggest possible underreporting of incidence and mortality data, particularly at older ages. Overall, the evaluation indicates that the data are reasonably comparable and thus may be used to describe the magnitude of the cancer burden in Ukraine. Given its central role in monitoring and evaluation of cancer control activities, ensuring the sustainability of NCRU operations throughout the process of healthcare system reform is of utmost importance.



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Disparity in breast cancer mortality by age and geography in 10 racially diverse US cities

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Dominique Sighoko, Bijou R. Hunt, Bethliz Irizarry, Karriem Watson, David Ansell, Anne Marie Murphy
ObjectivesAssess geographic variation in breast cancer racial mortality disparity by age cohorts in US and ten cities with large African American populations.MethodsNon-Hispanic Black (NHB) and Non-Hispanic White (NHW) female breast cancer mortality rates and NHB:NHW rate ratio (RR) (disparity) were calculated by four age group categories: <40, 40–49, 50–64 and 65+ with time period 1999–2013.ResultsIn all 10 cities and the US, the most pronounced breast cancer disparities, measured by RR, were seen among younger women. In age group <40, the RR ranges from 1.71 in Houston to 5.37 in Washington, DC. For age group 50–64, the disparity was less pronounced, ranging from 1.24 in New York to 1.72 in Chicago. For 65+ age group, there was wide city to city variation in breast cancer mortality disparity. Three cities had higher mortality for NHW compared to NHB; Baltimore 0.78, Washington DC 0.94 and New York 0.98. One city had no statistically significant racial variation in breast cancer mortality in this age group and six cities had increased NHB: NHW mortality disparities.ConclusionsWhile the mortality rate for breast cancer is lower among younger women, the NHB:NHW disparities, as measured by rate ratios, are most pronounced in these age groups. Given the absence of available data regarding incidence, stage and subtypes, further research is necessary and such research is important, given the possible policy implications of these results with respect to screening guidelines and coverage for mammography and breast cancer treatment in particular for younger NHB women.



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Incidence of malignant lymphoma in adolescents and young adults in the 58 counties of California with varying synthetic turf field density

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Archie Bleyer, Theresa Keegan
BackgroundCase reports of cancer among soccer players raised concerns that the crumb rubber infill in synthetic turf fields may cause malignant lymphoma. One prior epidemiologic study on the topic found no association.MethodsAn ecologic evaluation of county-level incidence of lymphomas by race/ethnicity and socioeconomic status for the state of California with data obtained from the National Cancer Institute Surveillance, Epidemiology, and End Results Program. Synthetic turf field density by county was obtained from the Synthetic Turf Council. During 2000–2013, 7214 14- to 30-year-old Californians were diagnosed with malignant lymphoma.ResultsAnnual lymphoma county incidence trends were not associated with the county-level synthetic turf field density. None of 20 sub-analyses by race/ethnicity, sex and county median household income indicated a correlation of lymphoma incidence with synthetic turf field density. In California, there was no evidence at the county-level that synthetic turf fields are associated with an increased incidence of lymphoma in adolescents and young adults.ConclusionOur findings in the state with the greatest number of such fields and a large, diverse patient population are consistent with those of a prior study observing no association between individual-level exposures to turf fields and cancer incidence. Avoidance of synthetic turf fields for fear of increased cancer risk is not warranted.



http://ift.tt/2HD6aRA

Maintenance proton pump inhibition therapy and risk of oesophageal cancer

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Nele Brusselaers, Lars Engstrand, Jesper Lagergren
BackgroundThe association of long-term use of proton pump inhibitors (PPIs) with oesophageal adenocarcinoma has been poorly defined. Our aim was to assess the risk of oesophageal cancer assessing confounding by indication.MethodsThis population-based cohort study included all 796,492 adults exposed to maintenance therapy with PPIs in Sweden in 2005–2012. Standardised incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated to assess the risk of oesophageal adenocarcinoma (and squamous cell carcinoma as a comparison) among long-term PPI users relative to the corresponding background population. The different indications for maintenance PPI therapy were analysed separately.ResultsAmong all individuals using maintenance PPI therapy, the overall SIR of oesophageal adenocarcinoma was 3.93 (95% CI 3.63–4.24). The SIRs of adenocarcinoma were increased also among individuals without gastro-oesophageal reflux disease who used PPIs for indications not associated with any increased risk of oesophageal adenocarcinoma. For example, the SIRs among participants using maintenance PPI therapy because of maintenance treatment with non-steroidal anti-inflammatory drugs and aspirin were 2.74 (95% CI 1.96–3.71) and 2.06 (95% CI 1.60–2.60), respectively. The SIRs of oesophageal squamous cell carcinoma were increased for most investigated indications, but to a lesser degree than for oesophageal adenocarcinoma.ConclusionIn conclusion, the long term use of PPIs is associated with increased risk of oesophageal adenocarcinoma in the absence of other risk factors. Long term use of PPIs should be addressed with caution.



http://ift.tt/2GCPFDN

Impact of metformin on gastric adenocarcinoma survival: A Belgian population based study

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Olivia Lacroix, Alexandra Couttenier, Evelien Vaes, Chris R. Cardwell, Harlinde De Schutter, Annie Robert
BackgroundPreclinical studies have shown anticancer activities of metformin in gastric cancer and a recent epidemiological study showed a decrease in recurrence and mortality of gastric cancer in metformin users. This study aimed to assess the impact of metformin on gastric cancer survival in diabetic patients at a Belgian population level.MethodsWe conducted an observational, population-based study by linking data of the Belgian Cancer Registry with medical claims data coming from the health insurance companies for patients diagnosed with stage I to III gastric adenocarcinoma between 2006 and 2012. Information on gastric cancer-specific deaths was retrieved from mortality records collected by regional governments. Time-dependent Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival (OS) and cancer-specific mortality (CSS).ResultsIn our population of 371 patients, a reduction in all-cause mortality was observed in metformin users (adjusted HR = 0.73, 95% CI: [0.52; 1.01], p = 0.06) but not for cancer specific mortality (adjusted HR = 0.86, 95% CI: [0.56; 1.33], p = 0.50). Pre-diagnosis exposure to metformin was associated with a significant improvement in OS (adjusted HR = 0.75, 95% CI: [0.57; 0.98], p = 0.04) that was not significant for CSS (adjusted HR = 0.89, 95% CI: [0.62; 1.28], p = 0.52). Moreover, no dose-response relationship between metformin use and either all-cause or cancer-specific mortality was observed.ConclusionIn the first population based study of metformin use in gastric cancer adenocarcinoma patients with previous diabetes, our findings suggest that metformin use might improve overall mortality. However, no such association was found for cancer-specific survival. Additional studies in other populations are required.



http://ift.tt/2BLyiS0

Evaluation of data quality at the National Cancer Registry of Ukraine

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Anton Ryzhov, Freddie Bray, Jacques Ferlay, Zoya Fedorenko, Liudmyla Goulak, Yevgeniy Gorokh, Olena Soumkina, Ariana Znaor
BackgroundCancer notification has been mandatory in Ukraine since 1953, with the National Cancer Registry of Ukraine (NCRU) established in 1996. The aim of this study was to provide a comprehensive evaluation of the data quality at the NCRU.MethodsQualitative and semi-quantitative methods were used to assess the comparability, completeness, validity and timeliness of cancer incidence data from the NCRU for the period 2002–2012.ResultsCancer registration procedures at the NCRU are in accordance with international standards and recommendations. Semi-quantitative methods suggested the NCRU's data was reasonably complete, although decreases in age-specific incidence and mortality rates in the elderly indicated some missing cases at older ages. The proportion of microscopically-verified cases increased from 73.6% in 2002 to 82.3% in 2012, with death-certificate-only (DCO) proportions stable at around 0.1% and unknown stage recorded in 9.6% of male and 7.5% of female solid tumours. Timeliness was considered acceptable, with reporting >99% complete within a turn-around time of 15 months.ConclusionWhile timely reporting of national data reflects the advantages of a mandatory data collection system, a low DCO% and observed age-specific declines suggest possible underreporting of incidence and mortality data, particularly at older ages. Overall, the evaluation indicates that the data are reasonably comparable and thus may be used to describe the magnitude of the cancer burden in Ukraine. Given its central role in monitoring and evaluation of cancer control activities, ensuring the sustainability of NCRU operations throughout the process of healthcare system reform is of utmost importance.



http://ift.tt/2CdMbJP

The investigation for potential modifier genes in patients with neurofibromatosis type 1 based on next-generation sequencing

http://ift.tt/2CdKaNZ

Postoperative hepatic arterial infusion chemotherapy improved survival of pancreatic cancer after radical pancreatectomy: a retrospective study

http://ift.tt/2BJIafg

Low levels of tumor suppressor candidate 3 predict poor prognosis of patients with hepatocellular carcinoma

http://ift.tt/2CfkhNC

Epigenetic silencing of RNF144A expression in breast cancer cells through promoter hypermethylation and MBD4

Abstract

Emerging evidence shows that ring finger protein 144A (RNF144A), a poorly characterized member of the Ring-between-Ring (RBR) family of E3 ubiquitin ligases, is a potential tumor suppressor gene. However, its regulatory mechanism in breast cancer remains undefined. Here, we report that RNF144A promoter contains a putative CpG island and the methylation levels of RNF144A promoter are higher in primary breast tumors than those in normal breast tissues. Consistently, RNF144A promoter methylation levels are associated with its transcriptional silencing in breast cancer cells, and treatment with DNA methylation inhibitor 5-Aza-2-deoxycytidine (AZA) reactivates RNF144A expression in cells with RNF144A promoter hypermethylation. Furthermore, genetic knockdown or pharmacological inhibition of endogenous methyl-CpG-binding domain 4 (MBD4) results in increased RNF144A expression. These findings suggest that RNF144A is epigenetically silenced in breast cancer cells by promoter hypermethylation and MBD4.

RNF144A is epigenetically silenced in breast cancer cells by promoter hypermethylation and MBD4.

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Clofarabine exerts antileukemic activity against cytarabine-resistant B-cell precursor acute lymphoblastic leukemia with low deoxycytidine kinase expression

Abstract

Cytosine arabinoside (Ara-C) is one of the key drugs for the treatment of acute myeloid leukemia. It is also used for consolidation therapy of acute lymphoblastic leukemia (ALL). Ara-C is a deoxyadenosine analog and is phosphorylated to form cytosine arabinoside triphosphate (Ara-CTP) as an active form. In the first step of the metabolic pathway, Ara-C is phosphorylated to Ara-CMP by deoxycytidine kinase (DCK). However, the current cumulative evidence in the association of the Ara-C sensitivity in ALL appears inconclusive. We analyzed various cell lines for the possible involvement of DCK in the sensitivities of B-cell precursor ALL (BCP-ALL) to Ara-C. Higher DCK expression was associated with higher Ara-C sensitivity. DCK knockout by genome editing with a CRISPR-Cas9 system in an Ara-C-sensitive-ALL cell line induced marked resistance to Ara-C, but not to vincristine and daunorubicin, indicating the involvement of DCK expression in the Ara-C sensitivity of BCP-ALL. DCK gene silencing due to the hypermethylation of a CpG island and reduced DCK activity due to a nonsynonymous variant allele were not associated with Ara-C sensitivity. Clofarabine is a second-generation deoxyadenosine analog rationally synthesized to improve stability and reduce toxicity. The IC50 of clofarabine in 79 BCP-ALL cell lines was approximately 20 times lower than that of Ara-C. In contrast to Ara-C, although the knockout of DCK induced marked resistance to clofarabine, sensitivity to clofarabine was only marginally associated with DCK gene expression level, suggesting a possible efficacy of clofarabine for BCP-ALL that shows relative Ara-C resistance due to low DCK expression.

We demonstrated that DCK knockout by genome editing with a CRISPR-Cas9 system in an Ara-C-sensitive-ALL cell line induced resistance to Ara-C and clofarabine, a second-generation deoxyadenosine analog, and that higher DCK expression was associated with higher AraC sensitivity in a series of B-cell precursor ALL (BCP–ALL) cell lines. In contrast, sensitivity to clofarabine was only marginally associated with DCK gene expression level, suggesting the high antileukemic potential of clofarabine may overcome low DCK expression in Ara-C-resistant BCP–ALL.

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The current state and future perspectives of cannabinoids in cancer biology

Abstract

To date, cannabinoids have been allowed in the palliative medicine due to their analgesic and antiemetic effects, but increasing number of preclinical studies indicates their anticancer properties. Cannabinoids exhibit their action by a modulation of the signaling pathways crucial in the control of cell proliferation and survival. Many in vitro and in vivo experiments have shown that cannabinoids inhibit proliferation of cancer cells, stimulate autophagy and apoptosis, and have also a potential to inhibit angiogenesis and metastasis. In this review, we present an actual state of knowledge regarding molecular mechanisms of cannabinoids' anticancer action, but we discuss also aspects that are still not fully understood such as the role of the endocannabinoid system in a carcinogenesis, the impact of cannabinoids on the immune system in the context of cancer development, or the cases of a stimulation of cancer cells' proliferation by cannabinoids. The review includes also a summary of currently ongoing clinical trials evaluating the safety and efficacy of cannabinoids as anticancer agents.

Preclinical studies have shown that cannabinoids can exhibit anticancer action, but the role of the endocannabinoid system in carcinogenesis is not fully elucidated. There are also cases of stimulation of cancer cells' proliferation by cannabinoids. We present an actual state of knowledge regarding mechanisms of cannabinoids' impact on cancer cells.

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MiR-634 sensitizes glioma cells to temozolomide by targeting CYR61 through Raf-ERK signaling pathway

Abstract

Glioma is the most common intracranial malignant tumors, accounting for about 40% of intracranial tumors. Primary or secondary drug resistance is one of the main reasons for the failure of treatment. The oncogenic or tumor-suppressive roles of miR-634 have been revealed in different types of cancer. However, the role of miR-634 in glioma remains unknown and whether miR-634 could sensitize glioma cells to temozolomide also is unclear. Here, we aim to investigate the biological function of miR-634 and the possible mechanisms in glioma. In this study, we found that miR-634 was downregulated in glioma tissues compared with normal brain tissues, and its expression was associated with tumor size and WHO grade. Importantly, glioma patients with low miR-634 expression showed a shorter survival time than patients which had high expression of miR-634. This study also showed that miR-634 was decreased in temozolomide-resistant glioma cells, and restoration of miR-634 could sensitize the resistant cells to temozolomide by targeting CYR61 through Raf-ERK signaling. Our study provides a potential target for overcome drug resistance in glioma.

miR-634 was decreased in temozolomide-resistant glioma cells, and restoration of miR-634 could sensitize the resistant cells to temozolomide by targeting CYR61 through Raf-ERK signaling.

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A nomogram incorporating six easily obtained parameters to discriminate intrahepatic cholangiocarcinoma and hepatocellular carcinoma

Abstract

Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are the most prevalent histologic types of primary liver cancer (PLC). Although ICC and HCC share similar risk factors and clinical manifestations, ICC usually bears poorer prognosis than HCC. Confidently discriminating ICC and HCC before surgery is beneficial to both treatment and prognosis. Given the lack of effective differential diagnosis biomarkers and methods, construction of models based on available clinicopathological characteristics is in need. Nomograms present a simple and efficient way to make a discrimination. A total of 2894 patients who underwent surgery for PLC were collected. Of these, 1614 patients formed the training cohort for nomogram construction, and thereafter, 1280 patients formed the validation cohort to confirm the model's performance. Histopathologically confirmed ICC was diagnosed in 401 (24.8%) and 296 (23.1%) patients in these two cohorts, respectively. A nomogram integrating six easily obtained variables (Gender, Hepatitis B surface antigen, Aspartate aminotransferase, Alpha-fetoprotein, Carcinoembryonic antigen, Carbohydrate antigen 19-9) is proposed in accordance with Akaike's Information Criterion (AIC). A score of 15 was determined as the cut-off value, and the corresponding discrimination efficacy was sufficient. Additionally, patients who scored higher than 15 suffered poorer prognosis than those with lower scores, regardless of the subtype of PLC. A nomogram for clinical discrimination of ICC and HCC has been established, where a higher score indicates ICC and poor prognosis. Further application of this nomogram in multicenter investigations may confirm the practicality of this tool for future clinical use.

Confidently discriminating ICC and HCC before surgery can improve both treatment and prognosis. The authors have used a large-scale study to construct a simple nomogram model incorporating six easily obtained parameters, which demonstrates high accuracy (AUC >0.85) when compared with clinical histologic examination.

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Epigenetic silencing of RNF144A expression in breast cancer cells through promoter hypermethylation and MBD4

Abstract

Emerging evidence shows that ring finger protein 144A (RNF144A), a poorly characterized member of the Ring-between-Ring (RBR) family of E3 ubiquitin ligases, is a potential tumor suppressor gene. However, its regulatory mechanism in breast cancer remains undefined. Here, we report that RNF144A promoter contains a putative CpG island and the methylation levels of RNF144A promoter are higher in primary breast tumors than those in normal breast tissues. Consistently, RNF144A promoter methylation levels are associated with its transcriptional silencing in breast cancer cells, and treatment with DNA methylation inhibitor 5-Aza-2-deoxycytidine (AZA) reactivates RNF144A expression in cells with RNF144A promoter hypermethylation. Furthermore, genetic knockdown or pharmacological inhibition of endogenous methyl-CpG-binding domain 4 (MBD4) results in increased RNF144A expression. These findings suggest that RNF144A is epigenetically silenced in breast cancer cells by promoter hypermethylation and MBD4.

RNF144A is epigenetically silenced in breast cancer cells by promoter hypermethylation and MBD4.

http://ift.tt/2HHzruI

Clofarabine exerts antileukemic activity against cytarabine-resistant B-cell precursor acute lymphoblastic leukemia with low deoxycytidine kinase expression

Abstract

Cytosine arabinoside (Ara-C) is one of the key drugs for the treatment of acute myeloid leukemia. It is also used for consolidation therapy of acute lymphoblastic leukemia (ALL). Ara-C is a deoxyadenosine analog and is phosphorylated to form cytosine arabinoside triphosphate (Ara-CTP) as an active form. In the first step of the metabolic pathway, Ara-C is phosphorylated to Ara-CMP by deoxycytidine kinase (DCK). However, the current cumulative evidence in the association of the Ara-C sensitivity in ALL appears inconclusive. We analyzed various cell lines for the possible involvement of DCK in the sensitivities of B-cell precursor ALL (BCP-ALL) to Ara-C. Higher DCK expression was associated with higher Ara-C sensitivity. DCK knockout by genome editing with a CRISPR-Cas9 system in an Ara-C-sensitive-ALL cell line induced marked resistance to Ara-C, but not to vincristine and daunorubicin, indicating the involvement of DCK expression in the Ara-C sensitivity of BCP-ALL. DCK gene silencing due to the hypermethylation of a CpG island and reduced DCK activity due to a nonsynonymous variant allele were not associated with Ara-C sensitivity. Clofarabine is a second-generation deoxyadenosine analog rationally synthesized to improve stability and reduce toxicity. The IC50 of clofarabine in 79 BCP-ALL cell lines was approximately 20 times lower than that of Ara-C. In contrast to Ara-C, although the knockout of DCK induced marked resistance to clofarabine, sensitivity to clofarabine was only marginally associated with DCK gene expression level, suggesting a possible efficacy of clofarabine for BCP-ALL that shows relative Ara-C resistance due to low DCK expression.

We demonstrated that DCK knockout by genome editing with a CRISPR-Cas9 system in an Ara-C-sensitive-ALL cell line induced resistance to Ara-C and clofarabine, a second-generation deoxyadenosine analog, and that higher DCK expression was associated with higher AraC sensitivity in a series of B-cell precursor ALL (BCP–ALL) cell lines. In contrast, sensitivity to clofarabine was only marginally associated with DCK gene expression level, suggesting the high antileukemic potential of clofarabine may overcome low DCK expression in Ara-C-resistant BCP–ALL.

http://ift.tt/2GBfFzG