Drug repurposing screening identifies bortezomib and panobinostat as drugs targeting cancer associated fibroblasts (CAFs) by synergistic induction of apoptosis

Summary

Cancer associated fibroblasts (CAFs) are the most abundant components of cancer-microenvironment. They play important roles in cancer initiation, progression, and metastasis. In addition, CAFs can confer drug-resistance to cancer cells. Considering their pro-tumorigenic roles, it is recommended to remove CAFs to prevent cancer recurrence after chemotherapy. Despite their clinical significance, few anti-CAF drugs have been developed. The objective of this study was to find a drug that could suppress the viability of patient-derived CAFs through repurposed screening of 51 drugs that were in clinical trials or received FDA approval. As a result, bortezomib (BTZ), carfilzomib (CFZ), and panobinostat (PST) were identified as anti-CAF drug candidates. It was confirmed that BTZ and PST could decrease the viability of various patients derived CAFs through inducing of caspase-3 mediated apoptosis. Interestingly, combination therapy with BTZ and PST showed better efficacy of inhibiting CAFs than single treatment. The synergistic effect between BTZ and PST on viability of CAFs was observed both in vitro CAF culture and in vivo mouse model. Furthermore, combination therapy with BTZ/PST and conventional anticancer compound docetaxel strongly inhibited tumor growth in xenografts of mouse breast cancer cells with mouse CAFs. In conclusion, our present study revealed that BTZ and PST could significantly reduce the viability of CAFs. Therefore, a combination therapy with BTZ/PST and anticancer drugs might be considered as a new rational for the development of anticancer therapy.

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Cancers, Vol. 10, Pages 21: IRF4 Mediates the Oncogenic Effects of STAT3 in Anaplastic Large Cell Lymphomas

Cancers, Vol. 10, Pages 21: IRF4 Mediates the Oncogenic Effects of STAT3 in Anaplastic Large Cell Lymphomas

Cancers doi: 10.3390/cancers10010021

Authors: Cecilia Bandini Aldi Pupuleku Elisa Spaccarotella Elisa Pellegrino Rui Wang Nicoletta Vitale Carlotta Duval Daniela Cantarella Andrea Rinaldi Paolo Provero Ferdinando Di Cunto Enzo Medico Francesco Bertoni Giorgio Inghirami Roberto Piva

Systemic anaplastic large cell lymphomas (ALCL) are a category of T-cell non-Hodgkin's lymphomas which can be divided into anaplastic lymphoma kinase (ALK) positive and ALK negative subgroups, based on ALK gene rearrangements. Among several pathways aberrantly activated in ALCL, the constitutive activation of signal transducer and activator of transcription 3 (STAT3) is shared by all ALK positive ALCL and has been detected in a subgroup of ALK negative ALCL. To discover essential mediators of STAT3 oncogenic activity that may represent feasible targets for ALCL therapies, we combined gene expression profiling analysis and RNA interference functional approaches. A shRNA screening of STAT3-modulated genes identified interferon regulatory factor 4 (IRF4) as a key driver of ALCL cell survival. Accordingly, ectopic IRF4 expression partially rescued STAT3 knock-down effects. Treatment with immunomodulatory drugs (IMiDs) induced IRF4 down regulation and resulted in cell death, a phenotype rescued by IRF4 overexpression. However, the majority of ALCL cell lines were poorly responsive to IMiDs treatment. Combination with JQ1, a bromodomain and extra-terminal (BET) family antagonist known to inhibit MYC and IRF4, increased sensitivity to IMiDs. Overall, these results show that IRF4 is involved in STAT3-oncogenic signaling and its inhibition provides alternative avenues for the design of novel/combination therapies of ALCL.

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Cancers, Vol. 10, Pages 21: IRF4 Mediates the Oncogenic Effects of STAT3 in Anaplastic Large Cell Lymphomas

Cancers, Vol. 10, Pages 21: IRF4 Mediates the Oncogenic Effects of STAT3 in Anaplastic Large Cell Lymphomas

Cancers doi: 10.3390/cancers10010021

Authors: Cecilia Bandini Aldi Pupuleku Elisa Spaccarotella Elisa Pellegrino Rui Wang Nicoletta Vitale Carlotta Duval Daniela Cantarella Andrea Rinaldi Paolo Provero Ferdinando Di Cunto Enzo Medico Francesco Bertoni Giorgio Inghirami Roberto Piva

Systemic anaplastic large cell lymphomas (ALCL) are a category of T-cell non-Hodgkin's lymphomas which can be divided into anaplastic lymphoma kinase (ALK) positive and ALK negative subgroups, based on ALK gene rearrangements. Among several pathways aberrantly activated in ALCL, the constitutive activation of signal transducer and activator of transcription 3 (STAT3) is shared by all ALK positive ALCL and has been detected in a subgroup of ALK negative ALCL. To discover essential mediators of STAT3 oncogenic activity that may represent feasible targets for ALCL therapies, we combined gene expression profiling analysis and RNA interference functional approaches. A shRNA screening of STAT3-modulated genes identified interferon regulatory factor 4 (IRF4) as a key driver of ALCL cell survival. Accordingly, ectopic IRF4 expression partially rescued STAT3 knock-down effects. Treatment with immunomodulatory drugs (IMiDs) induced IRF4 down regulation and resulted in cell death, a phenotype rescued by IRF4 overexpression. However, the majority of ALCL cell lines were poorly responsive to IMiDs treatment. Combination with JQ1, a bromodomain and extra-terminal (BET) family antagonist known to inhibit MYC and IRF4, increased sensitivity to IMiDs. Overall, these results show that IRF4 is involved in STAT3-oncogenic signaling and its inhibition provides alternative avenues for the design of novel/combination therapies of ALCL.

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Association of conformality index and post-treatment radiation pneumonitis in early-stage non-small cell lung cancer treated with stereotactic body radiotherapy

Abstract

Purpose

Conformality index of the 50% prescription isodose volume (CI50) is an important variable in lung stereotactic body radiotherapy (SBRT) planning but has not been previously correlated to radiation pneumonitis (RP). We hypothesized that adherence to recommended CI50 for patients undergoing lung SBRT would result in decreased incidence and/or severity of RP compared to that for patients with minimal deviations and unacceptable deviations.

Methods and materials

We retrospectively identified patients treated between 2006 and 2016, with > 3 months follow up from lung SBRT treatment. CTCAE v4.0 toxicity grades were used to classify RP. Clinically significant RP was defined as grade ≥ 2 toxicity. Using Radiation Therapy Oncology Group CI50 planning guidelines, patients were separated into three groups: acceptable, minor deviation, and unacceptable deviation. CI25 and CI75 values in patients with and without clinically significant RP were also reported in this study.

Results

One hundred seventy-four patients with a median follow-up time of 26.8 months were included in this analysis. Overall incidence of grade ≥ 2 RP was 12.7%. Thirty-eight (21.8%) patients had acceptable CI50, 100 (57.5%) had minor deviations, and 36 (20.7%) had unacceptable deviations. Incidence of RP did not significantly differ between patients with acceptable, minor deviation, and unacceptable CI50. Additionally, CI25 and CI75 did not significantly differ between patients with and without clinically significant RP.

Conclusions

Adhering to recommended CI50 values does not significantly decrease the incidence of clinically significant RP in patients with NSCLC treated with SBRT. To the authors' knowledge, this observation has not been published previously.

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Defining limited stage small cell lung cancer: a radiation oncologists perspective

Description

Small cell lung cancer (SCLC) comprises 13%–15% of all diagnosed lung carcinomas and approximately 30% of those will be defined as limited stage-SCLC (LS-SCLC).1 The definition of LS-SCLC has undergone many modifications and there is no universally accepted definition till date (figure 1).2 It was first defined by the Veteran Affairs Lung cancer study Group (VALG) in 1973 and further redefined by the International Association for the Study of Lung Cancer (IASLC) and American Joint Committee on Cancer (AJCC) in 1989 and 2010, respectively.1 2 Considerable heterogeneity exists pertaining to which definition is used for treating patients in routine practice. As a direct consequence of this, discussions often arise in multidisciplinary tumour board meetings in which different oncologists classify the same patient differently. The subsequent images demonstrate the heterogeneity in subjective classification of patients with SCLC and the role of radiotherapy (RT) in...

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Sarcomatoid carcinoma of the duodenum

Description

A 69-year-old Caucasian man presented to the gastroenterology clinic with complaints of nausea, abdominal pain and more than 100-pound unintentional weight loss over the past 1 year. He had a history of colon polyps and was overdue for surveillance colonoscopy. He was subsequently scheduled for an outpatient oesophagogastroduodenoscopy (EGD) and colonoscopy as initial work-up for his symptoms. One week later, the patient underwent endoscopy. EGD showed an ulcerated mass in the second portion of the duodenum (figure 1). Biopsy of the lesion showed features of pleomorphic cells without glandular differentiation (figures 2 and 3). Immunohistochemical studies revealed pleomorphic cells positive for cytokeratin AE1/AE3 (figure 4), CAM 5.2 and vimentin (figure 5), focally positive for CK7 (figure 6), and weakly for CK20. They were negative for neuroendocrine markers chromogranin, synaptophysin, and CD45 which is a lymphoid marker. Additional...

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Morbid jealousy reactivated by mood episodes

A middle-aged man who has been enduring financial constraint experienced a period of irritability, increased goal-directed activities and insomnia occurring along with extreme jealousy with his current wife. The episode was followed by depressed mood and non-prominent auditory hallucination. His previous history revealed a forensic psychiatry case of a murder he committed 20 years ago.

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Bruns nystagmus: an important clinical clue for cerebellopontine angle tumours

Description

A 24-year-old woman presented with gradual-onset left-sided hearing loss, progressive diminution of vision, headache and unsteadiness of gait. Comprehensive clinical evaluation revealed a left-sided lower motor neuron type of facial nerve palsy (figure 1), bilateral papilloedema, sensory loss in the distribution of ophthalmic branch of the left trigeminal nerve and cerebellar ataxia. Sensorineural hearing loss and absent corneal reflex were also observed on the left side. A coarse, left-beating nystagmus with leftward gaze and a fine primary-position right-beating nystagmus which increased on rightward gaze, consistent with Bruns nystagmus (video 1), were appreciated. In view of the clinical findings, a diagnosis of a space-occupying lesion involving the left cerebellopontine angle was considered. MRI of the brain documented a space-occupying lesion (4x3.5 cm) in the left cerebellopontine angle, most likely a vestibular schwannoma (figures 2 and 3). The condition was explained to...

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An unusual case of basilar artery aneurysm presenting with spastic quadriparesis

Unruptured aneurysm usually presents with headache and neuro-ophthalmic features; when it ruptures, it presents with subarachnoid haemorrhage. Basilar artery aneurysm represents only 3–5% of cerebral aneurysms. Non-haemorrhagic symptoms and the signs of unruptured aneurysms are manifested as mass effect, thromboembolic phenomenon or epileptical attacks. Clinical presentation of unruptured aneurysm depends on structures which are involved. In our case, the patient had insidious onset headache and spastic quadriparesis with sixth cranial nerve palsy, which implicate involvement of corticospinal pathways at the level of pons.

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Urinary Bladder Mass Due To Chronic Lymphocytic Leukaemia

Description

A 66-year-old man was diagnosed with chronic lymphocytic leukaemia (CLL) in November 2014. At diagnosis, his lymphocyte count was 169.66x10⁹/L (table 1). The fluorescent in situ hybridisation (FISH) panel revealed 13q deletion, but there was no evidence of 17p deletion, 11q deletion or t (11;14). He then received four cycles of bendamustine and rituximab, and at the end of the treatment complete blood count showed a lymphocyte count of 1.01x10⁹/L (table 1), and an interval bone marrow biopsy showed only small lymphoid aggregate suggestive of partial response.1 In June 2017, his lymphocyte count was found to be elevated at 14.5x10⁹/L (table 1). An immunophenotypic analysis of the peripheral blood demonstrated approximately 78% lymphocytes and 0.5% mature CD14-positive monocytes. A predominant monoclonal B cell population was identified, comprising approximately 85% of lymphocytes and 67% of the processed specimen. It was...

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Budd-Chiari syndrome: a rare and life-threatening complication of Crohns disease

Budd-Chiari syndrome (BCS) is characterised by obstruction of hepatic venous outflow and may be triggered by the prothrombotic state associated with inflammatory bowel disease (IBD). We reported a case of Crohn's disease (CD) that presented with anasarca, ascites, symptomatic hepatomegaly, elevated liver enzymes, increased prothrombin time and low albumin. Oesophagogastroduodenoscopy and colonoscopy confirmed active CD. Abdominal CT showed hepatic vein thrombosis. Liver biopsy revealed severe perivenular sinusoidal dilation with areas of hepatocyte dropout, bands of hepatocyte atrophy and centrizonal fibrosis, suggestive of BCS. The patient was treated with steroids for CD and systemic anticoagulants for BCS. His liver function and enzymes normalised, and he reported symptomatic improvement. The precise mechanism responsible for increased hypercoagulability in IBD remains unclear. Early recognition and treatment for possible thrombotic complications of CD is critical to prevent potentially fatal events like pulmonary embolism or liver failure.

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Recurrent hiccups may signal brainstem pathology and should be investigated

While occasional hiccups are normal, their persistent recurrence is distressing and may have an underlying aetiology. Patients with recurrent hiccups may undergo a long journey and see many physicians before the diagnosis is finally made. The purpose of this report is to increase awareness of central nervous system lesions as a possible cause for recurrent hiccups and provide an illustrative case of an otherwise fit man presenting with ongoing hiccups caused by a medullary haemangioblastoma.

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Vancomycin-induced coronary artery spasm: a case of Kounis syndrome

Kounis syndrome defined as the appearance of acute coronary syndrome in the context of an allergic reaction is a relatively rare phenomenon. There are three variants of this syndrome in which the patient presents with symptoms of an acute chest. Herein, we describe a case of an 83-year-old woman who demonstrated type I variant of Kounis syndrome in response to vancomycin administration. After initialisation of vancomycin, she became unresponsive and an ECG demonstrated ST changes consistent with inferior-lateral myocardial infarction. Once allergic stimulus was removed, ECG normalised. Differential diagnosis includes, myocardial infarctions, angina as well as intravascular stent thrombosis, which must all be ruled out. The patient was monitored and discharged soon thereafter.

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Early intrauterine pregnancy during major surgery: the importance of preoperative assessment and advice

We present a case of a live birth occurring post radical laparoscopic excision of endometriosis, hysteroscopy, curettage and test of tubal patency in the presence of an early intrauterine gestation.

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Acquired pyloric stenosis resulting in hypokalaemic, hyperchloraemic normal anion gap metabolic acidosis. Persistent vomiting in an adult: cause and effect

A 24-year-old woman presented with a history of persistent vomiting for at least 3 months. This resulted in severe dehydration with risk of acute kidney injury. In addition to volume depletion, loss of gastric fluid resulted in a specific metabolic derangement—hypokalaemic, hypochloraemic normal anion gap metabolic alkalosis with a reduced ionised calcium concentration and paradoxical aciduria. These metabolic changes were reflected in her ECG. Investigation demonstrated acquired gastric outflow tract obstruction secondary to a pyloric peptic ulcer. The patient was resuscitated with intravenous crystalloid and electrolyte supplements. The acquired pyloric stenosis was treated medically with a proton pump inhibitor and Helicobacter pylori eradication therapy with excellent recovery.

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Marked cachexia in probable invasive pulmonary aspergillosis with bronchopleural fistula

A 49-year-old man with a medical history of diabetes and heavy smoking was admitted to intensive care with severe bilateral pneumonia associated with marked cachexia. He developed a complex right-sided bronchopleural fistula and was transferred to our tertiary centre for consideration of surgical intervention.

Despite escalation of antibiotic therapy, he did not improve and further investigations led to a diagnosis of invasive pulmonary aspergillosis. Definitive treatment plans required a right pneumonectomy; however, given the severity of cachexia, he remained unable to undergo such a large operation. This case demonstrates an atypical presentation of invasive pulmonary aspergillosis in a mildly immunodeficient individual. It highlights the challenges in assessment and management of critically ill patients' nutrition as well as optimal timing for surgical intervention.

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Portal vein embolisation in a patient with situs inversus

Portal vein embolisation (PVE) is a well-established technique used for patients who require major hepatic resections without sufficient volume of future remnant liver (FRL). We describe a case of PVE in a patient with situs inversus. Computed Tomography (CT) 4 weeks after the procedure demonstrated significant hypertrophy of the FRL. However, the surgical procedure was aborted due to signs of extrahepatic progression.

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'Clinically suspected myocarditis with pseudoinfarct presentation complicated with left ventricular aneurysm

A 51-year-old man presented with chest pain, high troponin level, inflammatory syndrome and ST-segment elevation in the anterior leads. While the transthoracic echocardiogram (TTE) showed anteroseptal hypokinesis and apical akinesis, the coronary angiogram was normal. Cardiac MR demonstrated a typical aspect of myocarditis (multiple areas of mid-myocardial late gadolinium enhancement, sparing the subendocardial layer, along with oedema). The initial diagnosis was clinically suspected myocarditis with pseudoinfarct presentation. However, the short-term evolution was not typical of this syndrome, since an apical transmural scar with aneurysm developed within 2 weeks. Seven years later, the patient remained asymptomatic, while Q waves persisted in anterior leads along with an apical aneurysm on TTE. A transmural myocardial necrosis with aneurysm is an unusual complication of acute myocarditis. The potential mechanisms accounting for the development of these lesions are reviewed, and the clinical implications for the diagnosis and monitoring of acute myocarditis are discussed.

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A ping-pong ball in left atrium

Description

Rheumatic heart disease (RHD) is much prevalent in low/middle-income  country like India with the prevalence ranging from 0.2 to 1.1/1000 for RHD and from 0.0007 to 0.2/1000 for rheumatic fever.1 Factors that precipitate the formation of clot are atrial fibrillation (AF) rhythm, left atrial (LA) size, duration of symptoms, advanced age and severity of mitral stenosis (MS).2 The prevalence of LA clot in patients with MS is 26% in the AF group and 13.5% in the normal sinus rhythm group.3 The risk of thromboembolism is 9–14% of patients suffering from RHD.4 5 Anticoagulation (vitamin K antagonist or heparin) is indicated in patients with MS with (1) AF (paroxysmal, persistent or permanent) or (2) prior embolic event or (3) a LA thrombus.6

We present a case of a 30-year-old man, a known case of RHD who had balloon mitral valvotomy (BMV) 10 years...

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Chronic strongyloidiasis with recurrent asthma exacerbations and steroid-associated 'hives

A 74-year-old man experienced worsening asthma for several years. Oral steroids were required on multiple occasions for asthma treatment. During his steroid courses, he developed a hive-like rash, which would resolve after completion of each steroid course. He was from Romania, and had lived in the USA for many years. Laboratory testing had shown eosinophilia. He was eventually diagnosed with strongyloidiasis by serology. Treatment with ivermectin led to marked improvement but not resolution of his long-term asthma. His hive-like rash, which was likely larva currens, did not recur with a subsequent steroid course. Improved recognition of strongyloidiasis, particularly in steroid-treated patients, is needed.

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Laryngeal tuberculosis: a rare cause of critical airway obstruction

Laryngeal tuberculosis (TB) is a rare condition, occurring in less than 1% of patients infected with pulmonary TB. We present a case of a 57-year-old male patient, who presented in extremis with audible stridor, increased work of breathing and cyanosis. In addition, the patient had a complex medical history, including a recent diagnosis of congenital malformation of the epiglottis. Emergency intervention was required to secure the airway, and after initial attempts at intubation were unsuccessful, an emergency tracheostomy was performed. Four days after initial presentation, his sputum tested positive for acid-fast bacilli, and a subsequent CT chest revealed pulmonary as well as laryngeal TB, which was confirmed on biopsy of the larynx. The patient was commenced on a 24-week course of anti-tuberculous treatment and was successfully decannulated 6 months after the emergency airway was established.

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Unusual 'feathery cause of a parapharyngeal abscess in an infant

A 7-month-old boy presented to the emergency department with reduced oral intake, neck swelling and fever. Clinical examination revealed a 3 cm left parotid and left level I neck swelling with left medialised tonsil but no trismus. Computed imaging confirmed the presence of an abscess in the peritonsillar area with extension into the parapharyngeal space and deep lobe of the parotid gland. The abscess was incised and drained transorally. Following drainage of the abscess, a small 3 mm suspicious foreign body was seen. After extraction, this was revealed to be a 60 mm feather. We would like to highlight this unusual case in an infant and to ensure that foreign body is considered as aetiology. There are only a handful of cases in the literature involving feathers causing neck abscesses and, to our knowledge, this is the first case where the patient presented with a pharyngeal abscess, which was drained transorally.

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Microangiopathies in pregnancy

Thrombotic thrombocytopenic purpura (TTP) is a potentially reversible, life-threatening medical emergency. We present a case of a 21-year-old female with evidence of haemolytic anaemia based on the presence of positive markers of haemolysis. Negative Coomb's test, thrombocytopenia and placental infarcts raised suspicion for a thrombotic microangiopathy. She was diagnosed with TTP and managed with emergency plasma exchange. Her recovery was immediate.

A presumptive diagnosis of TTP should be based on the presence of microangiopathic haemolytic anaemia with thrombocytopenia and plasma exchange should be initiated while complete work up is pending. Using the regular pentad solely for diagnosis of TTP will lead to underdiagnosis of many cases and should be avoided.

Several microangiopathies can be seen during pregnancy including TTP/atypical haemolytic uraemic syndrome, HELLP syndrome, pre-eclampsia, disseminated intravascular coagulopathy and antiphospholipid antibody syndrome. Distinction between each type will be the focus of our discussion as treatment decisions differ accordingly.

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Sinogenic intracranial complications: is adalimumab a culprit?

We present two 11-year-old girls with chronic recurrent multifocal osteomyelitis, treated with adalimumab. Both developed severe intracranial complications to sinusitis. Patient 1 had been treated with adalimumab for 15 months when she developed acute sinusitis complicated by an orbital abscess, forehead swelling, a subdural empyema and osteomyelitis of the frontal bone. She was treated with a rhinosurgical and neurosurgical approach with intravenous antibiotics.Patient 2 had been in adalimumab treatment for 10 weeks. Adalimumab was discontinued 8 weeks prior to developing subdural empyema and subcortical abscesses in combination with sinusitis. She was treated with endoscopic sinus surgery and intravenous antibiotics. Both patients had developed psoriasis and episodes of infection during treatment. They were non-septic and had low fever on presentation. None of the patients suffered any long-term neurological sequelae. The immunosuppressive treatment with adalimumab is considered to be the cause of the sinogenic intracranial complications in our cases.

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Significance of combined preoperative serum Alb and dNLR for diagnosis of pancreatic cancer

Future Oncology, Ahead of Print.


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Significance of combined preoperative serum Alb and dNLR for diagnosis of pancreatic cancer

Future Oncology, Ahead of Print.


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Minimally Invasive Esophagectomy with Thoracic Duct Resection Post Neoadjuvant Chemoradiotherapy for Carcinoma Esophagus—Impact on Lymph Node Yield and Hemodynamic Parameters

Abstract

Background

Neoadjuvant therapy followed by surgery is the current recommended treatment for locally advanced esophageal carcinoma. Thoracic duct (TD) resection was indicated for radical mediastinal lymphadenectomy. However, TD resection can cause hemodynamic disturbances. The presence of metastasis in TD has not been previously studied.

Methods

Twenty-two patients who underwent minimally invasive esophagectomy with D2 lymphadenectomy after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma were analyzed. Ten patients had their TD resected from thoracic inlet till the esophageal hiatus. Multiple histopathological sections of the TD were examined for evidence of tumor spread. Intraoperative and immediate (48 h) postoperative hemodynamic parameters, lymph node yield, and postoperative morbidity were compared between TD-resected and TD-preserved groups.

Results

The median postoperative day 1 fluid requirement (3310 mL vs. 2875 mL, P = 0.059) and the median postoperative day 2 pulse rate were higher in the TD-resected group (111/min vs. 95/min, P = 0.043). There was no significant difference in the intraoperative fluid infusion, blood loss, urine output, mean blood pressure, pulse rate, postoperative urine output, and mean blood pressure between two groups. Median (range) mediastinal lymph node count was similar in TD-resected and TD-preserved groups [15(11–32) vs. 14(9–31), P = 0.283]. Pathological examination of TD did not reveal tumor cells in any of the patients. There was no significant difference in the postoperative morbidity between two groups except for cervical anastomotic dehiscence (P = 0.007).

Conclusions

Minimally invasive esophagectomy with TD resection causes minor hemodynamic changes in the immediate postoperative period, without adversely affecting the postoperative outcome. In the setting of neoadjuvant chemoradiotherapy, TD resection does not increase lymph node yield.

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Minimally Invasive Esophagectomy with Thoracic Duct Resection Post Neoadjuvant Chemoradiotherapy for Carcinoma Esophagus—Impact on Lymph Node Yield and Hemodynamic Parameters

Abstract

Background

Neoadjuvant therapy followed by surgery is the current recommended treatment for locally advanced esophageal carcinoma. Thoracic duct (TD) resection was indicated for radical mediastinal lymphadenectomy. However, TD resection can cause hemodynamic disturbances. The presence of metastasis in TD has not been previously studied.

Methods

Twenty-two patients who underwent minimally invasive esophagectomy with D2 lymphadenectomy after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma were analyzed. Ten patients had their TD resected from thoracic inlet till the esophageal hiatus. Multiple histopathological sections of the TD were examined for evidence of tumor spread. Intraoperative and immediate (48 h) postoperative hemodynamic parameters, lymph node yield, and postoperative morbidity were compared between TD-resected and TD-preserved groups.

Results

The median postoperative day 1 fluid requirement (3310 mL vs. 2875 mL, P = 0.059) and the median postoperative day 2 pulse rate were higher in the TD-resected group (111/min vs. 95/min, P = 0.043). There was no significant difference in the intraoperative fluid infusion, blood loss, urine output, mean blood pressure, pulse rate, postoperative urine output, and mean blood pressure between two groups. Median (range) mediastinal lymph node count was similar in TD-resected and TD-preserved groups [15(11–32) vs. 14(9–31), P = 0.283]. Pathological examination of TD did not reveal tumor cells in any of the patients. There was no significant difference in the postoperative morbidity between two groups except for cervical anastomotic dehiscence (P = 0.007).

Conclusions

Minimally invasive esophagectomy with TD resection causes minor hemodynamic changes in the immediate postoperative period, without adversely affecting the postoperative outcome. In the setting of neoadjuvant chemoradiotherapy, TD resection does not increase lymph node yield.

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RASA1/NF1 mutant lung cancer: Racing to the clinic?

Although mutation of NF1 has been described in non-small cell lung cancer (NSCLC), co-mutation with RASA1, another Ras-GTPase activating protein (RasGAP), defines a novel genetically defined subclass of NSCLC. RASA1/NF1 mutant cell lines are highly sensitive to MEK inhibitors, warranting clinical evaluation of MAPK inhibition in this subclass of patients.

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DICER1 and associated conditions: Identification of at-risk individuals and recommended surveillance strategies

Pathogenic germline DICER1 variants cause a hereditary cancer predisposition syndrome with a variety of manifestations. In addition to conferring increased cancer risks for pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors, particularly Sertoli-Leydig cell tumor, individuals with pathogenic germline DICER1 variants may also develop lung cysts, cystic nephroma, renal sarcoma and Wilms tumor, nodular hyperplasia of the thyroid, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, genitourinary embryonal rhabdomyosarcoma and brain tumors including pineoblastoma and pituitary blastoma. In May 2016, the International PPB Registry convened the inaugural International DICER1 Symposium to develop consensus testing, surveillance and treatment recommendations. Attendees from North America, Europe and Russia provided expert representation from the disciplines of pediatric oncology, endocrinology, genetics, genetic counseling, radiology, pediatric surgery, pathology and clinical research. Recommendations are provided for genetic testing, prenatal management, and surveillance for DICER1-associated pulmonary, renal, gynecologic, thyroid, ophthalmologic, otolaryngologic, central nervous system tumors and gastrointestinal polyps. Risk for most DICER1-associated neoplasms is highest in early childhood and decreases in adulthood. Individual and caregiver education and judicious imaging-based surveillance are the primary recommended approaches. These testing and surveillance recommendations reflect a consensus of expert opinion and current literature. As DICER1 research expands, guidelines for screening and treatment will continue to be updated.

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RASA1/NF1 mutant lung cancer: Racing to the clinic?

Although mutation of NF1 has been described in non-small cell lung cancer (NSCLC), co-mutation with RASA1, another Ras-GTPase activating protein (RasGAP), defines a novel genetically defined subclass of NSCLC. RASA1/NF1 mutant cell lines are highly sensitive to MEK inhibitors, warranting clinical evaluation of MAPK inhibition in this subclass of patients.

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DICER1 and associated conditions: Identification of at-risk individuals and recommended surveillance strategies

Pathogenic germline DICER1 variants cause a hereditary cancer predisposition syndrome with a variety of manifestations. In addition to conferring increased cancer risks for pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors, particularly Sertoli-Leydig cell tumor, individuals with pathogenic germline DICER1 variants may also develop lung cysts, cystic nephroma, renal sarcoma and Wilms tumor, nodular hyperplasia of the thyroid, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, genitourinary embryonal rhabdomyosarcoma and brain tumors including pineoblastoma and pituitary blastoma. In May 2016, the International PPB Registry convened the inaugural International DICER1 Symposium to develop consensus testing, surveillance and treatment recommendations. Attendees from North America, Europe and Russia provided expert representation from the disciplines of pediatric oncology, endocrinology, genetics, genetic counseling, radiology, pediatric surgery, pathology and clinical research. Recommendations are provided for genetic testing, prenatal management, and surveillance for DICER1-associated pulmonary, renal, gynecologic, thyroid, ophthalmologic, otolaryngologic, central nervous system tumors and gastrointestinal polyps. Risk for most DICER1-associated neoplasms is highest in early childhood and decreases in adulthood. Individual and caregiver education and judicious imaging-based surveillance are the primary recommended approaches. These testing and surveillance recommendations reflect a consensus of expert opinion and current literature. As DICER1 research expands, guidelines for screening and treatment will continue to be updated.

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A novel L-asparaginase with low L-glutaminase coactivity is highly efficacious against both T and B cell acute lymphoblastic leukemias in vivo

Acute lymphoblastic leukemia (ALL) is the most common type of pediatric cancer, although about 4 of every 10 cases occur in adults. The enzyme drug L-asparaginase serves as a cornerstone of ALL therapy and exploits the asparagine-dependency of ALL cells. In addition to hydrolyzing the amino acid L-asparagine, all FDA-approved L-asparaginases also have significant L-glutaminase coactivity. Since several reports suggest that L-glutamine depletion correlates with many of the side effects of these drugs, enzyme variants with reduced L-glutaminase coactivity might be clinically beneficial if their anti-leukemic activity would be preserved. Here we show that novel low L-glutaminase variants developed on the backbone of the FDA-approved Erwinia chrysanthemi L-asparaginase were highly efficacious against both T and B cell ALL, while displaying reduced acute toxicity features. These results support the development of a new generation of safer L-asparaginases without L-glutaminase activity for the treatment of human ALL.

http://ift.tt/2mJIJwj

Antitumor properties of RAF709, a highly selective and potent inhibitor of RAF kinase dimers, in tumors driven by mutant RAS or BRAF

Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF. In cell lines and murine xenograft models, RAF709 demonstrated selective antitumor activity in tumor cells harboring BRAF or RAS mutations compared to cells with wild-type BRAF and RAS genes. RAF709 demonstrated a direct pharmacokinetic/pharmacodynamic relationship in in vivo tumor models harboring KRAS mutation. Further, RAF709 elicited regression of primary human tumor derived xenograft models with BRAF, NRAS or KRAS mutations with excellent tolerability. Our results support further development of inhibitors like RAF709, which represents a next generation RAF inhibitor with unique biochemical and cellular properties that enables antitumor activities in RAS mutant tumors.

http://ift.tt/2DoUh2u

Polyol pathway links glucose metabolism to the aggressiveness of cancer cells

Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 (AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGF-β signature genes. Excess glucose was found to promote EMT through autocrine TGF-β stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target.

http://ift.tt/2mJQB0L

T-type Ca2+ Channels: T for Targetable

In the past decade, T-type Ca2+ channels (TTCC) have been unveiled as key regulators of cancer cell biology and thus have been proposed as chemotherapeutic targets. Indeed, in vitro and in vivo studies indicate that TTCC pharmacologic blockers have a negative impact on the viability of cancer cells and reduce tumor size, respectively. Consequently mibefradil, a TTCC blocker approved in 1997 as an antihypertensive agent but withdrawn in 1998 because of drug–drug interactions, was granted 10 years later the orphan drug status by the FDA to investigate its efficacy against brain, ovary, and pancreatic cancer. However, the existence of different channel isoforms with distinct physiologic roles, together with the lack of selective pharmacologic agents, has hindered a conclusive chemotherapeutic evaluation. Here, we review the available evidence on TTCC expression, value as prognostic markers, and effectiveness of their pharmacologic blockade on cancer cells in vitro and in preclinical models. We additionally summarize the status of clinical trials using mibefradil against glioblastoma multiforme. Finally, we discuss the future perspectives and the importance of further development of multidisciplinary research efforts on the consideration of TTCCs as biomarkers or targetable molecules in cancer. Cancer Res; 78(3); 1–7. ©2018 AACR.

http://ift.tt/2Dpe8OZ

Evidence for the ISG15-Specific Deubiquitinase USP18 as an Antineoplastic Target

Ubiquitination and ubiquitin-like posttranslational modifications (PTM) regulate activity and stability of oncoproteins and tumor suppressors. This implicates PTMs as antineoplastic targets. One way to alter PTMs is to inhibit activity of deubiquitinases (DUB) that remove ubiquitin or ubiquitin-like proteins from substrate proteins. Roles of DUBs in carcinogenesis have been intensively studied, yet few inhibitors exist. Prior work provides a basis for the ubiquitin-specific protease 18 (USP18) as an antineoplastic target. USP18 is the major DUB that removes IFN-stimulated gene 15 (ISG15) from conjugated proteins. Prior work discovered that engineered loss of USP18 increases ISGylation and in contrast to its gain decreases cancer growth by destabilizing growth-regulatory proteins. Loss of USP18 reduced cancer cell growth by triggering apoptosis. Genetic loss of USP18 repressed cancer formation in engineered murine lung cancer models. The translational relevance of USP18 was confirmed by finding its expression was deregulated in malignant versus normal tissues. Notably, the recent elucidation of the USP18 crystal structure offers a framework for developing an inhibitor to this DUB. This review summarizes strong evidence for USP18 as a previously unrecognized pharmacologic target in oncology. Cancer Res; 78(3); 1–6. ©2018 AACR.

http://ift.tt/2mJQe6n

A novel L-asparaginase with low L-glutaminase coactivity is highly efficacious against both T and B cell acute lymphoblastic leukemias in vivo

Acute lymphoblastic leukemia (ALL) is the most common type of pediatric cancer, although about 4 of every 10 cases occur in adults. The enzyme drug L-asparaginase serves as a cornerstone of ALL therapy and exploits the asparagine-dependency of ALL cells. In addition to hydrolyzing the amino acid L-asparagine, all FDA-approved L-asparaginases also have significant L-glutaminase coactivity. Since several reports suggest that L-glutamine depletion correlates with many of the side effects of these drugs, enzyme variants with reduced L-glutaminase coactivity might be clinically beneficial if their anti-leukemic activity would be preserved. Here we show that novel low L-glutaminase variants developed on the backbone of the FDA-approved Erwinia chrysanthemi L-asparaginase were highly efficacious against both T and B cell ALL, while displaying reduced acute toxicity features. These results support the development of a new generation of safer L-asparaginases without L-glutaminase activity for the treatment of human ALL.

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via IFTTT

Antitumor properties of RAF709, a highly selective and potent inhibitor of RAF kinase dimers, in tumors driven by mutant RAS or BRAF

Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF. In cell lines and murine xenograft models, RAF709 demonstrated selective antitumor activity in tumor cells harboring BRAF or RAS mutations compared to cells with wild-type BRAF and RAS genes. RAF709 demonstrated a direct pharmacokinetic/pharmacodynamic relationship in in vivo tumor models harboring KRAS mutation. Further, RAF709 elicited regression of primary human tumor derived xenograft models with BRAF, NRAS or KRAS mutations with excellent tolerability. Our results support further development of inhibitors like RAF709, which represents a next generation RAF inhibitor with unique biochemical and cellular properties that enables antitumor activities in RAS mutant tumors.

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via IFTTT

Polyol pathway links glucose metabolism to the aggressiveness of cancer cells

Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 (AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGF-β signature genes. Excess glucose was found to promote EMT through autocrine TGF-β stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target.

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T-type Ca2+ Channels: T for Targetable

In the past decade, T-type Ca2+ channels (TTCC) have been unveiled as key regulators of cancer cell biology and thus have been proposed as chemotherapeutic targets. Indeed, in vitro and in vivo studies indicate that TTCC pharmacologic blockers have a negative impact on the viability of cancer cells and reduce tumor size, respectively. Consequently mibefradil, a TTCC blocker approved in 1997 as an antihypertensive agent but withdrawn in 1998 because of drug–drug interactions, was granted 10 years later the orphan drug status by the FDA to investigate its efficacy against brain, ovary, and pancreatic cancer. However, the existence of different channel isoforms with distinct physiologic roles, together with the lack of selective pharmacologic agents, has hindered a conclusive chemotherapeutic evaluation. Here, we review the available evidence on TTCC expression, value as prognostic markers, and effectiveness of their pharmacologic blockade on cancer cells in vitro and in preclinical models. We additionally summarize the status of clinical trials using mibefradil against glioblastoma multiforme. Finally, we discuss the future perspectives and the importance of further development of multidisciplinary research efforts on the consideration of TTCCs as biomarkers or targetable molecules in cancer. Cancer Res; 78(3); 1–7. ©2018 AACR.

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via IFTTT

Evidence for the ISG15-Specific Deubiquitinase USP18 as an Antineoplastic Target

Ubiquitination and ubiquitin-like posttranslational modifications (PTM) regulate activity and stability of oncoproteins and tumor suppressors. This implicates PTMs as antineoplastic targets. One way to alter PTMs is to inhibit activity of deubiquitinases (DUB) that remove ubiquitin or ubiquitin-like proteins from substrate proteins. Roles of DUBs in carcinogenesis have been intensively studied, yet few inhibitors exist. Prior work provides a basis for the ubiquitin-specific protease 18 (USP18) as an antineoplastic target. USP18 is the major DUB that removes IFN-stimulated gene 15 (ISG15) from conjugated proteins. Prior work discovered that engineered loss of USP18 increases ISGylation and in contrast to its gain decreases cancer growth by destabilizing growth-regulatory proteins. Loss of USP18 reduced cancer cell growth by triggering apoptosis. Genetic loss of USP18 repressed cancer formation in engineered murine lung cancer models. The translational relevance of USP18 was confirmed by finding its expression was deregulated in malignant versus normal tissues. Notably, the recent elucidation of the USP18 crystal structure offers a framework for developing an inhibitor to this DUB. This review summarizes strong evidence for USP18 as a previously unrecognized pharmacologic target in oncology. Cancer Res; 78(3); 1–6. ©2018 AACR.

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Boost Irradiation Integrated to Whole Brain Radiotherapy in the Management of Brain Metastases

Abstract

Our retrospective analysis aimed to evaluate the clinical value of dose intensification schemes: WBRT and consecutive, delayed, or simultaneous integrated boost (SIB) in brain metastasis (BM) management. Clinical data and overall survival (OS) of 468 patients with BM from various primaries treated with 10 × 3 Gy WBRT (n = 195), WBRT+ 10 × 2 Gy boost (n = 125), or simultaneously 15 × 2.2 Gy WBRT+0.7 Gy boost (n = 148) during a 6-year period were statistically analysed. Significant difference in OS could be detected with additional boost to WBRT (3.3 versus 6.5 months) and this difference was confirmed for BMs of lung cancer and melanoma and both for oligo- and multiplex lesions. The OS was prolonged for the RPA 2 and RPA3 categories, if patients received escalated dose, 4.0 vs. 7.7 months; (p = 0.002) in class RPA2 and 2.6 vs. 4.2 months; (p < 0.0001) in the class RPA 3 respectively. The significant difference in OS was also achieved with SIB. The shortened overall treatment time of SIB with lower WBRT fraction dose exhibited survival benefit over WBRT alone, and could be applied for patients developing BM even with unfavourable prognostic factors. These results warrant for further study of this approach with dose escalation using the lately available solutions for hippocampus sparing and fractionated stereotactic irradiation. The simultaneous delivery of WBRT with reduced fraction dose and boost proved to be advantageous prolonging the OS with shortened treatment time and reduced probability for cognitive decline development even for patients with poor performance status and progressing extracranial disease.

http://ift.tt/2mI3DMv

Boost Irradiation Integrated to Whole Brain Radiotherapy in the Management of Brain Metastases

Abstract

Our retrospective analysis aimed to evaluate the clinical value of dose intensification schemes: WBRT and consecutive, delayed, or simultaneous integrated boost (SIB) in brain metastasis (BM) management. Clinical data and overall survival (OS) of 468 patients with BM from various primaries treated with 10 × 3 Gy WBRT (n = 195), WBRT+ 10 × 2 Gy boost (n = 125), or simultaneously 15 × 2.2 Gy WBRT+0.7 Gy boost (n = 148) during a 6-year period were statistically analysed. Significant difference in OS could be detected with additional boost to WBRT (3.3 versus 6.5 months) and this difference was confirmed for BMs of lung cancer and melanoma and both for oligo- and multiplex lesions. The OS was prolonged for the RPA 2 and RPA3 categories, if patients received escalated dose, 4.0 vs. 7.7 months; (p = 0.002) in class RPA2 and 2.6 vs. 4.2 months; (p < 0.0001) in the class RPA 3 respectively. The significant difference in OS was also achieved with SIB. The shortened overall treatment time of SIB with lower WBRT fraction dose exhibited survival benefit over WBRT alone, and could be applied for patients developing BM even with unfavourable prognostic factors. These results warrant for further study of this approach with dose escalation using the lately available solutions for hippocampus sparing and fractionated stereotactic irradiation. The simultaneous delivery of WBRT with reduced fraction dose and boost proved to be advantageous prolonging the OS with shortened treatment time and reduced probability for cognitive decline development even for patients with poor performance status and progressing extracranial disease.

http://ift.tt/2mI3DMv

Impact of individual and neighborhood factors on disparities in prostate cancer survival

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Mindy C. DeRouen, Clayton W. Schupp, Jocelyn Koo, Juan Yang, Andrew Hertz, Salma Shariff-Marco, Myles Cockburn, David O. Nelson, Sue A. Ingles, Esther M. John, Scarlett L. Gomez
BackgroundWe addressed the hypothesis that individual-level factors act jointly with social and built environment factors to influence overall survival for men with prostate cancer and contribute to racial/ethnic and socioeconomic (SES) survival disparities.MethodsWe analyzed multi-level data, combining (1) individual-level data from the California Collaborative Prostate Cancer Study, a population-based study of non-Hispanic White (NHW), Hispanic, and African American prostate cancer cases (N = 1800) diagnosed from 1997 to 2003, with (2) data on neighborhood SES (nSES) and social and built environment factors from the California Neighborhoods Data System, and (3) data on tumor characteristics, treatment and follow-up through 2009 from the California Cancer Registry. Multivariable, stage-stratified Cox proportional hazards regression models with cluster adjustments were used to assess education and nSES main and joint effects on overall survival, before and after adjustment for social and built environment factors.ResultsAfrican American men had worse survival than NHW men, which was attenuated by nSES. Increased risk of death was associated with residence in lower SES neighborhoods (quintile 1 (lowest nSES) vs. 5: HR = 1.56, 95% CI: 1.11–2.19) and lower education (<high school vs. college: HR = 1.32, 95% CI: 1.05–1.67), and a joint association of low education and low nSES was observed. Adjustment for behavioral, hospital, and restaurant and food environment characteristics only slightly attenuated these associations between SES and survival.ConclusionBoth individual- and contextual-level SES influence overall survival of men with prostate cancer. Additional research is needed to identify the mechanisms underlying these robust associations.



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Impact of individual and neighborhood factors on disparities in prostate cancer survival

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Mindy C. DeRouen, Clayton W. Schupp, Jocelyn Koo, Juan Yang, Andrew Hertz, Salma Shariff-Marco, Myles Cockburn, David O. Nelson, Sue A. Ingles, Esther M. John, Scarlett L. Gomez
BackgroundWe addressed the hypothesis that individual-level factors act jointly with social and built environment factors to influence overall survival for men with prostate cancer and contribute to racial/ethnic and socioeconomic (SES) survival disparities.MethodsWe analyzed multi-level data, combining (1) individual-level data from the California Collaborative Prostate Cancer Study, a population-based study of non-Hispanic White (NHW), Hispanic, and African American prostate cancer cases (N = 1800) diagnosed from 1997 to 2003, with (2) data on neighborhood SES (nSES) and social and built environment factors from the California Neighborhoods Data System, and (3) data on tumor characteristics, treatment and follow-up through 2009 from the California Cancer Registry. Multivariable, stage-stratified Cox proportional hazards regression models with cluster adjustments were used to assess education and nSES main and joint effects on overall survival, before and after adjustment for social and built environment factors.ResultsAfrican American men had worse survival than NHW men, which was attenuated by nSES. Increased risk of death was associated with residence in lower SES neighborhoods (quintile 1 (lowest nSES) vs. 5: HR = 1.56, 95% CI: 1.11–2.19) and lower education (<high school vs. college: HR = 1.32, 95% CI: 1.05–1.67), and a joint association of low education and low nSES was observed. Adjustment for behavioral, hospital, and restaurant and food environment characteristics only slightly attenuated these associations between SES and survival.ConclusionBoth individual- and contextual-level SES influence overall survival of men with prostate cancer. Additional research is needed to identify the mechanisms underlying these robust associations.



http://ift.tt/2FMIGIZ

Takayasu arteritis a cause of hypertensive disorder of pregnancy: a case report

Takayasu arteritis is a rare, chronic, granulomatous systemic vasculitis of unknown etiology and a few cases have been reported in pregnancy. In pregnancies concomitant with Takayasu arteritis or after diagnos...

http://ift.tt/2DlNtn2

Hyperhomocysteinemia in bilateral anterior ischemic optic neuropathy after conventional coronary artery bypass graft: a case report

The incidence of anterior ischemic optic neuropathy after coronary artery bypass graft procedures ranges from 1.3 to 0.25%. The mechanisms of anterior ischemic optic neuropathy after cardiovascular procedures ...

http://ift.tt/2Bbw6iQ

Periorbital Necrobiotic Xanthogranuloma Successfully Treated with Intravenous Immunoglobulin

Background: Necrobiotic xanthogranuloma (NXG) is a rare non-Langerhans histiocytosis with cutaneous manifestations, most commonly of the periorbital skin, and is often associated with hematologic disorders such as monoclonal gammopathy. Treatment of NXG is notoriously difficult, and fraught with recurrence and progression. Case Presentation: The authors describe a case of NXG with periorbital involvement in a patient with a complex autoimmune and hematologic medical history. The biopsy of this rare lesion prompted subsequent evaluation for an underlying disorder, which led to the diagnosis of multiple myeloma. Her NXG lesions demonstrated remarkable clinical improvement after treatment with intravenous immunoglobulin (IVIG). Conclusions: This case demonstrates the ophthalmologist's critical role in the diagnosis and management of NXG, as early detection cannot only prevent ophthalmic consequences such as ocular perforation and blindness, but also prompt further investigation that may reveal an underlying disorder or systemic involvement, including hematologic malignancy as in this case. NXG has been effectively treated with IVIG in a handful of reported cases. To the author's knowledge, this is the third case of periorbital NXG successfully treated with IVIG, and the first in the ophthalmic literature.
Case Rep Ophthalmol 2018;9:70–75

http://ift.tt/2DKsFTm

Tamoxifen Use in a Patient with Idiopathic Macular Telangiectasia Type 2

Crystalline deposits and neurosensory retinal cavitary changes can develop in both tamoxifen retinopathy and nonproliferative idiopathic macular telangiectasia type 2 (MacTel2). MacTel2 is typically differentiated from tamoxifen retinopathy based on the presence of late leakage and mid-phase telangiectatic vessels on fluorescein angiography (FA) and the presence of hyperautofluorescence. Unlike MacTel2, tamoxifen retinopathy is known to be a progressive disease and the cessation of tamoxifen results in resolution of retinopathy. We report a unique case of nonproliferative MacTel2 in a 36-year-old Hispanic woman with tamoxifen use and the vision outcome 30 months after cessation of tamoxifen. The FA and optical coherence tomography angiography findings of this patient support the diagnosis of MacTel2, but her cessation of tamoxifen led to partial reversal of the topographic findings and improvement in visual acuity. This patient is also unique in the unusually young age of presentation for MacTel2. Our case supports that there are common pathways in the pathogenesis of tamoxifen retinopathy and MacTel2, and tamoxifen use could potentially accelerate foveal atrophy in patients with MacTel2.
Case Rep Ophthalmol 2018;9:54–60

http://ift.tt/2DeVSEO

Repair of Traumatic Rhegmatogenous Retinal Detachment Combined with Congenital Falciform Retinal Detachment

Purpose: To report a case of surgical repair of traumatic rhegmatogenous retinal detachment combined with congenital falciform retinal detachment (FRD). Methods: A retrospective case report. Results: A 36-year-old man with traumatic rhegmatogenous retinal detachment complicating a previously known FRD was successfully treated despite residual FRD following pars plana lensectomy, vitrectomy, and encircling scleral buckling. His best corrected visual acuity improved from hand motion at 50 cm to 20/1,000. Conclusion: We concluded that the root of the FRD is susceptible to trauma because of the contraction of fibrovascular tissue. The early intervention of modern vitrectomy to traumatic rhegmatogenous retinal detachment complicating a previously known FRD is an important consideration for enhanced quality of care and optimal patient outcomes.
Case Rep Ophthalmol 2018;9:49–53

http://ift.tt/2DHf7YE

Two Cases of Rhegmatogenous Retinal Detachment Associated with Asteroid Hyalosis

Background: To report two cases of rhegmatogenous retinal detachment (RRD) associated with asteroid hyalosis (AH). Case Presentation: Two patients presented with RRD originating from a flap tear. Case 1 involved a 62-year-old male who was found to have bullous RRD in his left eye originating from a flap tear. During vitreous surgery, a thick vitreous cortex was found to have strongly adhered to the entire retinal surface, from the center to the periphery. A bimanual method was then used in conjunction with the vitrectomy to create an artificial posterior vitreous detachment. After surgery, the retina was successfully reattached, and his corrected visual acuity (VA) improved. Case 2 involved a 70-year-old male who was found to have localized RRD in his left eye originating from a flap tear. During vitreous surgery, a thick vitreous cortex was found to have strongly adhered to the entire retinal surface. After surgery, the retina was successfully reattached, and his corrected VA improved. Conclusions: RRD associated with AH presents with stronger vitreoretinal adhesion compared to typical RRD, thus requiring a more complicated surgical technique to properly treat the patient.
Case Rep Ophthalmol 2018;9:43–48

http://ift.tt/2Ddsa2N

microRNA-124 inhibits bone metastasis of breast cancer by repressing Interleukin-11

Abstract

Background

Most patients with breast cancer in advanced stages of the disease suffer from bone metastases which lead to fractures and nerve compression syndromes. microRNA dysregulation is an important event in the metastases of breast cancer to bone. microRNA-124 (miR-124) has been proved to inhibit cancer progression, whereas its effect on bone metastases of breast cancer has not been reported. Therefore, this study aimed to investigate the role and underlying mechanism of miR-124 in bone metastases of breast cancer.

Methods

In situ hybridization (ISH) was used to detect the expression of miR-124 in breast cancer tissues and bone metastatic tissues. Ventricle injection model was constructed to explore the effect of miR-124 on bone metastasis in vivo. The function of cancer cell derived miR-124 in the differentiation of osteoclast progenitor cells was verified in vitro. Dual-luciferase reporter assay was conducted to confirm Interleukin-11 (IL-11) as a miR-124 target. The involvement of miR-124/IL-11 in the prognosis of breast cancer patients with bone metastasis was determined by Kaplan-Meier analysis.

Results

Herein, we found that miR-124 was significantly reduced in metastatic bone tissues from breast cancers. Down-regulation of miR-124 was associated with aggressive clinical characteristics and shorter bone metastasis-free survival and overall survival. Restoration of miR-124 suppressed, while inhibition of miR-124 promoted the bone metastasis of breast cancer cells in vivo. At the cellular level, gain of function and loss-of function assays indicated that cancer cell-derived miR-124 inhibited the survival and differentiation of osteoclast progenitor cells. At the molecular level, we demonstrated that IL-11 partially mediated osteoclastogenesis suppression by miR-124 using in vitro and in vivo assays. Furthermore, IL-11 levels were inversely correlated with miR-124, and up-regulation IL-11 in bone metastases was associated with a poor prognosis.

Conclusions

Thus, the identification of a dysregulated miR-124/IL-11 axis helps elucidate mechanisms of breast cancer metastases to bone, uncovers new prognostic markers, and facilitates the development of novel therapeutic targets to treat and even prevent bone metastases of breast cancer.

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Liquid biomarkers in melanoma: detection and discovery

Abstract

A vast array of tumor-derived genetic, proteomic and cellular components are constantly released into the circulation of cancer patients. These molecules including circulating tumor DNA and RNA, proteins, tumor and immune cells are emerging as convenient and accurate liquid biomarkers of cancer. Circulating cancer biomarkers provide invaluable information on cancer detection and diagnosis, prognosticate patient outcomes, and predict treatment response. In this era of effective molecular targeted treatments and immunotherapies, there is now an urgent need to implement use of these circulating biomarkers in the clinic to facilitate personalized therapy. In this review, we present recent findings in circulating melanoma biomarkers, examine the challenges and promise of evolving technologies used for liquid biomarker discovery, and discuss future directions and perspectives in melanoma biomarker research.

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microRNA-124 inhibits bone metastasis of breast cancer by repressing Interleukin-11

Abstract

Background

Most patients with breast cancer in advanced stages of the disease suffer from bone metastases which lead to fractures and nerve compression syndromes. microRNA dysregulation is an important event in the metastases of breast cancer to bone. microRNA-124 (miR-124) has been proved to inhibit cancer progression, whereas its effect on bone metastases of breast cancer has not been reported. Therefore, this study aimed to investigate the role and underlying mechanism of miR-124 in bone metastases of breast cancer.

Methods

In situ hybridization (ISH) was used to detect the expression of miR-124 in breast cancer tissues and bone metastatic tissues. Ventricle injection model was constructed to explore the effect of miR-124 on bone metastasis in vivo. The function of cancer cell derived miR-124 in the differentiation of osteoclast progenitor cells was verified in vitro. Dual-luciferase reporter assay was conducted to confirm Interleukin-11 (IL-11) as a miR-124 target. The involvement of miR-124/IL-11 in the prognosis of breast cancer patients with bone metastasis was determined by Kaplan-Meier analysis.

Results

Herein, we found that miR-124 was significantly reduced in metastatic bone tissues from breast cancers. Down-regulation of miR-124 was associated with aggressive clinical characteristics and shorter bone metastasis-free survival and overall survival. Restoration of miR-124 suppressed, while inhibition of miR-124 promoted the bone metastasis of breast cancer cells in vivo. At the cellular level, gain of function and loss-of function assays indicated that cancer cell-derived miR-124 inhibited the survival and differentiation of osteoclast progenitor cells. At the molecular level, we demonstrated that IL-11 partially mediated osteoclastogenesis suppression by miR-124 using in vitro and in vivo assays. Furthermore, IL-11 levels were inversely correlated with miR-124, and up-regulation IL-11 in bone metastases was associated with a poor prognosis.

Conclusions

Thus, the identification of a dysregulated miR-124/IL-11 axis helps elucidate mechanisms of breast cancer metastases to bone, uncovers new prognostic markers, and facilitates the development of novel therapeutic targets to treat and even prevent bone metastases of breast cancer.

http://ift.tt/2mCYVj0

Liquid biomarkers in melanoma: detection and discovery

Abstract

A vast array of tumor-derived genetic, proteomic and cellular components are constantly released into the circulation of cancer patients. These molecules including circulating tumor DNA and RNA, proteins, tumor and immune cells are emerging as convenient and accurate liquid biomarkers of cancer. Circulating cancer biomarkers provide invaluable information on cancer detection and diagnosis, prognosticate patient outcomes, and predict treatment response. In this era of effective molecular targeted treatments and immunotherapies, there is now an urgent need to implement use of these circulating biomarkers in the clinic to facilitate personalized therapy. In this review, we present recent findings in circulating melanoma biomarkers, examine the challenges and promise of evolving technologies used for liquid biomarker discovery, and discuss future directions and perspectives in melanoma biomarker research.

http://ift.tt/2DnYa7L

Human papillomavirus genotype distribution in cervical cancer biopsies from Nepalese women

Abstract

Background

Cervical cancer (CC) is the leading cause of morbidity and mortality from cancer in Nepalese women. Nearly all cases of CC are caused by infection with certain genotypes of human papillomavirus (HPV). Data on HPV genotype distribution in Nepalese CC patients is sparse. We aimed to determine the distribution of HPV genotypes in biopsies of CC tissue from Nepalese women.

Methods

This study examined 248 archived paraffin-embedded tissue specimens from CC cases from patients of B.P. Koirala Memorial Cancer Hospital, Bharatpur, Chitwan, Nepal. DNA was extracted from the biopsies and HPV detection performed by PCR. HPV genotyping was then carried out by a reverse line hybridization technique capable of identifying 36 distinct HPV genotypes.

Results

Most of the samples were from tumors that had been designated by hospital pathologists as squamous cell carcinoma (77.6%). 165 of the 248 samples contained DNA of sufficient quality for rigorous PCR testing. All the analyzable specimens were positive for HPV. The most common HPV genotypes, in decreasing order of frequency were 16, 18, 45, 33, 52, 56 and 31; most were found as single infections (94.5%). Together, HPV types 16, 18, and 45 were found in 92% of the tumor samples.

Conclusion

This study strengthens the knowledge-base of HPV genotype distribution in CC cases in Nepal. Hopefully, this information will be useful to the medical community and public health policy-makers in generating improved HPV-surveillance, −prevention and -treatment strategies in Nepal.

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Human papillomavirus genotype distribution in cervical cancer biopsies from Nepalese women

Abstract

Background

Cervical cancer (CC) is the leading cause of morbidity and mortality from cancer in Nepalese women. Nearly all cases of CC are caused by infection with certain genotypes of human papillomavirus (HPV). Data on HPV genotype distribution in Nepalese CC patients is sparse. We aimed to determine the distribution of HPV genotypes in biopsies of CC tissue from Nepalese women.

Methods

This study examined 248 archived paraffin-embedded tissue specimens from CC cases from patients of B.P. Koirala Memorial Cancer Hospital, Bharatpur, Chitwan, Nepal. DNA was extracted from the biopsies and HPV detection performed by PCR. HPV genotyping was then carried out by a reverse line hybridization technique capable of identifying 36 distinct HPV genotypes.

Results

Most of the samples were from tumors that had been designated by hospital pathologists as squamous cell carcinoma (77.6%). 165 of the 248 samples contained DNA of sufficient quality for rigorous PCR testing. All the analyzable specimens were positive for HPV. The most common HPV genotypes, in decreasing order of frequency were 16, 18, 45, 33, 52, 56 and 31; most were found as single infections (94.5%). Together, HPV types 16, 18, and 45 were found in 92% of the tumor samples.

Conclusion

This study strengthens the knowledge-base of HPV genotype distribution in CC cases in Nepal. Hopefully, this information will be useful to the medical community and public health policy-makers in generating improved HPV-surveillance, −prevention and -treatment strategies in Nepal.

http://ift.tt/2FJ094V

Does previous abdominal surgery adversely affect perioperative and oncologic outcomes of laparoscopic radical cystectomy?

Abstract

Background

Laparoscopic radical cystectomy (LRC) has been shown to have less estimated blood loss (EBL), transfusion rate, narcotic analgesic requirement, earlier return of bowel function, and shorter hospital stay. The aim of this study was to investigate the feasibility, peri-operative and oncologic outcomes of laparoscopic radical cystectomy (LRC) in patients with previous abdominal surgery (PAS).

Methods

We retrospectively reviewed 243 patients undergoing open radical cystectomy (ORC) or LRC with bilateral pelvic lymph node dissection and urinary diversion or cutaneous ureterostomy at a single center from January 2010 to December 2015. Demographic parameters, intra-operative variables, peri-operative records, pathologic outcomes, and complication rate were reviewed to assess the impact of PAS on peri-operative and oncologic outcomes.

Results

Patients in both ORC and LRC subgroups were homogeneous in terms of demography characteristics including age, gender, BMI, ASA score, and comorbidity. Estimated blood loss (EBL) was higher in patients with PAS undergoing ORC compared to those with no PAS (P = 0.008). However, there was no significant difference of EBL among patients undergoing LRC with or without PAS (P = 0.896). There was no statistical difference in peri-operative parameters and pathological outcomes. Patients with PAS undergoing ORC and ileal conduit had a higher vascular injury rate (P = 0.017). Comparing patients with PAS performed by LRC and ORC, the number of patients with the vascular injury was higher in ORC groups regardless of the type of diversion (ileal conduit, P = 0.001, cutaneous ureterostomy, P = 0.025). There is no significant difference in other complications.

Conclusion

The presence of adhesions from PAS is not a contraindication to LRC. Patients with PAS may benefit from LRC with lower estimated blood loss, fewer transfusion rates, and vascular injuries. Furthermore, the overall oncologic outcomes and complication rate are similar between LRC and ORC patients with PAS.

http://ift.tt/2mMuDLA

Does previous abdominal surgery adversely affect perioperative and oncologic outcomes of laparoscopic radical cystectomy?

Abstract

Background

Laparoscopic radical cystectomy (LRC) has been shown to have less estimated blood loss (EBL), transfusion rate, narcotic analgesic requirement, earlier return of bowel function, and shorter hospital stay. The aim of this study was to investigate the feasibility, peri-operative and oncologic outcomes of laparoscopic radical cystectomy (LRC) in patients with previous abdominal surgery (PAS).

Methods

We retrospectively reviewed 243 patients undergoing open radical cystectomy (ORC) or LRC with bilateral pelvic lymph node dissection and urinary diversion or cutaneous ureterostomy at a single center from January 2010 to December 2015. Demographic parameters, intra-operative variables, peri-operative records, pathologic outcomes, and complication rate were reviewed to assess the impact of PAS on peri-operative and oncologic outcomes.

Results

Patients in both ORC and LRC subgroups were homogeneous in terms of demography characteristics including age, gender, BMI, ASA score, and comorbidity. Estimated blood loss (EBL) was higher in patients with PAS undergoing ORC compared to those with no PAS (P = 0.008). However, there was no significant difference of EBL among patients undergoing LRC with or without PAS (P = 0.896). There was no statistical difference in peri-operative parameters and pathological outcomes. Patients with PAS undergoing ORC and ileal conduit had a higher vascular injury rate (P = 0.017). Comparing patients with PAS performed by LRC and ORC, the number of patients with the vascular injury was higher in ORC groups regardless of the type of diversion (ileal conduit, P = 0.001, cutaneous ureterostomy, P = 0.025). There is no significant difference in other complications.

Conclusion

The presence of adhesions from PAS is not a contraindication to LRC. Patients with PAS may benefit from LRC with lower estimated blood loss, fewer transfusion rates, and vascular injuries. Furthermore, the overall oncologic outcomes and complication rate are similar between LRC and ORC patients with PAS.

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INPP4B promotes cell survival via SGK3 activation in NPM1-mutated leukemia

Abstract

Background

Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1) has been recognized as a distinct leukemia entity in the 2016 World Health Organization (WHO) classification. The genetic events underlying oncogenesis in NPM1-mutated AML that is characterized by a normal karyotype remain unclear. Inositol polyphosphate 4-phosphatase type II (INPP4B), a new factor in the phosphoinositide-3 kinase (PI3K) pathway-associated cancers, has been recently found a clinically relevant role in AML. However, little is known about the specific mechanistic function of INPP4B in NPM1-mutated AML.

Methods

The INPP4B expression levels in NPM1-mutated AML primary blasts and AML OCI-AML3 cell lines were determined by qRT-PCR and western blotting. The effect of INPP4B knockdown on OCI-AML3 leukemia cell proliferation was evaluated, using the Cell Counting Kit-8 and colony formation assay. After INPP4B overexpression or knockdown, the activation of serum and glucocorticoid-regulated kinase 3 (SGK3) and AKT was assessed. The effects of PI3K signaling pathway inhibitors on the levels of p-SGK3 in OCI-AML3 cells were tested. The mass of PI (3,4) P₂ and PI (3) P was analyzed by ELISA upon INPP4B overexpression. Knockdown of SGK3 by RNA interference and a rescue assay were performed to confirm the critical role of SGK3 in INPP4B-mediated cell survival. In addition, the molecular mechanism underlying INPP4B expression in NPM1-mutated leukemia cells was explored. Finally, Kaplan–Meier survival analysis was conducted on the NPM1-mutated AML cohort stratified into quartiles for INPP4B expression in The Cancer Genome Atlas (TCGA) dataset.

Results

High expression of INPP4B was observed in NPM1-mutated AML. Knockdown of INPP4B repressed cell proliferation in OCI-AML3 cells, whereas recovered INPP4B rescued this inhibitory effect in vitro. Mechanically, INPP4B enhanced phosphorylated SGK3 (p-SGK3) status, but did not affect AKT activation. SGK3 was required for INPP4B-induced cell proliferation in OCI-AML3 cells. High levels of INPP4B were at least partially caused by the NPM1 mutant via ERK/Ets-1 signaling. Finally, high expression of INPP4B showed a trend towards lower overall survival and event-free survival in NPM1-mutated AML patients.

Conclusions

Our results indicate that INPP4B promotes leukemia cell survival via SGK3 activation, and INPP4B might be a potential target in the treatment of NPM1-mutated AML.

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INPP4B promotes cell survival via SGK3 activation in NPM1-mutated leukemia

Abstract

Background

Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1) has been recognized as a distinct leukemia entity in the 2016 World Health Organization (WHO) classification. The genetic events underlying oncogenesis in NPM1-mutated AML that is characterized by a normal karyotype remain unclear. Inositol polyphosphate 4-phosphatase type II (INPP4B), a new factor in the phosphoinositide-3 kinase (PI3K) pathway-associated cancers, has been recently found a clinically relevant role in AML. However, little is known about the specific mechanistic function of INPP4B in NPM1-mutated AML.

Methods

The INPP4B expression levels in NPM1-mutated AML primary blasts and AML OCI-AML3 cell lines were determined by qRT-PCR and western blotting. The effect of INPP4B knockdown on OCI-AML3 leukemia cell proliferation was evaluated, using the Cell Counting Kit-8 and colony formation assay. After INPP4B overexpression or knockdown, the activation of serum and glucocorticoid-regulated kinase 3 (SGK3) and AKT was assessed. The effects of PI3K signaling pathway inhibitors on the levels of p-SGK3 in OCI-AML3 cells were tested. The mass of PI (3,4) P₂ and PI (3) P was analyzed by ELISA upon INPP4B overexpression. Knockdown of SGK3 by RNA interference and a rescue assay were performed to confirm the critical role of SGK3 in INPP4B-mediated cell survival. In addition, the molecular mechanism underlying INPP4B expression in NPM1-mutated leukemia cells was explored. Finally, Kaplan–Meier survival analysis was conducted on the NPM1-mutated AML cohort stratified into quartiles for INPP4B expression in The Cancer Genome Atlas (TCGA) dataset.

Results

High expression of INPP4B was observed in NPM1-mutated AML. Knockdown of INPP4B repressed cell proliferation in OCI-AML3 cells, whereas recovered INPP4B rescued this inhibitory effect in vitro. Mechanically, INPP4B enhanced phosphorylated SGK3 (p-SGK3) status, but did not affect AKT activation. SGK3 was required for INPP4B-induced cell proliferation in OCI-AML3 cells. High levels of INPP4B were at least partially caused by the NPM1 mutant via ERK/Ets-1 signaling. Finally, high expression of INPP4B showed a trend towards lower overall survival and event-free survival in NPM1-mutated AML patients.

Conclusions

Our results indicate that INPP4B promotes leukemia cell survival via SGK3 activation, and INPP4B might be a potential target in the treatment of NPM1-mutated AML.

http://ift.tt/2DkGD1h

Circulating tumor DNA analyses reveal novel resistance mechanisms to CDK inhibition in metastatic breast cancer.

http://ift.tt/2DHbstW

Nivolumab associated bone marrow necrosis

Nivolumabimmunotherapybone marrow necrosis

http://ift.tt/2DccEo8

Circulating tumor DNA analyses reveal novel resistance mechanisms to CDK inhibition in metastatic breast cancer.

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Nivolumab associated bone marrow necrosis

Nivolumabimmunotherapybone marrow necrosis

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Benefit of the addition of hormone therapy to neoadjuvant anthracycline-based chemotherapy for breast cancer: comparison of predicted and observed pCR

Abstract

Introduction

Neoadjuvant hormonal therapy is generally considered a valid option for hormone receptor positive breast cancer (BC) patients who are unfit for chemotherapy or surgery.

Aims

Whilst numerous studies analyzed efficacy of neoadjuvant chemotherapy (CT) or endocrine therapy (HT) alone in hormone receptor positive patients, there is a lack of research looking at the usefulness of a preoperative combinatorial approach of CT and HT in this patient subgroup.

Methods

Using a predictive model previously described in the literature, developed to analyze the probability of benefit from preoperative chemotherapy, we were able to compare pathological complete response (pCR) rates expected with the use of CT alone with the pCR rates reported in a population of 192 patients treated with the combination of tamoxifen plus anthracycline-based CT at Cremona Hospital between 2003 and 2006.

Results

Even with a relatively small patient population, this approach provided insightful information for the selection of hormone receptor positive BC patients most likely to benefit from the use of preoperative HT and CT in combination. Whilst no statistically significant benefit was obtained with the addition of tamoxifen to neoadjuvant chemotherapy in the entire population, or in any of the molecular stratification subgroups, the analysis of the calibration curve showed that a combinatorial approach may improve pCR in patients with luminal B tumors. More specific trials should be designed to confirm our initial results.

Conclusion

To the best of our knowledge, this is the first report investigating the efficacy of the combination of CT and HT in the neoadjuvant treatment of hormone receptor positive BC.

from Cancer via ola Kala on Inoreader http://ift.tt/2B9bDeJ
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Benefit of the addition of hormone therapy to neoadjuvant anthracycline-based chemotherapy for breast cancer: comparison of predicted and observed pCR

Abstract

Introduction

Neoadjuvant hormonal therapy is generally considered a valid option for hormone receptor positive breast cancer (BC) patients who are unfit for chemotherapy or surgery.

Aims

Whilst numerous studies analyzed efficacy of neoadjuvant chemotherapy (CT) or endocrine therapy (HT) alone in hormone receptor positive patients, there is a lack of research looking at the usefulness of a preoperative combinatorial approach of CT and HT in this patient subgroup.

Methods

Using a predictive model previously described in the literature, developed to analyze the probability of benefit from preoperative chemotherapy, we were able to compare pathological complete response (pCR) rates expected with the use of CT alone with the pCR rates reported in a population of 192 patients treated with the combination of tamoxifen plus anthracycline-based CT at Cremona Hospital between 2003 and 2006.

Results

Even with a relatively small patient population, this approach provided insightful information for the selection of hormone receptor positive BC patients most likely to benefit from the use of preoperative HT and CT in combination. Whilst no statistically significant benefit was obtained with the addition of tamoxifen to neoadjuvant chemotherapy in the entire population, or in any of the molecular stratification subgroups, the analysis of the calibration curve showed that a combinatorial approach may improve pCR in patients with luminal B tumors. More specific trials should be designed to confirm our initial results.

Conclusion

To the best of our knowledge, this is the first report investigating the efficacy of the combination of CT and HT in the neoadjuvant treatment of hormone receptor positive BC.

http://ift.tt/2B9bDeJ

Blocking NOTCH pathway can enhance the effect of EGFR inhibitor through targeting CD133+ endometrial cancer cells

Volume 19, Issue 2, February 2018, Page 113-119
.


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Blocking NOTCH pathway can enhance the effect of EGFR inhibitor through targeting CD133+ endometrial cancer cells

Volume 19, Issue 2, February 2018, Page 113-119
.


http://ift.tt/2DFCdyH

Long-term visual outcomes of craniopharyngioma in children

Abstract

Visual function is a critical factor in the diagnosis, monitoring, and prognosis of craniopharyngiomas in children. The aim of this study was to report the long-term visual outcomes in a cohort of pediatric patients with craniopharyngioma. The study design is a retrospective chart review of craniopharyngioma patients from a single tertiary-care pediatric hospital. 59 patients were included in the study. Mean age at presentation was 9.4 years old (range 0.7–18.0 years old). The most common presenting features were headache (76%), nausea/vomiting (32%), and vision loss (31%). Median follow-up was 5.2 years (range 1.0–17.2 years). During follow-up, visual decline occurred in 17 patients (29%). On Kaplan Meier survival analysis, 47% of the cases of visual decline occurred within 4 months of diagnosis, with the remaining cases occurring sporadically during follow-up (up to 8 years after diagnosis). In terms of risk factors, younger age at diagnosis, optic nerve edema at presentation, and tumor recurrence were found to have statistically significant associations with visual decline. At final follow-up, 58% of the patients had visual impairment in at least one eye but only 10% were legally blind in both eyes (visual acuity 20/200 or worse or < 20° of visual field). Vision loss is a common presenting symptom of craniopharyngiomas in children. After diagnosis, monitoring vision is important as about 30% of patients will experience significant visual decline. Long-term vision loss occurs in the majority of patients, but severe binocular visual impairment is uncommon.

from Cancer via ola Kala on Inoreader http://ift.tt/2DFoSXc
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Long-term visual outcomes of craniopharyngioma in children

Abstract

Visual function is a critical factor in the diagnosis, monitoring, and prognosis of craniopharyngiomas in children. The aim of this study was to report the long-term visual outcomes in a cohort of pediatric patients with craniopharyngioma. The study design is a retrospective chart review of craniopharyngioma patients from a single tertiary-care pediatric hospital. 59 patients were included in the study. Mean age at presentation was 9.4 years old (range 0.7–18.0 years old). The most common presenting features were headache (76%), nausea/vomiting (32%), and vision loss (31%). Median follow-up was 5.2 years (range 1.0–17.2 years). During follow-up, visual decline occurred in 17 patients (29%). On Kaplan Meier survival analysis, 47% of the cases of visual decline occurred within 4 months of diagnosis, with the remaining cases occurring sporadically during follow-up (up to 8 years after diagnosis). In terms of risk factors, younger age at diagnosis, optic nerve edema at presentation, and tumor recurrence were found to have statistically significant associations with visual decline. At final follow-up, 58% of the patients had visual impairment in at least one eye but only 10% were legally blind in both eyes (visual acuity 20/200 or worse or < 20° of visual field). Vision loss is a common presenting symptom of craniopharyngiomas in children. After diagnosis, monitoring vision is important as about 30% of patients will experience significant visual decline. Long-term vision loss occurs in the majority of patients, but severe binocular visual impairment is uncommon.

http://ift.tt/2DFoSXc

Patient-reported symptoms before palliative radiotherapy predict survival differences

Abstract

Background

Widely used prognostic scores, e. g., for brain or bone metastases, are based on disease- and patient-related factors such as extent of metastases, age and performance status, which were available in the databases used to develop the scores. Few groups were able to include patient-reported symptoms. In our department, all patients were assessed with the Edmonton Symptom Assessment System (ESAS, a one-sheet questionnaire addressing 11 major symptoms and wellbeing on a numeric scale of 0–10) at the time of treatment planning since 2012. Therefore, we analyzed the prognostic impact of baseline ESAS symptom severity.

Methods

Retrospective review of 102 patients treated with palliative radiotherapy (PRT) between 2012 and 2015. All ESAS items were dichotomized (below/above median). Uni- and multivariate analyses were performed to identify prognostic factors for survival.

Results

The most common tumor types were prostate, breast and non-small cell lung cancer, predominantly with distant metastases. Median survival was 6 months. Multivariate analysis resulted in six significant prognostic factors. These were ESAS pain while not moving (median 3), ESAS appetite (median 5), Eastern Cooperative Oncology Group (ECOG) performance status, pleural effusion/metastases, intravenous antibiotics at start or within 2 weeks before PRT and no systemic cancer treatment.

Conclusions

Stronger pain while not moving and reduced appetite (below/above median) predicted significantly shorter survival. Development of new prognostic scores should include patient-reported symptoms and other innovative parameters because they were more important than primary tumor type, age and other traditional baseline parameters.

http://ift.tt/2mP0w64

Interleukin-1 receptor antagonist inhibits angiogenesis in gastric cancer

Abstract

Background

Interleukin-1 alpha (IL-1α) plays an important role in tumorigenesis and angiogenesis of gastric cancer. The interleukin-1 receptor antagonist (IL-1RA) inhibits IL-1 selectively and specifically through IL-1R type I (IL-1RI). However, the underlying mechanism by which IL-1RA modulates the interactions of tumor cells and their micro-environment is poorly understood. We have evaluated the role of IL-1RA in the metastatic process as well as the mutual or reciprocal actions between gastric cancer cells and stromal cells.

Materials and methods

The expressions of IL-1α, vascular endothelial growth factor (VEGF), and IL-1RI mRNA were determined by reverse transcriptase-PCR. The regulatory effect of IL-1RA on the secretion of VEGF in human gastric cancer cells and human umbilical vein endothelial cells (HUVECs) was detected by enzyme-linked immunosorbent assay. The effect of IL-1RA on metastatic potential was evaluated using proliferation, invasion, and angiogenesis assays, respectively, including in vitro co-culture system models consisting of tumor cells and stromal cells that were used to detect invasion and angiogenesis.

Results

Interleukin-1α mRNA was detected in the higher liver metastatic gastric cell line MKN45. IL-1α protein was expressed in MKN45 cells and in HUVECs. VEGF mRNA and protein were detected in the three gastric cancer cell lines (MKN4, NUGC-4, and AGS). Levels of VEGF secreted by gastric cancer cells and HUVECs appeared to be reduced through the action of IL-1RA via IL-1RI in a dose-dependent manner (P < 0.01). IL-1RA significantly inhibited the proliferation and migration of HUVECs (P < 0.01) and tube formation by HUVECs (P < 0.01), both in a dose-dependent manner. Compared with HUVECs grown without cancer cells (control) or with NUGC-4 cells, tube formation by HUVECs was significantly enhanced by co-culture with MKN45 cells (P < 0.01). The enhanced tube formation in the presence of MKN45 cells was inhibited by the addition of IL-1RA (P < 0.01).

Conclusions

The IL-1RA downregulated the metastatic potential of gastric cancer through blockage of the IL-1α/VEGF signaling pathways. IL-1RA has the potential to play a role in the treatment of gastric cancer.

http://ift.tt/2mHjYB3

Interleukin-1 receptor antagonist inhibits angiogenesis in gastric cancer

Abstract

Background

Interleukin-1 alpha (IL-1α) plays an important role in tumorigenesis and angiogenesis of gastric cancer. The interleukin-1 receptor antagonist (IL-1RA) inhibits IL-1 selectively and specifically through IL-1R type I (IL-1RI). However, the underlying mechanism by which IL-1RA modulates the interactions of tumor cells and their micro-environment is poorly understood. We have evaluated the role of IL-1RA in the metastatic process as well as the mutual or reciprocal actions between gastric cancer cells and stromal cells.

Materials and methods

The expressions of IL-1α, vascular endothelial growth factor (VEGF), and IL-1RI mRNA were determined by reverse transcriptase-PCR. The regulatory effect of IL-1RA on the secretion of VEGF in human gastric cancer cells and human umbilical vein endothelial cells (HUVECs) was detected by enzyme-linked immunosorbent assay. The effect of IL-1RA on metastatic potential was evaluated using proliferation, invasion, and angiogenesis assays, respectively, including in vitro co-culture system models consisting of tumor cells and stromal cells that were used to detect invasion and angiogenesis.

Results

Interleukin-1α mRNA was detected in the higher liver metastatic gastric cell line MKN45. IL-1α protein was expressed in MKN45 cells and in HUVECs. VEGF mRNA and protein were detected in the three gastric cancer cell lines (MKN4, NUGC-4, and AGS). Levels of VEGF secreted by gastric cancer cells and HUVECs appeared to be reduced through the action of IL-1RA via IL-1RI in a dose-dependent manner (P < 0.01). IL-1RA significantly inhibited the proliferation and migration of HUVECs (P < 0.01) and tube formation by HUVECs (P < 0.01), both in a dose-dependent manner. Compared with HUVECs grown without cancer cells (control) or with NUGC-4 cells, tube formation by HUVECs was significantly enhanced by co-culture with MKN45 cells (P < 0.01). The enhanced tube formation in the presence of MKN45 cells was inhibited by the addition of IL-1RA (P < 0.01).

Conclusions

The IL-1RA downregulated the metastatic potential of gastric cancer through blockage of the IL-1α/VEGF signaling pathways. IL-1RA has the potential to play a role in the treatment of gastric cancer.

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Role of complement in the pathogenesis of thrombotic microangiopathies

Summary

Thrombotic microangiopathies (TMAs) are rare but life-threatening disorders characterized by microvascular hemolytic anemia and acute thrombocytopenia with or without organ damage. The term TMA covers various subgroups of diseases, the pathogenesis of which is briefly summarized in this review. As highlighted here, complement activation may represent an important amalgamating process in all of these conditions, since it is able to link together activation and damage of multiple involved cell types, such as endothelial cells, platelets, and neutrophils.

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Role of complement in the pathogenesis of thrombotic microangiopathies

Summary

Thrombotic microangiopathies (TMAs) are rare but life-threatening disorders characterized by microvascular hemolytic anemia and acute thrombocytopenia with or without organ damage. The term TMA covers various subgroups of diseases, the pathogenesis of which is briefly summarized in this review. As highlighted here, complement activation may represent an important amalgamating process in all of these conditions, since it is able to link together activation and damage of multiple involved cell types, such as endothelial cells, platelets, and neutrophils.

http://ift.tt/2mLr9co

Combination of betulinic acid with diazen-1-ium-1,2-diolate nitric oxide moiety donating a novel anticancer candidate

http://ift.tt/2DjDhLS

Prognostic role of HSPs in human gastrointestinal cancer: a systematic review and meta-analysis

http://ift.tt/2B9gKLQ

Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis

Abstract

The clinical behavior of systemic mastocytosis (SM) is strongly associated with activating mutations in KIT (D816V in >80% of cases), with the severity of the phenotype influenced by additional somatic mutations, e.g. in SRSF2, ASXL1 or RUNX1. Complex molecular profiles are frequently associated with the presence of an associated hematologic neoplasm (AHN) and an unfavorable clinical outcome. However, little is known about the incidence and prognostic impact of cytogenetic aberrations. We analyzed cytogenetic and molecular characteristics of 109 patients (KIT D816V+, n=102, 94%) with indolent (ISM, n=26) and advanced SM (n=83) with (n=73, 88%) or without AHN. An aberrant karyotype was identified in SM-AHN (16/73, 22%) patients only. In patients with an aberrant karyotype additional somatic mutations were identified in 12/16 (75%) patients. Seven of 10 (70%) patients with a poor-risk karyotype, e.g. monosomy 7 or complex karyotype, and 1/6 (17%) patients with a good-risk karyotype progressed to secondary acute myeloid leukemia (n=7) or mast cell leukemia (n=1) within a median of 40 months (range 2-190, P=0.04). In advanced SM, the median overall survival (OS) of poor-risk karyotype patients was significantly shorter than in good-risk/normal karyotype patients (4 vs. 39 months; hazard ratio 11.7, 95% CI 5.0-27.3; P<0.0001). Additionally, the shortened OS in patients with poor-risk karyotype was independent from the mutation status. In summary, a poor-risk karyotype is an independent prognostic variable in advanced SM. Cytogenetic and molecular analyses should be routinely performed in all patients with advanced SM±AHN because these investigations greatly support prognostication and treatment decisions. This article is protected by copyright. All rights reserved.

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Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis

Abstract

The clinical behavior of systemic mastocytosis (SM) is strongly associated with activating mutations in KIT (D816V in >80% of cases), with the severity of the phenotype influenced by additional somatic mutations, e.g. in SRSF2, ASXL1 or RUNX1. Complex molecular profiles are frequently associated with the presence of an associated hematologic neoplasm (AHN) and an unfavorable clinical outcome. However, little is known about the incidence and prognostic impact of cytogenetic aberrations. We analyzed cytogenetic and molecular characteristics of 109 patients (KIT D816V+, n=102, 94%) with indolent (ISM, n=26) and advanced SM (n=83) with (n=73, 88%) or without AHN. An aberrant karyotype was identified in SM-AHN (16/73, 22%) patients only. In patients with an aberrant karyotype additional somatic mutations were identified in 12/16 (75%) patients. Seven of 10 (70%) patients with a poor-risk karyotype, e.g. monosomy 7 or complex karyotype, and 1/6 (17%) patients with a good-risk karyotype progressed to secondary acute myeloid leukemia (n=7) or mast cell leukemia (n=1) within a median of 40 months (range 2-190, P=0.04). In advanced SM, the median overall survival (OS) of poor-risk karyotype patients was significantly shorter than in good-risk/normal karyotype patients (4 vs. 39 months; hazard ratio 11.7, 95% CI 5.0-27.3; P<0.0001). Additionally, the shortened OS in patients with poor-risk karyotype was independent from the mutation status. In summary, a poor-risk karyotype is an independent prognostic variable in advanced SM. Cytogenetic and molecular analyses should be routinely performed in all patients with advanced SM±AHN because these investigations greatly support prognostication and treatment decisions. This article is protected by copyright. All rights reserved.

http://ift.tt/2B855gn