A rare cause of neonatal persistent jaundice

Description

A 22-year-old gravida 2, para 1 (G2P1) woman with immunoglobulin anti-D prophylaxis, insulin-treated gestational diabetes and first-trimester cytomegalovirus (CMV) infection vaginally delivered a 39-week boy weighing 3720 g (90th centile) and with Apgar scores of 8 and 10 at 1 and 5 min. Prenatal ultrasonographic assessment throughout gestation was normal. Nursery stay was uneventful. He was discharged on day 2, with a normal examination, except for the appearance of jaundice, with a transcutaneous bilirubin of 248 µmol/L (cut-off 250 µmol/L), not meeting the criteria for phototherapy. A follow-up clinic on day 4, arranged for bilirubin measurement and CMV testing, surprisingly revealed poor general appearance, lethargy, very icteric skin and a minor weight loss (9% of birth weight). Both liver and splenic edges were palpable. Vital signs were normal. Blood routine showed haemoglobin of 19 g/dL, haematocrit of 58%, white blood cells 11.6x10⁹/L and platelet count 128x10⁹/L. Biochemistry revealed total serum bilirubin...

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Maxillary chondrosarcoma mimicking torus palatinus

Description 

An 88-year-old man was referred to the head and neck surgery clinic for investigation of a painless hard palate lesion. The mass had been present for several months and was identified incidentally by the general practitioner. There were no oral or sinonasal symptoms. On examination, a 3x2 cm hard palatal swelling, covered by normal mucosa and resembling a torus palatinus was identified (figure 1). Flexible nasal endoscopy revealed the tumour to involve the floor of the nasal cavity bilaterally, displacing the inferior nasal turbinates. Examination of the neck was normal.

Figure 1

Midline palatal swelling covered by mucosa.

A biopsy was taken, and histological analysis described a welldifferentiated cartilaginous lesion consistent with a grade 1 chondrosarcoma. A CT scan was performed (figure 2). The regional head and neck and regional sarcoma multidisciplinary team meetings recommended surgical management. The patient underwent...

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Intractable hyperemesis gravidarum in a patient with type 1 diabetes

Hyperemesis gravidarum is not uncommon. Its pathogenies is multifactorial but not fully understood. We present a case of a middle class, Caucasian pregnant woman aged 24 years with coexisting type 1 diabetes, who had severe hyperemesis gravidarum from the sixth week of pregnancy and was resistant to all standard and off-the-label treatments raising questions about the pathogenesis of hyperemesis gravidarum. She was managed with a multidisciplinary approach and was supported with total parenteral nutrition till she had an emergency caesarean section in the 29th week of pregnancy. Her vomiting stopped as soon as a small for gestational age but otherwise healthy male baby was delivered.

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Intradural lumbar disc herniation detected by 3D CISS MRI

A 73-year-old man who presented with right lumbosciatic pain underwent a neurosurgical operation for a voluminous L2–L3 disc herniation, seen on conventional MRI images. No disc herniation was identified in the epidural space during the surgery. Just after the operation, the patient started to present pain in the left L3 territory and was not able to walk any more. A second MRI including three-dimensional (3D) high-resolution constructive interference in steady state (CISS) sequence showed that the voluminous L2–L3 disc split the posterior longitudinal ligament and the anterior dura mater, extended intradurally and compressed the cauda equina to the right. The patient underwent a second surgery, which permitted to cure the symptoms. 3D high-resolution CISS should be considered to accurately depict intradural disc herniation in order to optimally guide the surgical approach.

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Shah-Waardenburg syndrome: a case highlighting the importance of a holistic approach to assessing a child

We present the case of a 45-day-old child with the chief complaint of failure to pass stools for 10 days. After initial investigation, the patient was found to have Hirschsprung's disease. However, with further examination and analysis, the extremely rare diagnosis of type 4 Waardenburg syndrome was made (also known as Shah-Waardenburg syndrome or Waardenburg-Hirschsprung's disease).

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Solid pseudopapillary tumour (Frantzs tumour) of the pancreas in childhood: successful management of late liver metastases with sunitinib and chemoembolisation

The patient is a girl aged 17 years who originally presented at age 11 years with a solid pseudopapillary tumour (SPT) in the head of the pancreas treated by an R0 pylorus-preserving Whipple procedure. The patient underwent surveillance CT every 3 months for the first year followed by MRI every 6 months. She was noted to have a new liver lesion in Couinaud segment VI highly suspicious for metastasis at 30 months. Liver wedge biopsy confirmed metastatic SPT. Two months later two new lesions were noted in Couinaud segment VII. The family preferred medical management to surgery resulting in a treatment combination of the tyrosine kinase inhibitor sunitinib and hepatic artery embolisation. The patient developed a hepatic abscess following embolisation but recovered with antibiotics. The patient has subsequently been followed with serial MRIs every 3 months, and 20 months following chemoembolisation, she has no evidence of recurrence of the metastases.

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Unusual case of anxiety: trichloroethylene neurotoxicity

I present an uncommon case of recurrent, intractable anxiety that was presented acutely and slowly evolved into a chronic debilitating condition. A young previously fit and healthy 24-year-old patient presents with somewhat atypical symptoms of anxiety. Full medical work-up including examination, blood, ECG electrocardiogram, electroencephalogram and CT of the head was unremarkable. When the history was explored in detail, it was revealed he worked in the navy and was exposed to a neurotoxic solvent, trichloroethylene. This case highlights the importance of eliciting a detailed occupational history, particularly paying attention to patient demographics such as occupation and presenting symptoms that do not readily fit into diagnostic criteria.

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Cutaneous infection with paucibacillary Mycobacterium tuberculosis treated successfully with a modified antituberculous drug regimen

Tuberculosis is a serious infection that is increasing in prevalence, affecting many people worldwide. The diagnosis of cutaneous tuberculosis is challenging and requires the correlation of clinical findings with often inconclusive diagnostic testing. Extrapulmonary tuberculosis comprises approximately 10% of all cases of tuberculosis, and cutaneous tuberculosis makes up only a small proportion of these cases. Discussed here is the case of a 61-year-old immunocompetent female with a large cutaneous lesion on her index finger secondary to Mycobacterium tuberculosis. Tissue cultures taken at biopsy were negative; however, empiric antimycobacterial therapy was initiated. The initial regimen was not tolerated, and antituberculous therapy was substituted for moxifloxacin and clarithromycin. The lesion improved significantly with a concurrent improvement in function.

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Short-course high-dose ibuprofen causing both early and delayed jejunal perforations in a non-smoking man

Description

A 48-year-old non-smoking man underwent laparotomy for peritonitis immediately after taking ibuprofen 800 mg 6 hourly for 14 days for back pain. His only other medication was long-term omeprazole 20 mg per day. At operation he had three separate perforations in his proximal jejunum. Fifteen centimetres of jejunum were resected with primary anastomosis. Histology showed focal mucosal ischaemic changes with normal mucosa between. There was no vasculitis. The perforations were attributed to ibuprofen intake. He made an uneventful recovery and was instructed to refrain from non-steroidal anti-inflammatory drug (NSAID) intake.

He was readmitted 5 months later with abdominal pain. He had continued omeprazole but had taken no further NSAID. CT showed extensive free intra-abdominal fluid with free gas adjacent to his proximal jejunum (figure 1), indicating a further perforation. This was confirmed at laparotomy when a 5 mm perforated ulcer was found in his proximal jejunum (figure...

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Oyster-related tenosynovitis: a rare case of Mycobacterium szulgai in the immunocompromised

A 66-year-old man with a history of renal transplant on chronic immunosuppression presented to his primary care physician with a swollen right index finger. On examination, mild swelling was present. Conservative management failed and initial plain films were negative. Corticosteroid injection was performed by orthopaedics, but symptoms recurred several months later and an MRI showed flexor digitorum tenosynovitis and abscesses of the superficialis and profundus tendons. A flexor tenolysis was performed with cultures positive for Mycobacterium szulgai, a rare, non-tuberculous mycobacterial infection. Treatment was initiated with moxifloxacin, ethambutol and azithromycin daily for nearly 4 months. Repeat MRI 3 months after completion of antibiotics showed near resolution of the tenosynovitis.

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HHV-8-associated haemophagocytic lymphohistiocytosis in a patient with advanced AIDS

We present a patient with advanced AIDS admitted with recurrent shock of unclear aetiology, fevers, altered mental status and refractory cytopenias. His case posed a diagnostic challenge because evaluation of septic shock in the setting of advanced AIDS requires a time-consuming work-up for broad infectious aetiologies that can delay consideration of other diagnoses, including primary or secondary haemophagocytic lymphohistiocytosis (HLH). After this patient did not improve with supportive care and empiric antimicrobials, there was concern for HLH given that he met ≥5 of the HLH consortium criteria. He underwent bone marrow biopsy, which was non-diagnostic. Empiric therapy for HLH was initiated, but unfortunately, the patient died. Autopsy revealed extensive haemophagocytosis in the spleen, bone marrow and liver, confirming the diagnosis of HLH. Postmortem, his soluble CD-25 returned 18 890 pg/mL (<1033 pg/mL), and his serum HHV-8 PCR resulted positive. The diagnosis was HLH secondary to Human Herpes Virus 8 (HHV-8) in a patient with advanced AIDS.

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Chickenpox: an ageless disease

A 97-year-old woman presented with 4-day history of vesicular rash, initially at the feet but then spread up to the thighs bilaterally, abdomen and trunk. The initial differentials included bullous pemphigus and cellulitis by the emergency department. She was then managed as bullous pemphigus by the acute medical team and started on high-dose steroids, with no other differentials considered. When her care was taken over by the general medical team, varicella zoster virus (VZV) infection was suspected. After confirmation by the dermatology team regarding the clinical diagnosis and the positive VZV DNA swabs, she was started on acyclovir.

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Osteoid bezoar: a rare case causing small bowel obstruction

Acute intestinal obstruction due to foreign bodies or bezoar is a rare occurrence in an adult. We report an unusual case of a 27-year-old male patient with no previous history of abdominal surgery or other medical disease, who presented with an acute episode of intestinal obstruction due to ingestion of a bone piece which was managed surgically by enterotomy, and the patient had an uneventful postoperative course. He was advised regular follow-up once in 2 weeks initially and once a month subsequently. He had no problems at the end of 6 months.

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Syndrome of X linked intellectual disability, epilepsy, progressive brain atrophy and large head associated with SLC9A6 mutation

SLC9A6 gene encodes for a sodium/hydrogen exchanger-6 protein mainly involved in endosomal trafficking and maintaining intraluminal pH. Loss of function mutations in SLC9A6 gene in children has been associated with Christianson syndrome and autism spectrum disorder. We describe a 3-year-old boy with intellectual disability, infantile-onset drug-refractory epilepsy, progressive brain atrophy and large head with a novel missense hemizygous mutation in exon 16 of the SLC9A6 gene on chromosome X. Presence of large head, early developmental regression and progressive cerebral atrophy expand the phenotypic spectrum of SLC9A6 mutations. Our case also highlights the importance of genetic testing in children with unexplained intellectual disability, epilepsy and neurodevelopmental impairments.

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Idiopathic bilateral hypertrophic olivary degeneration

Description

A 55-year-old man presented with involuntary movements of the tongue and soft palate associated with unsteadiness in walking for a period of 3 months. The patient did not complain of ear clicking. Examination revealed palatal myoclonus, tongue fasciculation and ataxic gait. MRI of the brain showed increased T2 and Fluid Attenuation Inversion recovery (FLAIR) signal intensities in the bilateral inferior olivary complex without diffusion restriction (figure 1). Midbrain, pons, and cerebral and cerebellar parenchyma were normal (figure 2). Imaging features were consistent with bilateral hypertrophic olivary degeneration. Hypertrophic olivary degeneration is a unique type of trans-synaptic neuronal degeneration caused by damage to the dentatorubral pathway or the triangle of Guillain and Mollaret (figure 3). Focal lesions like infarction, haemorrhage, demyelination  and trauma involving this neuronal pathway lead to interruption, and following sequential pathological changes are described (table 1).1

Figure 1

Coronal T2 (A), axial T2 (B),...

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Contemporary non-surgical approach for faecal diversion in a case of Fourniers gangrene

Fournier's gangrene is a fatal necrotising fasciitis of the perineum, genitals and lower abdomen. Patients often need an aggressive surgical debridement, and in few cases, a diverting colostomy. We report the case of a 70-year-old man with multiple comorbidities diagnosed with Fournier's gangrene, who underwent debridement and had a wound complication due to faecal contamination. A novel, self-retaining rectal device was used to perform faecal diversion, which subsequently showed wound healing within a week, hence avoiding the need of a colostomy.

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Variant of Lemierres syndrome with internal jugular vein aneurysm

Internal jugular vein (IJV) aneurysm is a rare entity, and a thrombosed aneurysm poses diagnostic and management challenges. We came across a 53-year-old woman who presented with fever, vomiting and right neck swelling for a week. Laboratory investigations showed neutrophilic leucocytosis, raised acute phase reactant and blood culture yielded Klebsiella pneumoniae. Ultrasound and contrast-enhanced CT neck revealed a large fusiform aneurysm of the right IJV with filling defect extending from the aneurysm into the right transverse sinus. There was a cavity at the right lower third molar tooth. MRI confirmed the findings with additional enhancing focus at right lower periodontal region. The swelling reduced after 2 weeks of medical therapy, and follow-up imaging 4 months later showed complete resolution of the aneurysm with residual thrombosis. After extensive workup, dental infection remains the only identifiable primary source leading to thrombophlebitis of the right IJV and subsequent sequelae.

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Correction: Gangrenous digital infarcts in a severe case of cutaneous polyarteritis nodosa

The correct order of authors is as follows:

Hamzah Mahmood-Rao, Nirav Gandhi, Tina Ding

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Double hit! A unique case of resistant hypertension

A middle-aged woman with obesity, hyperlipidaemia and diet-controlled diabetes was referred for resistant hypertension. Her blood pressure (BP) was uncontrolled on five medications, including a diuretic. Physical exam revealed a systolic ejection murmur, and ECHO demonstrated moderate hypertrophy. Laboratory examination revealed elevated aldosterone level (20.7 ng/dL) and elevated aldosterone:renin ratio (41.4 (ng/dL)/(ng/mL/h)), meeting criteria for primary aldosteronism (PA), and confirmed by saline infusion testing. CT scan of the adrenals was non-localising. Adrenal venous sampling confirmed bilateral idiopathic adrenal hyperplasia. Concurrent primary hyperparathyroidism was demonstrated by elevated calcium and parathyroid hormone levels and localised by sestamibi scan. Idiopathic adrenal hyperplasia was treated medically with spironolactone. Her BP remained elevated until postparathyroidectomy. Evidence shows that a hyperfunctioning parathyroid gland may contribute to maintaining hyperaldosteronism in PA making this bidirectional link unique. The significance of this case is in the potential for further understanding of the pathophysiology of common causes of secondary hypertension.

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Cost comparison by treatment arm and center-level variations in cost and inpatient days on the phase III high-risk B acute lymphoblastic leukemia trial AALL0232

Abstract

The Children's Oncology Group (COG) develops and implements multi-institutional clinical trials with the primary goal of assessing the efficacy and safety profile of treatment regimens for various pediatric cancers. However, the monetary costs of treatment regimens are not measured. AALL0232 was a COG randomized phase III trial for children with acute lymphoblastic leukemia that found that dexamethasone (DEX) was a more effective glucocorticoid than prednisone (PRED) in patients younger than 10 years, but PRED was equally effective and less toxic in older patients. In addition, high-dose methotrexate (HD-MTX) led to better survival than escalating doses of methotrexate (C-MTX). Cost data from the Pediatric Health Information System database were merged with clinical data from the COG AALL0232 trial. Total and component costs were compared between treatment arms and across hospitals. Inpatient costs were higher in the HD-MTX and DEX arms when compared to the C-MTX and PRED arms at the end of therapy. There was no difference in cost between these arms at last follow-up. Considerable variation in total costs existed across centers to deliver the same therapy that was driven by differences in inpatient days and pharmacy costs. The more effective regimens were found to be more expensive during therapy but were ultimately cost-neutral in longer term follow-up. The variations in cost across centers suggest an opportunity to standardize resource utilization for patients receiving similar therapies, which could translate into reduced healthcare expenditures.

When comparing costs between treatment arms of the high-risk B acute lymphoblastic leukemia pediatric trial, high-dose methotrexate and dexamethasone arms were associated with higher costs when compared to the escalating methotrexate and prednisone arms during protocol therapy, but there was no difference in cost between the methotrexate or steroid arms at time of last follow up. We also found that costs vary significantly across hospitals to deliver identical therapy.

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Cost comparison by treatment arm and center-level variations in cost and inpatient days on the phase III high-risk B acute lymphoblastic leukemia trial AALL0232

Abstract

The Children's Oncology Group (COG) develops and implements multi-institutional clinical trials with the primary goal of assessing the efficacy and safety profile of treatment regimens for various pediatric cancers. However, the monetary costs of treatment regimens are not measured. AALL0232 was a COG randomized phase III trial for children with acute lymphoblastic leukemia that found that dexamethasone (DEX) was a more effective glucocorticoid than prednisone (PRED) in patients younger than 10 years, but PRED was equally effective and less toxic in older patients. In addition, high-dose methotrexate (HD-MTX) led to better survival than escalating doses of methotrexate (C-MTX). Cost data from the Pediatric Health Information System database were merged with clinical data from the COG AALL0232 trial. Total and component costs were compared between treatment arms and across hospitals. Inpatient costs were higher in the HD-MTX and DEX arms when compared to the C-MTX and PRED arms at the end of therapy. There was no difference in cost between these arms at last follow-up. Considerable variation in total costs existed across centers to deliver the same therapy that was driven by differences in inpatient days and pharmacy costs. The more effective regimens were found to be more expensive during therapy but were ultimately cost-neutral in longer term follow-up. The variations in cost across centers suggest an opportunity to standardize resource utilization for patients receiving similar therapies, which could translate into reduced healthcare expenditures.

When comparing costs between treatment arms of the high-risk B acute lymphoblastic leukemia pediatric trial, high-dose methotrexate and dexamethasone arms were associated with higher costs when compared to the escalating methotrexate and prednisone arms during protocol therapy, but there was no difference in cost between the methotrexate or steroid arms at time of last follow up. We also found that costs vary significantly across hospitals to deliver identical therapy.

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Acquired Resistance of PTEN-Deficient Cells to PARP Inhibitor and Ara-C Mediated by 53BP1 Loss and SAMHD1 Overexpression

Summary

With increasing uses of PARP inhibitors (PARPis) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the PTEN-deficient background is poorly understood. We generated 3 PARPi-resistant PTEN-deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP). These variants displayed consistent resistance (2.46~71.78-fold) to all 5 PARPis including niraparib and rucaparib and showed higher degrees of resistance to the PARPis to which the parental cells were more sensitive. The resistance was characteristic of fast emergence and high stability. However, the resistance acquirement did not cause an increasingly aggressive phenotype. The resistance was not correlated to various factors including PTEN mutations. The PARPi-treated variants produced less γH2AX and G2/M arrest. Consistently, loss of 53BP1 occurred in all variants and its compensation enhanced their sensitivity to PARPis by ~76%. The variants revealed slightly different cross-resistance profiles to 13 non-PARPi anticancer drugs. All were resistant to Ara-C (6~8-fold) but showed differential resistance to 5-fluorouracil, gemcitabine and paclitaxel. Almost no resistance was observed to the rest drugs including cisplatin. SAMHD1 was overexpressed in all the variants and its knockout completely restored their sensitivity to Ara-C but did not affect their PARPi sensitivity. This study demonstrates a consistent resistance profile to PARPis and a unique cross-resistance profile to non-PARPi drugs in different PARPi-resistant U251 cells and reveals 53BP1 loss and SAMHD1 overexpression as the primary mechanisms responsible for their resistance to PARPis and Ara-C, respectively. These effects probably result from heritable gene change(s) caused by persistent PARPi exposure.

This article is protected by copyright. All rights reserved.

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SLC35F2 is indispensable for papillary thyroid carcinoma progression via activation of TGFBR1/ASK-1/MAPK signaling axis

Summary

Solute carrier family control essential physiological functions and are tightly linked to human diseases. Solute carrier family 35 member F2 (SLC35F2) is aberrantly activated in several malignancies. However, the biological function and molecular mechanism of SLC35F2 in papillary thyroid carcinoma (PTC) are yet to be fully explored. Here, we showed that SLC35F2 was prominently up-regulated in PTC tissues at both protein and mRNA expression level compared with matched adjacent normal tissues. Besides, the high expression of SLC35F2 was significantly associated with lymph node metastasis in patients with PTC. CRISPR/Cas9-mediated knockout of SLC35F2 attenuated the tumorigenic properties of PTC, including cell proliferation, migration and invasion and induced G1 phase arrest. In contrast, ectopic expression of SLC35F2 brought about aggressive malignant phenotypes of PTC cells. Moreover, SLC35F2 expedited the proliferation and migration of PTC cells by targeting TGFBR1 and p-ASK-1, thereby activating the mitogen-activated protein kinase (MAPK) signaling pathway. Besides, the malignant behaviors induced by over-expression of SLC35F2 could be abrogated by silencing of TGFBR1 using a specific inhibitor. We conducted the first study on SLC35F2 in thyroid cancer with the aim of elucidating the functional significance and molecular mechanism of SLC35F2. Our findings suggest that SLC35F2 exerts its oncogenic effect on PTC progression through the MAPK pathway, with dependence on activation of TGFBR-1 and ASK-1.

This article is protected by copyright. All rights reserved.

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Acquired Resistance of PTEN-Deficient Cells to PARP Inhibitor and Ara-C Mediated by 53BP1 Loss and SAMHD1 Overexpression

Summary

With increasing uses of PARP inhibitors (PARPis) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the PTEN-deficient background is poorly understood. We generated 3 PARPi-resistant PTEN-deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP). These variants displayed consistent resistance (2.46~71.78-fold) to all 5 PARPis including niraparib and rucaparib and showed higher degrees of resistance to the PARPis to which the parental cells were more sensitive. The resistance was characteristic of fast emergence and high stability. However, the resistance acquirement did not cause an increasingly aggressive phenotype. The resistance was not correlated to various factors including PTEN mutations. The PARPi-treated variants produced less γH2AX and G2/M arrest. Consistently, loss of 53BP1 occurred in all variants and its compensation enhanced their sensitivity to PARPis by ~76%. The variants revealed slightly different cross-resistance profiles to 13 non-PARPi anticancer drugs. All were resistant to Ara-C (6~8-fold) but showed differential resistance to 5-fluorouracil, gemcitabine and paclitaxel. Almost no resistance was observed to the rest drugs including cisplatin. SAMHD1 was overexpressed in all the variants and its knockout completely restored their sensitivity to Ara-C but did not affect their PARPi sensitivity. This study demonstrates a consistent resistance profile to PARPis and a unique cross-resistance profile to non-PARPi drugs in different PARPi-resistant U251 cells and reveals 53BP1 loss and SAMHD1 overexpression as the primary mechanisms responsible for their resistance to PARPis and Ara-C, respectively. These effects probably result from heritable gene change(s) caused by persistent PARPi exposure.

This article is protected by copyright. All rights reserved.

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SLC35F2 is indispensable for papillary thyroid carcinoma progression via activation of TGFBR1/ASK-1/MAPK signaling axis

Summary

Solute carrier family control essential physiological functions and are tightly linked to human diseases. Solute carrier family 35 member F2 (SLC35F2) is aberrantly activated in several malignancies. However, the biological function and molecular mechanism of SLC35F2 in papillary thyroid carcinoma (PTC) are yet to be fully explored. Here, we showed that SLC35F2 was prominently up-regulated in PTC tissues at both protein and mRNA expression level compared with matched adjacent normal tissues. Besides, the high expression of SLC35F2 was significantly associated with lymph node metastasis in patients with PTC. CRISPR/Cas9-mediated knockout of SLC35F2 attenuated the tumorigenic properties of PTC, including cell proliferation, migration and invasion and induced G1 phase arrest. In contrast, ectopic expression of SLC35F2 brought about aggressive malignant phenotypes of PTC cells. Moreover, SLC35F2 expedited the proliferation and migration of PTC cells by targeting TGFBR1 and p-ASK-1, thereby activating the mitogen-activated protein kinase (MAPK) signaling pathway. Besides, the malignant behaviors induced by over-expression of SLC35F2 could be abrogated by silencing of TGFBR1 using a specific inhibitor. We conducted the first study on SLC35F2 in thyroid cancer with the aim of elucidating the functional significance and molecular mechanism of SLC35F2. Our findings suggest that SLC35F2 exerts its oncogenic effect on PTC progression through the MAPK pathway, with dependence on activation of TGFBR-1 and ASK-1.

This article is protected by copyright. All rights reserved.

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FDA Approves Trastuzumab Biosimilar [News in Brief]

Second biosimilar approved for cancer will be used for HER2-positive breast and stomach cancers.

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Tumor-associated CD204+ M2 macrophages is an unfavorable prognosticator in uterine cervical adenocarcinoma

Abstract

Uterine cervical adenocarcinoma is rare, but its prevalence has increased. To improve outcomes and ensure the suitability of recent immunotherapies, the aim of the study was to evaluate the clinicopathological impact of the tumor immune microenvironment of uterine cervical adenocarcinoma. We investigated 148 adenocarcinoma cases, including 21 cases of adenocarcinoma in situ (AIS) and 127 cases of invasive adenocarcinoma, using immunohistochemistry to detect tumor-infiltrating immune cells and the expression of PD-L1 and p16 on tumor cells, and we then conducted correlation and survival analyses. The density of immune cells and expression levels were compared between the tumor cell nest and stroma and between AIS and invasive adenocarcinoma using digital image analysis. A higher density of tumor-infiltrating CD204⁺ M2 macrophages was significantly associated with shorter disease-free survival, although no other tumor-infiltrating immune cells were prognostic, including CD4⁺, CD8⁺, FOXP3⁺, and PD-1⁺ lymphocytes and CD68⁺ macrophages. The density of stroma-infiltrating lymphocytes and macrophages was significantly higher in invasive adenocarcinoma than in AIS. The density of tumor-infiltrating lymphocytes in p16-expressing human papillomavirus (HPV)-positive tumors was significantly higher than that in HPV-negative tumors. HPV status was not associated with patient outcome. Expression of PD-L1 on tumor cells was found only in invasive adenocarcinoma cases (17.3%). A higher density of stroma-infiltrating lymphocytes and macrophages was found in PD-L1-positive tumors than in negative tumors. Patients with PD-L1-positive tumors tended to experience longer survival. It is suggested that tumor-infiltrating CD204⁺ M2 macrophages may predict poor prognoses in patients with cervical adenocarcinoma.

This article is protected by copyright. All rights reserved.

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Tumor-associated CD204+ M2 macrophages is an unfavorable prognosticator in uterine cervical adenocarcinoma

Abstract

Uterine cervical adenocarcinoma is rare, but its prevalence has increased. To improve outcomes and ensure the suitability of recent immunotherapies, the aim of the study was to evaluate the clinicopathological impact of the tumor immune microenvironment of uterine cervical adenocarcinoma. We investigated 148 adenocarcinoma cases, including 21 cases of adenocarcinoma in situ (AIS) and 127 cases of invasive adenocarcinoma, using immunohistochemistry to detect tumor-infiltrating immune cells and the expression of PD-L1 and p16 on tumor cells, and we then conducted correlation and survival analyses. The density of immune cells and expression levels were compared between the tumor cell nest and stroma and between AIS and invasive adenocarcinoma using digital image analysis. A higher density of tumor-infiltrating CD204⁺ M2 macrophages was significantly associated with shorter disease-free survival, although no other tumor-infiltrating immune cells were prognostic, including CD4⁺, CD8⁺, FOXP3⁺, and PD-1⁺ lymphocytes and CD68⁺ macrophages. The density of stroma-infiltrating lymphocytes and macrophages was significantly higher in invasive adenocarcinoma than in AIS. The density of tumor-infiltrating lymphocytes in p16-expressing human papillomavirus (HPV)-positive tumors was significantly higher than that in HPV-negative tumors. HPV status was not associated with patient outcome. Expression of PD-L1 on tumor cells was found only in invasive adenocarcinoma cases (17.3%). A higher density of stroma-infiltrating lymphocytes and macrophages was found in PD-L1-positive tumors than in negative tumors. Patients with PD-L1-positive tumors tended to experience longer survival. It is suggested that tumor-infiltrating CD204⁺ M2 macrophages may predict poor prognoses in patients with cervical adenocarcinoma.

This article is protected by copyright. All rights reserved.

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Interventions are needed to support patient–provider decision-making for DCIS: a scoping review

Abstract

Purpose

Prognostic and treatment uncertainty make ductal carcinoma in situ (DCIS) complex to manage. The purpose of this study was to describe research that evaluated DCIS communication experiences, needs and interventions among DCIS patients or physicians.

Methods

MEDLINE, EMBASE, CINAHL and The Cochrane Library were searched from inception to February 2017. English language studies that evaluated patient or physician DCIS needs, experiences or behavioural interventions were eligible. Screening and data extraction were done in duplicate. Summary statistics were used to describe study characteristics and findings.

Results

A total of 51 studies published from 1997 to 2016 were eligible for review, with a peak of 8 articles in year 2010. Women with DCIS lacked knowledge about the condition and its prognosis, although care partners were more informed, desired more information and experienced decisional conflict. Many chose mastectomy or prophylactic mastectomy, often based on physician's recommendation. Following treatment, women had anxiety and depression, often at levels similar to those with invasive breast cancer. Disparities were identified by education level, socioeconomic status, ethnicity and literacy. Physicians said that they had difficulty explaining DCIS and many referred to DCIS as cancer. Despite the challenges reported by patients and physicians, only two studies developed interventions designed to improve patient–physician discussion and decision-making.

Conclusions

As most women with DCIS undergo extensive treatment, and many experience treatment-related complications, the paucity of research on PE to improve and support informed decision-making for DCIS is profound. Research is needed to improve patient and provider discussions and decision-making for DCIS management.

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Oncogenic Ras Isoforms Signaling Specificity at the Membrane

How do Ras isoforms attain oncogenic specificity at the membrane? Oncogenic KRas, HRas, and NRas (K-Ras, H-Ras, and N-Ras) differentially populate distinct cancers. How they selectively activate effectors and why is KRas4B the most prevalent are highly significant questions. Here, we consider determinants that may bias isoform-specific effector activation and signaling at the membrane. We merge functional data with a conformational view to provide mechanistic insight. Cell-specific expression levels, pathway cross-talk, and distinct interactions are the key, but conformational trends can modulate selectivity. There are two major pathways in oncogenic Ras-driven proliferation: MAPK (Raf/MEK/ERK) and PI3Kα/Akt/mTOR. All membrane-anchored, proximally located, oncogenic Ras isoforms can promote Raf dimerization and fully activate MAPK signaling. So why the differential statistics of oncogenic isoforms in distinct cancers and what makes KRas so highly oncogenic? Many cell-specific factors may be at play, including higher KRAS mRNA levels. As a key factor, we suggest that because only KRas4B binds calmodulin, only KRas can fully activate PI3Kα/Akt signaling. We propose that full activation of both MAPK and PI3Kα/Akt proliferative pathways by oncogenic KRas4B—but not by HRas or NRas—may help explain why the KRas4B isoform is especially highly populated in certain cancers. We further discuss pharmacologic implications. Cancer Res; 1–10. ©2017 AACR.

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Oncogenic Ras Isoforms Signaling Specificity at the Membrane

How do Ras isoforms attain oncogenic specificity at the membrane? Oncogenic KRas, HRas, and NRas (K-Ras, H-Ras, and N-Ras) differentially populate distinct cancers. How they selectively activate effectors and why is KRas4B the most prevalent are highly significant questions. Here, we consider determinants that may bias isoform-specific effector activation and signaling at the membrane. We merge functional data with a conformational view to provide mechanistic insight. Cell-specific expression levels, pathway cross-talk, and distinct interactions are the key, but conformational trends can modulate selectivity. There are two major pathways in oncogenic Ras-driven proliferation: MAPK (Raf/MEK/ERK) and PI3Kα/Akt/mTOR. All membrane-anchored, proximally located, oncogenic Ras isoforms can promote Raf dimerization and fully activate MAPK signaling. So why the differential statistics of oncogenic isoforms in distinct cancers and what makes KRas so highly oncogenic? Many cell-specific factors may be at play, including higher KRAS mRNA levels. As a key factor, we suggest that because only KRas4B binds calmodulin, only KRas can fully activate PI3Kα/Akt signaling. We propose that full activation of both MAPK and PI3Kα/Akt proliferative pathways by oncogenic KRas4B—but not by HRas or NRas—may help explain why the KRas4B isoform is especially highly populated in certain cancers. We further discuss pharmacologic implications. Cancer Res; 1–10. ©2017 AACR.

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New Horizons

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Individual Supervision to Enhance Reflexivity and the Practice of Patient-Centered Care: Experience at the Undergraduate Level

Abstract

This article reports on what is at work during individual supervision of medical students in the context of teaching breaking bad news (BBN). Surprisingly, there is a relative lack of research and report on the topic of supervision, even though it is regularly used in medical training. Building on our research and teaching experience on BBN at the undergraduate level, as well as interviews of supervisors, the following key elements have been identified: learning objectives (e.g., raising student awareness of structural elements of the interview, emotion (patients and students) handling), pedagogical approach (being centered on student's needs and supportive to promote already existing competences), essentials (e.g., discussing skills and examples from the clinical practice), and enhancing reflexivity while discussing specific issues (e.g., confusion between the needs of the patient and those of the student). Individual supervision has been identified as crucial and most satisfactory by students to provide guidance and to foster a reflexive stance enabling them to critically apprehend their communication style. Ultimately, the challenge is to teach medical students to not only connect with the patient but also with themselves.

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New Horizons

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Individual Supervision to Enhance Reflexivity and the Practice of Patient-Centered Care: Experience at the Undergraduate Level

Abstract

This article reports on what is at work during individual supervision of medical students in the context of teaching breaking bad news (BBN). Surprisingly, there is a relative lack of research and report on the topic of supervision, even though it is regularly used in medical training. Building on our research and teaching experience on BBN at the undergraduate level, as well as interviews of supervisors, the following key elements have been identified: learning objectives (e.g., raising student awareness of structural elements of the interview, emotion (patients and students) handling), pedagogical approach (being centered on student's needs and supportive to promote already existing competences), essentials (e.g., discussing skills and examples from the clinical practice), and enhancing reflexivity while discussing specific issues (e.g., confusion between the needs of the patient and those of the student). Individual supervision has been identified as crucial and most satisfactory by students to provide guidance and to foster a reflexive stance enabling them to critically apprehend their communication style. Ultimately, the challenge is to teach medical students to not only connect with the patient but also with themselves.

http://ift.tt/2ziNvVS

Cyclin D1 mRNA as a molecular marker for minimal residual disease monitoring in patients with mantle cell lymphoma

Abstract

Chromosomal translocation t(11;14)(q13;q32) is a characteristic molecular marker of mantle cell lymphoma (MCL) and leads to the fusion of the immunoglobulin heavy chain enhancer-promoter with the cyclin D1 gene. Both aberrant cyclin D1 expression and underlying chromosomal aberration may be used as molecular targets for monitoring minimal residual disease (MRD). The present study aims to assess the usefulness of quantitative cyclin D1 gene expression compared to the standardised but more technologically demanding DNA-based method for immunoglobulin heavy chain (IGH) or t(11;14) clone-specific gene rearrangement quantification in a cohort of bone marrow (BM) and peripheral blood (PB) samples from patients with MCL. We simultaneously evaluated DNA-MRD and cyclin D1 expression levels in 234 samples from 57 patients. We observed that both in DNA-MRD positive and negative BM/PB pairs from the same time points the expression levels of cyclin D1 are lower in PB than in BM (median 19×, BM/PB range 0.41–352). The correlation of cyclin D1 transcript levels with DNA-MRD or with flow cytometry was good only in samples with a very high infiltration. In DNA-MRD-negative BM samples, we observed a significant heterogeneity of cyclin D1 expression (in the range of more than three orders of magnitude). This is in contrast to previous reports demonstrating the usefulness of cyclin D1 for MRD monitoring that did not use DNA-based method as a reference. In PB, the specificity of cyclin D1 expression was better due to a lower physiological background. In conclusion, we show that cyclin D1 is unsuitable for MRD monitoring in BM.

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MicroRNA-30e regulates neuroinflammation in MPTP model of Parkinson’s disease by targeting Nlrp3

Abstract

Accumulating evidences suggest that neuroinflammation is a pathological hallmark of Parkinson's disease (PD), a neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). MicroRNAs have been recently recognized as crucial regulators of inflammatory responses. Here, we found significant downregulation of microRNA-30e (miR-30e) in SNpc of MPTP-induced PD mice. Next, we employed miR-30e agomir to upregulate miR-30e expression in MPTP-treated mice. Our results showed that delivery of miR-30e agomir remarkably improved motor behavioral deficits and neuronal activity, and inhibited the loss of dopamine neurons. Moreover, the increased α-synuclein protein expression in SNpc of MPTP-PD mice was alleviated by the upregulation of miR-30e. Further, miR-30e agomir administration also attenuated the marked increase of inflammatory cytokines, such as TNF-α, COX-2, iNOS, and restored the decreased secretion of BDNF in SNpc. In addition, we demonstrated for the first time that miR-30e directly targeted to Nlrp3, thus suppressing Nlrp3 mRNA and protein expression. Finally, miR-30e upregulation significantly inhibited the activation of Nlrp3 inflammasome as evident from the decreased Nlrp3, Caspase-1 and ASC expressions and IL-18 and IL-1β secretions. Taken together, our study demonstrates that miR-30e ameliorates neuroinflammation in the MPTP model of PD by decreasing Nlrp3 inflammasome activity. These findings suggesting that miR30e may be a key inflammation-mediated molecule that could be a potential target for PD therapeutics.

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MicroRNA-30e regulates neuroinflammation in MPTP model of Parkinson’s disease by targeting Nlrp3

Abstract

Accumulating evidences suggest that neuroinflammation is a pathological hallmark of Parkinson's disease (PD), a neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). MicroRNAs have been recently recognized as crucial regulators of inflammatory responses. Here, we found significant downregulation of microRNA-30e (miR-30e) in SNpc of MPTP-induced PD mice. Next, we employed miR-30e agomir to upregulate miR-30e expression in MPTP-treated mice. Our results showed that delivery of miR-30e agomir remarkably improved motor behavioral deficits and neuronal activity, and inhibited the loss of dopamine neurons. Moreover, the increased α-synuclein protein expression in SNpc of MPTP-PD mice was alleviated by the upregulation of miR-30e. Further, miR-30e agomir administration also attenuated the marked increase of inflammatory cytokines, such as TNF-α, COX-2, iNOS, and restored the decreased secretion of BDNF in SNpc. In addition, we demonstrated for the first time that miR-30e directly targeted to Nlrp3, thus suppressing Nlrp3 mRNA and protein expression. Finally, miR-30e upregulation significantly inhibited the activation of Nlrp3 inflammasome as evident from the decreased Nlrp3, Caspase-1 and ASC expressions and IL-18 and IL-1β secretions. Taken together, our study demonstrates that miR-30e ameliorates neuroinflammation in the MPTP model of PD by decreasing Nlrp3 inflammasome activity. These findings suggesting that miR30e may be a key inflammation-mediated molecule that could be a potential target for PD therapeutics.

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Treatment of advanced nasopharyngeal cancer using low- or high-dose concurrent chemoradiotherapy with intensity-modulated radiotherapy: A propensity score-matched, nationwide, population-based cohort study

No large-scale, head-to-head, phase III, randomized, controlled trial with an adequate sample size has investigated the effect of concurrent low-dose (LD) or high-dose (HD) cisplatin with radiotherapy on nasopharyngeal cancer (NPC). Thus, we conducted a propensity-score-matched, nationwide, population-based cohort study in Taiwan to investigate the outcomes of LD-concurrent chemoradiotherapy (CCRT) or HD-CCRT with intensity-modulated radiotherapy (IMRT) in patients with advanced NPC.

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Phase I trial of stereotactic MR-guided online adaptive radiation therapy (SMART) for the treatment of oligometastatic or unresectable primary malignancies of the abdomen

SBRT is used to treat oligometastatic or unresectable primary abdominal malignancies, although ablative dose delivery is limited by proximity of organs-at-risk (OAR). Stereotactic, magnetic resonance (MR)-guided online-adaptive radiotherapy (SMART) may improve SBRT's therapeutic ratio. This prospective Phase I trial assessed feasibility and potential advantages of SMART to treat abdominal malignancies.

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Association between Treatment at High-Volume Facilities and Improved Overall Survival in Soft Tissue Sarcomas

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sriram Venigalla, Kevin T. Nead, Ronnie Sebro, David M. Guttmann, Sonam Sharma, Charles B. Simone, William P. Levin, Robert J. Wilson, Kristy L. Weber, Jacob E. Shabason
BackgroundSoft tissue sarcomas (STS) are rare malignancies requiring complex multidisciplinary management. Therefore, facilities with high sarcoma case volume may demonstrate superior outcomes. We hypothesized that STS treatment at high-volume facilities is associated with improved overall survival (OS).MethodsPatients ≥18 years with non-metastatic STS treated with surgery and radiotherapy at a single facility from 2004-2013 were identified from the National Cancer Database (NCDB). Facilities were dichotomized into high-volume (HV) and low-volume (LV) cohorts based on total case volume over the study period. OS was assessed using multivariable Cox regression with propensity-score matching. Patterns of care were assessed using multivariable logistic regression analysis.ResultsOf 9,025 total patients, 1,578 (17%) and 7,447 (83%) were treated at HV and LV facilities, respectively. On multivariable analysis, high educational attainment, larger tumor size, higher grade, and negative surgical margins were statistically significantly associated with treatment at HV facilities; conversely, black race and non-metropolitan residence were negative predictors of treatment at HV facilities. On propensity-score matched multivariable analysis, treatment at HV facilities versus LV facilities was associated with improved OS (hazard ratio (HR) = 0.87, 95% CI: 0.80-0.95, p = 0.001). Older age, lack of insurance, greater comorbidity, larger tumor size, higher tumor grade, and positive surgical margins were associated with statistically significantly worse OS.ConclusionsIn this observational cohort study using the NCDB, receipt of surgery and radiotherapy at HV facilities was associated with improved OS for patients with STS. Potential socio-demographic disparities limit access to care at HV facilities for certain populations. Our findings highlight the importance of receipt of care at HV facilities for patients with STS, and warrant further study into improving access to care at HV facilities.

Teaser

Patients with soft tissue sarcomas, a group of rare malignancies that require complex management, may benefit from care at high-volume treatment facilities as such facilities may offer greater physician expertise, superior resource availability, and delivery of highly coordinated care. Using the National Cancer Database, we demonstrate an association between high facility case volume and overall survival in patients with soft tissue sarcomas; these findings support centralization of care for sarcomas.


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Inhibitors of HIF-1α and CXCR4 Mitigate the Development of Radiation Necrosis in Mouse Brain

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Ruimeng Yang, Chong Duan, Liya Yuan, John A. Engelbach, Christina I. Tsien, Scott C. Beeman, Carlos J. Perez-Torres, Xia Ge, Keith M. Rich, Joseph J.H. Ackerman, Joel R. Garbow
PurposeThere is mounting evidence that, in addition to angiogenesis, hypoxia-induced inflammation via the hypoxia inducible factor-1α (HIF-1α) / CXC chemokine receptor-4 (CXCR4) pathway may also contribute to the pathogenesis of late-onset, radiation-induced necrosis (RN). The present study investigates the mitigative efficacy of a HIF-1α inhibitor, topotecan, and a CXCR4 antagonist, AMD3100, on the development of RN in an intracranial mouse model.Methods and MaterialsMice received a single-fraction, 50-Gy dose of hemispheric radiation from the Leksell GammaKnife® PerfexionTM and were then treated with either topotecan, a HIF-1α inhibitor, from 1-12 weeks post-irradiation (PIR), or AMD3100, a CXCR4 antagonist, from 4-12 weeks PIR. The onset and progression of RN were monitored longitudinally via noninvasive, in vivo MRI from 4-12 weeks PIR. Conventional hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) staining were performed to evaluate the treatment response.ResultsThe progression of brain RN was significantly mitigated for mice treated with either topotecan or AMD3100, compared to control animals. MR-derived lesion volumes were significantly smaller for both of the treated groups, and histologic findings correlated well with the MRI data. By H&E staining, both treated groups demonstrated reduced radiation-induced tissue damage compared with controls. Further, IHC results revealed that expression levels of VEGF, CXCL12, CD-68, CD3 and TNF-α in the lesion area were significantly lower in treated (topotecan or AMD3100) brains vs. control brains, while Iba-1 and HIF-1α expression was similar, though somewhat reduced. CXCR4 expression was reduced only in topotecan-treated mice, while IL-6 expression was unaffected by either topotecan or AMD3100.ConclusionsBy reducing inflammation, both topotecan and AMD3100 can, independently, mitigate the development of RN in mouse brain. When combined with first-line, anti–angiogenic treatment, anti-inflammation therapy may provide an adjuvant therapeutic strategy for clinical, post-radiation management of tumors, with additional benefits in the mitigation of RN development.

Teaser

The efficacy of a HIF-1α inhibitor, topotecan, and a CXCR4 antagonist, AMD3100, on the development of radiation necrosis was investigated in an intracranial mouse model. Mice were irradiated with the Leksell GammaKnife^® Perfexion^TM, and the development and progression of radiation necrosis were monitored longitudinally in vivo using magnetic resonance imaging, supported with correlative histology. Both topotecan and AMD3100 can, independently, mitigate the development of RN in mouse brain by reducing inflammation.


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Associations of Genetic Variations in the Seed Regions of MicroRNAs with Acute Adverse Events and Survival in Patients with Rectal Cancer Receiving Postoperative Chemoradiotherapy

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Ying Huang, Yanru Feng, Hua Ren, Meng Zhang, Hongmin Li, Yan Qiao, Ting Feng, Jie Yang, Weihu Wang, Shulian Wang, Yueping Liu, Yongwen Song, Yexiong Li, Jing Jin, Wen Tan, Dongxin Lin
PurposeThe aim of this study was to investigate the associations between single nucleotide polymorphisms (SNPs) in the seed regions of microRNAs and acute adverse events (AEs) and survival in patients with rectal cancer receiving postoperative chemoradiotherapy.Methods and MaterialsEighteen SNPs were genotyped in 365 patients with rectal cancer receiving postoperative chemoradiotherapy. The associations between genotypes and AEs were estimated by odds ratios (ORs) and 95% confidence intervals (CIs), which were computed by using multivariate logistic regression models. The hazard ratios (HRs) and 95% CIs to assess death of patients for different genotypes were calculated by Cox proportional regression models. Overall survival (OS) and disease-free survival (DFS) of patients with different genotypes were estimated by Kaplan-Meier plot and the statistical significance was determined by using log-rank test.ResultsIn these patients, the most common grade ≥ 2 AEs were diarrhea (44.1%), leukopenia (29.6%) and dermatitis (18.9%). We found that, with false discovery rate (FDR) correction, SNP rs2273626 was significantly associated with a decreased risk of grade ≥ 2 leukopenia (OR = 0.48, 95% CI = 0.31–0.74; P = 0.0009). We also found that SNP rs202195689 was associated with OS and DFS in patients receiving postoperative chemoradiotherapy, with the HRs for death being 2.02 (95% CI = 1.36–3.01; P = 0.0006) and 1.91 (95% CI = 1.36–2.70; P = 0.0002), respectively. However, no significant association between these SNPs with diarrhea and dermatitis was observed.ConclusionsThese results suggest that rs2273626 and rs202195689 in microRNA seed regions might serve as independent biomarkers for predicting AEs and prognosis in patients with rectal cancer receiving postoperative chemoradiotherapy. Independent replication of these findings is required to confirm these results.

Teaser

MicroRNAs play a key role in posttranscriptional regulation of mRNA and multiple cellular biological processes. We analyzed 18 SNPs in microRNA seed regions and identified two SNPs associated with acute adverse events and survival time in patients with rectal cancer receiving CAP-based chemoradiotherapy. These SNPs might serve as independent biomarkers for predicting acute adverse events and prognosis in patients with rectal cancer. Independent replication studies are required to confirm these results.


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Adaptive boost target definition in high-risk head and neck cancer based on multi-imaging risk biomarkers

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Feifei Teng, Madhava Aryal, Jae Lee, Choonik Lee, Xioajin Shen, Peter Hawkins, Michelle Mierzwa, Avraham Eisbruch, Yue Cao
Purpose¹⁸F-deoxyglucose (FDG) PET, dynamic contrast enhanced (DCE) and diffusion weighted (DW) MRI each identify unique risk factors for treatment outcomes in head-and-neck cancer (HNC). Clinical trials in HNC largely rely on a single imaging modality to define targets for boosting. This study aimed to investigate spatial correspondence of FDG uptake, perfusion and apparent diffusion coefficient (ADC) in HNC and their response to chemoradiation therapy (CRT), and to determine implication of this overlap or lack thereof for adaptive boosting.Materials and methodsForty patients with HNC enrolled in a clinical trial had FDG-PET/CT pre-CRT, and DCE and DW MRI scans pre and during CRT. Gross tumor volume (GTV) of primary tumor was contoured on post-Gd T1-weighted images. Tumor subvolumes with high FDG uptake, low blood volume (BV), and low ADC were created by using previously established thresholds. Spatial correspondences between subvolumes were analyzed using Dice coefficient and between each pair of image parameters at voxel-level were analyzed by Spearman's rank correlation coefficient.ResultsPrior to CRT, median subvolumes of high FDG, low BV and low ADC relative to primary GTV were 20%, 21% and 45%, respectively. Spearman's correlation coefficients between BV and ADC varied from -0.47 to 0.22, between BV and FDG from -0.08 to 0.59, and between ADC and FDG from -0.68 to 0.25. Dice coefficients between subvolumes of FDG and BV, FDG and ADC, and BV and ADC were 10%, 46%, and 15%, respectively. The union of the three parameters was 64% of GTV. The union of the subvolumes of BV and ADC was 56% of GTV pre-CRT, but reduced significantly by 57% after 10 fractions of RT.ConclusionHigh FDG uptake, low BV and low ADC as imaging risk biomarkers of HNC identify largely distinct tumor characteristics. A single imaging modality may not define the boosting target adequately.

Teaser

Several imaging risk biomarkers for treatment failure in head and neck cancer have been identified, largely in isolation. Understanding the spatial association between these imaging risk biomarkers is lacking, which could impact on decision making in clinical trials. This study found that high FDG uptake, low blood volume and low diffusion coefficient in head-and neck cancer identifies large distinct tumor subvolumes. Boosting target defined on a single imaging modality may not be adequate to achieve sufficient clinical benefits.


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Radiotherapy for Aggressive Fibromatosis: The Association Between Local Control and Age

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): James E. Bates, Christopher G. Morris, Nicole M. Iovino, Michael Rutenberg, Robert A. Zlotecki, C. Parker Gibbs, Mark Scarborough, Daniel J. Indelicato
PurposeRadiotherapy is often used in the treatment of unresectable or recurrent aggressive fibromatosis (also known as desmoid tumor) typically with excellent local control. Prior reports have suggested that local control in pediatric patients with aggressive fibromatosis is poor. We aimed to report a long-term single-institution experience with the radiotherapeutic treatment of these tumors with a focus on age-dependent outcomes.Methods and MaterialsA total of 101 patients treated with radiotherapy for aggressive fibromatosis between 1975 and 2015 at a single institution were identified. A variety of demographic and treatment related variables were abstracted from patients' medical records. Kaplan-Meier analyses were performed to investigate the relationship between these variables and local control.ResultsOverall survival was excellent (98% and 95% at 5 and 10 years); local control was likewise excellent (82% and 78% at 5 and 10 years). Patients ≤20 years at diagnosis had significantly worse 5-year local control compared to those over the age of 40 at diagnosis (72% vs 97%; HR = 9.0; p = 0.009). Those treated with once-daily fractionation had significantly improved 5-year local control compared to those treated with twice-daily fractionation (90% vs 73%; HR = 0.3; p = 0.008). Neither the presence of gross versus microscopic residual disease, initial versus recurrent presentation, number of prior surgeries, nor tumor size had any effect on 5-year local control. A total of 36.6% of patients developed CTCAE grade 3 or 4 toxicity following treatment; the frequency of toxicities was reduced in those treated after 1995 (24.5%) relative to those treated prior to 1995 (51.9%, p=0.02).ConclusionsRadiotherapy for aggressive fibromatosis offers excellent local control and should remain the standard of care for patients with unresectable or recurrent disease. Younger patients have diminished local control relative to older patients, suggesting possible biologic differences contributing to radioresistance in the pediatric and young adult population.

Teaser

Radiotherapy is used in the treatment of unresectable or recurrent aggressive fibromatosis; prior data suggests that local control may be diminished in younger patients. We analyzed a single-institution experience of patients treated with radiotherapy for aggressive fibromatosis over 4 decades. Patients 20 years or under at diagnosis experience diminished local control following radiotherapy compared with patients over 40 years old at diagnosis, suggesting possible biologic differences between tumors in these age groups.


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External Beam Radiotherapy and Brachytherapy for Cervical Cancer: The experience of The National Centre for Radiotherapy in Accra, Ghana

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Horia Vulpe, Francis Adumata Asamoah, Manjula Maganti, Verna Vanderpuye, Anthony Fyles, Joel Yarney
PurposeMost women with cervical cancer in Sub-Saharan Africa present with locally advanced disease. These women require external beam radiotherapy (EBRT) and brachytherapy for curative treatment, but data on their outcomes remain sparse. We report data on treatment characteristics, follow-up, toxicity, and cancer outcomes in a large population of patients from the XXXXX Centre XXX XXXXXXXXX in XXXX, Ghana.Materials/MethodsThe charts of patients treated from 2006-2011 were reviewed. Patients treated without brachytherapy or with palliative intent were excluded. Staging CT scans were not routinely performed. Cobalt-60 EBRT was followed by 2 low-dose-rate brachytherapy insertions. Concurrent weekly cisplatin was recommended. Because many patients experienced delays from diagnosis to treatment, we calculated overall survival (OS) and locoregional recurrence (LRR) from the date of first radiotherapy to the event date, or last follow-up, when no event recurred, using the Kaplan-Meier product-limit method.Results250 patients had a median age at diagnosis of 55 years. FIGO stage was IIB or lower in 63% of patients. Median dose to point A was 83Gy (range 60-97.5Gy). Median doses to the ICRU bladder and rectal points were 71Gy and 65Gy. 69% of patients received 4 or more cycles of concurrent cisplatin. Median overall treatment time was 73 days. Median follow-up was 2.4 years with a 3-year OS and LRR of 86% and 19% respectively. The most commonly reported late side effect was vaginal stenosis and shortening in 32% of patients. We also identified nearly 300 patients who were offered curative treatment but never returned to start.ConclusionWe report promising outcomes in a population of women with cervical cancer treated with concurrent chemo-RT and brachytherapy in Ghana. To our knowledge, this is the largest series of its kind, and demonstrates what can be achieved with a well-established cancer program in SSA.

Teaser

Most women with cervical cancer in Sub-Saharan Africa present with advanced disease. These women require treatment with concurrent chemo-radiotherapy and brachytherapy, but there is a scarcity of data on patient outcomes. We retrospectively reviewed the experience of The XXXX XXXX for XXXX and I in XXXXX, Ghana. We report encouraging results, demonstrating what can be achieved with a well-established cancer program in Sub-Saharan Africa.


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Outcomes of Patients with Primary Sacral Chordoma Treated with Definitive Proton Beam Therapy

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Norihiro Aibe, Yusuke Demizu, Nor Shazrina Sulaiman, Yoshirou Matsuo, Masayuki Mima, Fumiko Nagano, Kazuki Terashima, Sunao Tokumaru, Tomokatsu Hayakawa, Masaki Suga, Takashi Daimon, Gen Suzuki, Yamazaki Hideya, Kei Yamada, Ryohei Sasaki, Nobukazu Fuwa, Tomoaki Okimoto
PurposeTo evaluate the efficacy and safety of definitive proton beam therapy (PBT) for primary sacral chordoma.Methods and MaterialsWe conducted a retrospective analysis of the clinical outcomes of eligible patients with primary sacral chordoma who underwent definitive PBT with 70.4 Gy (relative biological effectiveness) in 32 fractions at our institution between September 2009 and October 2015. Local progression-free survival, distant metastasis-free survival, disease-free survival, cause-specific survival, and overall survival were evaluated. To explore the factors that influenced local progression, the following parameters were analyzed: sex, the presence of a spacer (GORE-TEX sheets), gross tumor volume (mL), and the extent of cranial tumor extension. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. To assess the impact of PBT on pain relief, the change in pain grades was investigated between the initiation of PBT and the last follow-up.ResultsThirty-three eligible patients were analyzed. The median follow-up period was 37 months. The 3-year estimated local progression-free survival, distant metastasis-free survival, disease-free survival, cause-specific survival, and overall survival rates were 89.6%, 88.2%, 81.9%, 95.7%, and 92.7%, respectively. There was no significant association between the patients' clinicopathological characteristics and local progression-free survival. Four patients developed Grade 3 adverse events, including acute dermatitis (n = 1), ileus (n = 1), and pain due to sacral insufficiency fractures (n = 2). The pain grades were improved, unchanged, or deteriorated in 15, 7, and 11 patients, respectively.ConclusionsDefinitive PBT with 70.4 Gy (relative biological effectiveness) in 32 fractions is an effective treatment with acceptable toxicity for primary sacral chordoma, and has the potential to reduce pain.

Teaser

We conducted a retrospective analysis to evaluate the safety and efficacy of definitive proton beam therapy with 70.4 Gy (relative biological effectiveness) in 32 fractions for primary sacral chordoma. This cohort study of 33 eligible patients shows that this treatment modality is safe and effective, and has the potential to reduce pain.


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Risk Factors for Malignant Transformation of Low Grade Glioma

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Erin S. Murphy, Charles M. Leyrer, Michael Parsons, John H. Suh, Samuel T. Chao, Jennifer S. Yu, Rupesh Kotecha, Xuefei Jia, David M. Peereboom, Richard A. Prayson, Glen HJ. Stevens, Gene H. Barnett, Michael A. Vogelbaum, Manmeet S. Ahluwalia
BackgroundThe incidence, risk factors, and outcomes of LGG patients who undergo malignant transformation (MT) in the era of temozolomide (TMZ) are not well known. This study evaluates these factors from a large group of WHO Grade II glioma patients treated at a tertiary care institution.MethodsPatient, tumor, and treatment factors were analyzed from an IRB-approved LGG database. Characteristics were compared using Chi-square and Wilcoxon signed-rank tests. Time-to-event was summarized using proportional hazards models. Univariate and multivariate survival analyses were performed.ResultsFrom a total of 599 patients, 124 underwent MT; 76 (61.3%) were biopsy-proven. MT incidence was 21% and median time to MT 56.4 months. The 5 and 10-year PFS for MT patients was 30.6% ± 4.2% and 4.8 % ± 1.9%, and for non-MT patients was 60% ± 2.4% and 38% ± 2.7%, respectively. The 5 and 10-year OS for MT was 75% ± 4.0% and 46 % ± 5.0% and non-MT patients was 87% ± 1.7% and 78% ± 2.3%, respectively. On MVA, older age (p=0.001), male sex (p=0.004), multiple tumor locations (p=0.004), chemotherapy alone (p=0.012), and extent of resection (p=0.045) remained significant predictors of MT.ConclusionsMT impacts survival. Risk factors include older age, male sex, multiple tumor locations, use of chemotherapy alone, and presence of residual disease. Our findings that initial interventions could impact the rate of MT are provocative, but this data should be validated using data from prospective trials. In addition to improving survival, future therapeutic efforts should focus on preventing MT.

Teaser

The incidence, risk factors, and outcomes of LGG patients who undergo malignant transformation in the era of temozolomide are not well known. This study evaluates these factors from a large group of WHO Grade II glioma patients treated at our tertiary care institution. We found that older age, male sex, multiple tumor locations, chemotherapy alone, and extent of resection were significant predictors of malignant transformation.


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Associations of Genetic Variations in the Seed Regions of MicroRNAs with Acute Adverse Events and Survival in Patients with Rectal Cancer Receiving Postoperative Chemoradiotherapy

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Ying Huang, Yanru Feng, Hua Ren, Meng Zhang, Hongmin Li, Yan Qiao, Ting Feng, Jie Yang, Weihu Wang, Shulian Wang, Yueping Liu, Yongwen Song, Yexiong Li, Jing Jin, Wen Tan, Dongxin Lin
PurposeThe aim of this study was to investigate the associations between single nucleotide polymorphisms (SNPs) in the seed regions of microRNAs and acute adverse events (AEs) and survival in patients with rectal cancer receiving postoperative chemoradiotherapy.Methods and MaterialsEighteen SNPs were genotyped in 365 patients with rectal cancer receiving postoperative chemoradiotherapy. The associations between genotypes and AEs were estimated by odds ratios (ORs) and 95% confidence intervals (CIs), which were computed by using multivariate logistic regression models. The hazard ratios (HRs) and 95% CIs to assess death of patients for different genotypes were calculated by Cox proportional regression models. Overall survival (OS) and disease-free survival (DFS) of patients with different genotypes were estimated by Kaplan-Meier plot and the statistical significance was determined by using log-rank test.ResultsIn these patients, the most common grade ≥ 2 AEs were diarrhea (44.1%), leukopenia (29.6%) and dermatitis (18.9%). We found that, with false discovery rate (FDR) correction, SNP rs2273626 was significantly associated with a decreased risk of grade ≥ 2 leukopenia (OR = 0.48, 95% CI = 0.31–0.74; P = 0.0009). We also found that SNP rs202195689 was associated with OS and DFS in patients receiving postoperative chemoradiotherapy, with the HRs for death being 2.02 (95% CI = 1.36–3.01; P = 0.0006) and 1.91 (95% CI = 1.36–2.70; P = 0.0002), respectively. However, no significant association between these SNPs with diarrhea and dermatitis was observed.ConclusionsThese results suggest that rs2273626 and rs202195689 in microRNA seed regions might serve as independent biomarkers for predicting AEs and prognosis in patients with rectal cancer receiving postoperative chemoradiotherapy. Independent replication of these findings is required to confirm these results.

Teaser

MicroRNAs play a key role in posttranscriptional regulation of mRNA and multiple cellular biological processes. We analyzed 18 SNPs in microRNA seed regions and identified two SNPs associated with acute adverse events and survival time in patients with rectal cancer receiving CAP-based chemoradiotherapy. These SNPs might serve as independent biomarkers for predicting acute adverse events and prognosis in patients with rectal cancer. Independent replication studies are required to confirm these results.


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Association between Treatment at High-Volume Facilities and Improved Overall Survival in Soft Tissue Sarcomas

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sriram Venigalla, Kevin T. Nead, Ronnie Sebro, David M. Guttmann, Sonam Sharma, Charles B. Simone, William P. Levin, Robert J. Wilson, Kristy L. Weber, Jacob E. Shabason
BackgroundSoft tissue sarcomas (STS) are rare malignancies requiring complex multidisciplinary management. Therefore, facilities with high sarcoma case volume may demonstrate superior outcomes. We hypothesized that STS treatment at high-volume facilities is associated with improved overall survival (OS).MethodsPatients ≥18 years with non-metastatic STS treated with surgery and radiotherapy at a single facility from 2004-2013 were identified from the National Cancer Database (NCDB). Facilities were dichotomized into high-volume (HV) and low-volume (LV) cohorts based on total case volume over the study period. OS was assessed using multivariable Cox regression with propensity-score matching. Patterns of care were assessed using multivariable logistic regression analysis.ResultsOf 9,025 total patients, 1,578 (17%) and 7,447 (83%) were treated at HV and LV facilities, respectively. On multivariable analysis, high educational attainment, larger tumor size, higher grade, and negative surgical margins were statistically significantly associated with treatment at HV facilities; conversely, black race and non-metropolitan residence were negative predictors of treatment at HV facilities. On propensity-score matched multivariable analysis, treatment at HV facilities versus LV facilities was associated with improved OS (hazard ratio (HR) = 0.87, 95% CI: 0.80-0.95, p = 0.001). Older age, lack of insurance, greater comorbidity, larger tumor size, higher tumor grade, and positive surgical margins were associated with statistically significantly worse OS.ConclusionsIn this observational cohort study using the NCDB, receipt of surgery and radiotherapy at HV facilities was associated with improved OS for patients with STS. Potential socio-demographic disparities limit access to care at HV facilities for certain populations. Our findings highlight the importance of receipt of care at HV facilities for patients with STS, and warrant further study into improving access to care at HV facilities.

Teaser

Patients with soft tissue sarcomas, a group of rare malignancies that require complex management, may benefit from care at high-volume treatment facilities as such facilities may offer greater physician expertise, superior resource availability, and delivery of highly coordinated care. Using the National Cancer Database, we demonstrate an association between high facility case volume and overall survival in patients with soft tissue sarcomas; these findings support centralization of care for sarcomas.


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Inhibitors of HIF-1α and CXCR4 Mitigate the Development of Radiation Necrosis in Mouse Brain

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Ruimeng Yang, Chong Duan, Liya Yuan, John A. Engelbach, Christina I. Tsien, Scott C. Beeman, Carlos J. Perez-Torres, Xia Ge, Keith M. Rich, Joseph J.H. Ackerman, Joel R. Garbow
PurposeThere is mounting evidence that, in addition to angiogenesis, hypoxia-induced inflammation via the hypoxia inducible factor-1α (HIF-1α) / CXC chemokine receptor-4 (CXCR4) pathway may also contribute to the pathogenesis of late-onset, radiation-induced necrosis (RN). The present study investigates the mitigative efficacy of a HIF-1α inhibitor, topotecan, and a CXCR4 antagonist, AMD3100, on the development of RN in an intracranial mouse model.Methods and MaterialsMice received a single-fraction, 50-Gy dose of hemispheric radiation from the Leksell GammaKnife® PerfexionTM and were then treated with either topotecan, a HIF-1α inhibitor, from 1-12 weeks post-irradiation (PIR), or AMD3100, a CXCR4 antagonist, from 4-12 weeks PIR. The onset and progression of RN were monitored longitudinally via noninvasive, in vivo MRI from 4-12 weeks PIR. Conventional hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) staining were performed to evaluate the treatment response.ResultsThe progression of brain RN was significantly mitigated for mice treated with either topotecan or AMD3100, compared to control animals. MR-derived lesion volumes were significantly smaller for both of the treated groups, and histologic findings correlated well with the MRI data. By H&E staining, both treated groups demonstrated reduced radiation-induced tissue damage compared with controls. Further, IHC results revealed that expression levels of VEGF, CXCL12, CD-68, CD3 and TNF-α in the lesion area were significantly lower in treated (topotecan or AMD3100) brains vs. control brains, while Iba-1 and HIF-1α expression was similar, though somewhat reduced. CXCR4 expression was reduced only in topotecan-treated mice, while IL-6 expression was unaffected by either topotecan or AMD3100.ConclusionsBy reducing inflammation, both topotecan and AMD3100 can, independently, mitigate the development of RN in mouse brain. When combined with first-line, anti–angiogenic treatment, anti-inflammation therapy may provide an adjuvant therapeutic strategy for clinical, post-radiation management of tumors, with additional benefits in the mitigation of RN development.

Teaser

The efficacy of a HIF-1α inhibitor, topotecan, and a CXCR4 antagonist, AMD3100, on the development of radiation necrosis was investigated in an intracranial mouse model. Mice were irradiated with the Leksell GammaKnife^® Perfexion^TM, and the development and progression of radiation necrosis were monitored longitudinally in vivo using magnetic resonance imaging, supported with correlative histology. Both topotecan and AMD3100 can, independently, mitigate the development of RN in mouse brain by reducing inflammation.


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Adaptive boost target definition in high-risk head and neck cancer based on multi-imaging risk biomarkers

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Feifei Teng, Madhava Aryal, Jae Lee, Choonik Lee, Xioajin Shen, Peter Hawkins, Michelle Mierzwa, Avraham Eisbruch, Yue Cao
Purpose¹⁸F-deoxyglucose (FDG) PET, dynamic contrast enhanced (DCE) and diffusion weighted (DW) MRI each identify unique risk factors for treatment outcomes in head-and-neck cancer (HNC). Clinical trials in HNC largely rely on a single imaging modality to define targets for boosting. This study aimed to investigate spatial correspondence of FDG uptake, perfusion and apparent diffusion coefficient (ADC) in HNC and their response to chemoradiation therapy (CRT), and to determine implication of this overlap or lack thereof for adaptive boosting.Materials and methodsForty patients with HNC enrolled in a clinical trial had FDG-PET/CT pre-CRT, and DCE and DW MRI scans pre and during CRT. Gross tumor volume (GTV) of primary tumor was contoured on post-Gd T1-weighted images. Tumor subvolumes with high FDG uptake, low blood volume (BV), and low ADC were created by using previously established thresholds. Spatial correspondences between subvolumes were analyzed using Dice coefficient and between each pair of image parameters at voxel-level were analyzed by Spearman's rank correlation coefficient.ResultsPrior to CRT, median subvolumes of high FDG, low BV and low ADC relative to primary GTV were 20%, 21% and 45%, respectively. Spearman's correlation coefficients between BV and ADC varied from -0.47 to 0.22, between BV and FDG from -0.08 to 0.59, and between ADC and FDG from -0.68 to 0.25. Dice coefficients between subvolumes of FDG and BV, FDG and ADC, and BV and ADC were 10%, 46%, and 15%, respectively. The union of the three parameters was 64% of GTV. The union of the subvolumes of BV and ADC was 56% of GTV pre-CRT, but reduced significantly by 57% after 10 fractions of RT.ConclusionHigh FDG uptake, low BV and low ADC as imaging risk biomarkers of HNC identify largely distinct tumor characteristics. A single imaging modality may not define the boosting target adequately.

Teaser

Several imaging risk biomarkers for treatment failure in head and neck cancer have been identified, largely in isolation. Understanding the spatial association between these imaging risk biomarkers is lacking, which could impact on decision making in clinical trials. This study found that high FDG uptake, low blood volume and low diffusion coefficient in head-and neck cancer identifies large distinct tumor subvolumes. Boosting target defined on a single imaging modality may not be adequate to achieve sufficient clinical benefits.


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Radiotherapy for Aggressive Fibromatosis: The Association Between Local Control and Age

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): James E. Bates, Christopher G. Morris, Nicole M. Iovino, Michael Rutenberg, Robert A. Zlotecki, C. Parker Gibbs, Mark Scarborough, Daniel J. Indelicato
PurposeRadiotherapy is often used in the treatment of unresectable or recurrent aggressive fibromatosis (also known as desmoid tumor) typically with excellent local control. Prior reports have suggested that local control in pediatric patients with aggressive fibromatosis is poor. We aimed to report a long-term single-institution experience with the radiotherapeutic treatment of these tumors with a focus on age-dependent outcomes.Methods and MaterialsA total of 101 patients treated with radiotherapy for aggressive fibromatosis between 1975 and 2015 at a single institution were identified. A variety of demographic and treatment related variables were abstracted from patients' medical records. Kaplan-Meier analyses were performed to investigate the relationship between these variables and local control.ResultsOverall survival was excellent (98% and 95% at 5 and 10 years); local control was likewise excellent (82% and 78% at 5 and 10 years). Patients ≤20 years at diagnosis had significantly worse 5-year local control compared to those over the age of 40 at diagnosis (72% vs 97%; HR = 9.0; p = 0.009). Those treated with once-daily fractionation had significantly improved 5-year local control compared to those treated with twice-daily fractionation (90% vs 73%; HR = 0.3; p = 0.008). Neither the presence of gross versus microscopic residual disease, initial versus recurrent presentation, number of prior surgeries, nor tumor size had any effect on 5-year local control. A total of 36.6% of patients developed CTCAE grade 3 or 4 toxicity following treatment; the frequency of toxicities was reduced in those treated after 1995 (24.5%) relative to those treated prior to 1995 (51.9%, p=0.02).ConclusionsRadiotherapy for aggressive fibromatosis offers excellent local control and should remain the standard of care for patients with unresectable or recurrent disease. Younger patients have diminished local control relative to older patients, suggesting possible biologic differences contributing to radioresistance in the pediatric and young adult population.

Teaser

Radiotherapy is used in the treatment of unresectable or recurrent aggressive fibromatosis; prior data suggests that local control may be diminished in younger patients. We analyzed a single-institution experience of patients treated with radiotherapy for aggressive fibromatosis over 4 decades. Patients 20 years or under at diagnosis experience diminished local control following radiotherapy compared with patients over 40 years old at diagnosis, suggesting possible biologic differences between tumors in these age groups.


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External Beam Radiotherapy and Brachytherapy for Cervical Cancer: The experience of The National Centre for Radiotherapy in Accra, Ghana

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Horia Vulpe, Francis Adumata Asamoah, Manjula Maganti, Verna Vanderpuye, Anthony Fyles, Joel Yarney
PurposeMost women with cervical cancer in Sub-Saharan Africa present with locally advanced disease. These women require external beam radiotherapy (EBRT) and brachytherapy for curative treatment, but data on their outcomes remain sparse. We report data on treatment characteristics, follow-up, toxicity, and cancer outcomes in a large population of patients from the XXXXX Centre XXX XXXXXXXXX in XXXX, Ghana.Materials/MethodsThe charts of patients treated from 2006-2011 were reviewed. Patients treated without brachytherapy or with palliative intent were excluded. Staging CT scans were not routinely performed. Cobalt-60 EBRT was followed by 2 low-dose-rate brachytherapy insertions. Concurrent weekly cisplatin was recommended. Because many patients experienced delays from diagnosis to treatment, we calculated overall survival (OS) and locoregional recurrence (LRR) from the date of first radiotherapy to the event date, or last follow-up, when no event recurred, using the Kaplan-Meier product-limit method.Results250 patients had a median age at diagnosis of 55 years. FIGO stage was IIB or lower in 63% of patients. Median dose to point A was 83Gy (range 60-97.5Gy). Median doses to the ICRU bladder and rectal points were 71Gy and 65Gy. 69% of patients received 4 or more cycles of concurrent cisplatin. Median overall treatment time was 73 days. Median follow-up was 2.4 years with a 3-year OS and LRR of 86% and 19% respectively. The most commonly reported late side effect was vaginal stenosis and shortening in 32% of patients. We also identified nearly 300 patients who were offered curative treatment but never returned to start.ConclusionWe report promising outcomes in a population of women with cervical cancer treated with concurrent chemo-RT and brachytherapy in Ghana. To our knowledge, this is the largest series of its kind, and demonstrates what can be achieved with a well-established cancer program in SSA.

Teaser

Most women with cervical cancer in Sub-Saharan Africa present with advanced disease. These women require treatment with concurrent chemo-radiotherapy and brachytherapy, but there is a scarcity of data on patient outcomes. We retrospectively reviewed the experience of The XXXX XXXX for XXXX and I in XXXXX, Ghana. We report encouraging results, demonstrating what can be achieved with a well-established cancer program in Sub-Saharan Africa.


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Outcomes of Patients with Primary Sacral Chordoma Treated with Definitive Proton Beam Therapy

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Norihiro Aibe, Yusuke Demizu, Nor Shazrina Sulaiman, Yoshirou Matsuo, Masayuki Mima, Fumiko Nagano, Kazuki Terashima, Sunao Tokumaru, Tomokatsu Hayakawa, Masaki Suga, Takashi Daimon, Gen Suzuki, Yamazaki Hideya, Kei Yamada, Ryohei Sasaki, Nobukazu Fuwa, Tomoaki Okimoto
PurposeTo evaluate the efficacy and safety of definitive proton beam therapy (PBT) for primary sacral chordoma.Methods and MaterialsWe conducted a retrospective analysis of the clinical outcomes of eligible patients with primary sacral chordoma who underwent definitive PBT with 70.4 Gy (relative biological effectiveness) in 32 fractions at our institution between September 2009 and October 2015. Local progression-free survival, distant metastasis-free survival, disease-free survival, cause-specific survival, and overall survival were evaluated. To explore the factors that influenced local progression, the following parameters were analyzed: sex, the presence of a spacer (GORE-TEX sheets), gross tumor volume (mL), and the extent of cranial tumor extension. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. To assess the impact of PBT on pain relief, the change in pain grades was investigated between the initiation of PBT and the last follow-up.ResultsThirty-three eligible patients were analyzed. The median follow-up period was 37 months. The 3-year estimated local progression-free survival, distant metastasis-free survival, disease-free survival, cause-specific survival, and overall survival rates were 89.6%, 88.2%, 81.9%, 95.7%, and 92.7%, respectively. There was no significant association between the patients' clinicopathological characteristics and local progression-free survival. Four patients developed Grade 3 adverse events, including acute dermatitis (n = 1), ileus (n = 1), and pain due to sacral insufficiency fractures (n = 2). The pain grades were improved, unchanged, or deteriorated in 15, 7, and 11 patients, respectively.ConclusionsDefinitive PBT with 70.4 Gy (relative biological effectiveness) in 32 fractions is an effective treatment with acceptable toxicity for primary sacral chordoma, and has the potential to reduce pain.

Teaser

We conducted a retrospective analysis to evaluate the safety and efficacy of definitive proton beam therapy with 70.4 Gy (relative biological effectiveness) in 32 fractions for primary sacral chordoma. This cohort study of 33 eligible patients shows that this treatment modality is safe and effective, and has the potential to reduce pain.


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Risk Factors for Malignant Transformation of Low Grade Glioma

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Erin S. Murphy, Charles M. Leyrer, Michael Parsons, John H. Suh, Samuel T. Chao, Jennifer S. Yu, Rupesh Kotecha, Xuefei Jia, David M. Peereboom, Richard A. Prayson, Glen HJ. Stevens, Gene H. Barnett, Michael A. Vogelbaum, Manmeet S. Ahluwalia
BackgroundThe incidence, risk factors, and outcomes of LGG patients who undergo malignant transformation (MT) in the era of temozolomide (TMZ) are not well known. This study evaluates these factors from a large group of WHO Grade II glioma patients treated at a tertiary care institution.MethodsPatient, tumor, and treatment factors were analyzed from an IRB-approved LGG database. Characteristics were compared using Chi-square and Wilcoxon signed-rank tests. Time-to-event was summarized using proportional hazards models. Univariate and multivariate survival analyses were performed.ResultsFrom a total of 599 patients, 124 underwent MT; 76 (61.3%) were biopsy-proven. MT incidence was 21% and median time to MT 56.4 months. The 5 and 10-year PFS for MT patients was 30.6% ± 4.2% and 4.8 % ± 1.9%, and for non-MT patients was 60% ± 2.4% and 38% ± 2.7%, respectively. The 5 and 10-year OS for MT was 75% ± 4.0% and 46 % ± 5.0% and non-MT patients was 87% ± 1.7% and 78% ± 2.3%, respectively. On MVA, older age (p=0.001), male sex (p=0.004), multiple tumor locations (p=0.004), chemotherapy alone (p=0.012), and extent of resection (p=0.045) remained significant predictors of MT.ConclusionsMT impacts survival. Risk factors include older age, male sex, multiple tumor locations, use of chemotherapy alone, and presence of residual disease. Our findings that initial interventions could impact the rate of MT are provocative, but this data should be validated using data from prospective trials. In addition to improving survival, future therapeutic efforts should focus on preventing MT.

Teaser

The incidence, risk factors, and outcomes of LGG patients who undergo malignant transformation in the era of temozolomide are not well known. This study evaluates these factors from a large group of WHO Grade II glioma patients treated at our tertiary care institution. We found that older age, male sex, multiple tumor locations, chemotherapy alone, and extent of resection were significant predictors of malignant transformation.


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Breast metastasis from squamous cell carcinoma of the oropharynx: a case report

Breast metastases from extramammary tumors are extremely rare, the most common primary tumors being contralateral breast carcinoma, followed by lung, gynecological, gastrointestinal, melanoma, and hematologica...

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Objective assessment of reconstructed breast hardness using a durometer

Abstract

Background

Whether a durometer was suitable for objectively measuring reconstructed breast hardness was evaluated.

Methods

Subjects were 81 women who underwent expander-implant reconstructions following breast cancer ablation. Capsular contracture was evaluated with Baker grading. Capsular thickness was measured with T1-weighted MRI at the upper areola area. The durometer was placed on the upper areola. Multiple logistic regression analysis was performed to compare variables.

Results

On Baker grading, 17 breasts were Baker grade I, 52 breasts were Baker grade II, 11 breasts were Baker grade III, and 1 breast was Baker grade IV. Mean capsular thickness on MRI was 1.1 (SD 0.4) mm with Baker grade I, 1.2 (SD 0.3) mm with Baker grade II, 1.4 (SD 0.4) mm with Baker grade III, and 1.9 mm with Baker grade IV. Mean durometer value was 0 with Baker grade I, 0.2 (SD 0.5) with Baker grade II, 2.0 (SD 1.7), with Baker grade III, and 8 with Baker grade IV. Baker grade IV was excluded from analysis because there was only one case. When Baker grade III was defined as positive for hardness, multiple logistic regression analysis showed that durometer value was associated with Baker grade III (p = 0.0005), but capsular thickness was not. On receiver operating characteristic curve analysis of the durometer value for Baker grade III, the optimal cutoff value was 0.5 (sensitivity 0.92, 1-specificity 0.17, area under the curve 0.92).

Conclusions

The durometer offers an objective index of hardness that might replace the subjective Baker grading. Further studies are needed to confirm the utility of this index.

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Diagnosis and treatment of ALT tumors: is Trabectedin a new therapeutic option?

Telomeres are specialized nucleoprotein structures responsible for protecting chromosome ends in order to prevent the loss of genomic information. Telomere maintenance is required for achieving immortality by ...

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Curcumin synergizes with 5-fluorouracil by impairing AMPK/ULK1-dependent autophagy, AKT activity and enhancing apoptosis in colon cancer cells with tumor growth inhibition in xenograft mice

Chemoresistance is a major obstacle that limits the benefits of 5-Fluorouracil (5-Fu)-based chemotherapy for colon cancer patients. Autophagy is an important cellular mechanism underlying chemoresistance. Rece...

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Significant suppression of radiation dermatitis in breast cancer patients using a topically applied adrenergic vasoconstrictor

Our previous studies showed that vasoconstrictor applied topically to rat skin minutes before irradiation completely prevented radiodermatitis. Here we report on a Phase IIa study of topically applied NG12-1 v...

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Highly conformal combined radiotherapy with cisplatin and gemcitabine for treatment of loco-regionally advanced cervical cancer – a retrospective study

Cisplatin and gemcitabine combined with conventional radiation therapy in the treatment of cervical cancer patients results in a favorable outcome but with excess toxicity. The purpose of this study was to eva...

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Significant suppression of radiation dermatitis in breast cancer patients using a topically applied adrenergic vasoconstrictor

Our previous studies showed that vasoconstrictor applied topically to rat skin minutes before irradiation completely prevented radiodermatitis. Here we report on a Phase IIa study of topically applied NG12-1 v...

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Highly conformal combined radiotherapy with cisplatin and gemcitabine for treatment of loco-regionally advanced cervical cancer – a retrospective study

Cisplatin and gemcitabine combined with conventional radiation therapy in the treatment of cervical cancer patients results in a favorable outcome but with excess toxicity. The purpose of this study was to eva...

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Prognostic value of tumor–stroma ratio combined with the immune status of tumors in invasive breast carcinoma

Abstract

Purpose

Complex interactions occur between cancer cells and cells in the tumor microenvironment. In this study, the prognostic value of the interplay between tumor–stroma ratio (TSR) and the immune status of tumors in breast cancer patients was evaluated.

Methods

A cohort of 574 breast cancer patients was analyzed. The percentage of tumor stroma was visually estimated on Hematoxylin and Eosin (H&E) stained histological tumor tissue sections. Immunohistochemical staining was performed for classical human leukocyte antigen (HLA) class I, HLA-E, HLA-G, markers for regulatory T (Treg) cells, natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs).

Results

TSR (P < .001) and immune status of tumors (P < .001) were both statistically significant for recurrence free period (RFP) and both independent prognosticators (P < .001) in which tumors with a high stromal content behave more aggressively as well as tumors with a low immune status. Ten years RFP for patients with a stroma-low tumor and high immune status profile was 87% compared to 17% of patients with a stroma-high tumor combined with low immune status profile (P < .001). Classical HLA class I is the most prominent immune marker in the immune status profiles.

Conclusions

Determination of TSR is a simple, fast and cheap method. The effect on RFP of TSR when combined with immune status of tumors or expression of classical HLA class I is even stronger. Both are promising for further prediction and achievement of tailored treatment for breast cancer patients.

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Calendar

Publication date: January 2018
Source:European Journal of Surgical Oncology, Volume 44, Issue 1





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List of Reviewers 2017

Publication date: January 2018
Source:European Journal of Surgical Oncology, Volume 44, Issue 1





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Editorial Board

Publication date: January 2018
Source:European Journal of Surgical Oncology, Volume 44, Issue 1





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Systematic review and meta-analysis of prognostic role of splenic vessels infiltration in resectable pancreatic cancer

Publication date: January 2018
Source:European Journal of Surgical Oncology, Volume 44, Issue 1
Author(s): Stefano Crippa, Roberto Cirocchi, Patrick Maisonneuve, Stefano Partelli, Ilaria Pergolini, Domenico Tamburrino, Francesca Aleotti, Michele Reni, Massimo Falconi
BackgroundIdentification of factors associated with dismal survival after surgery in resectable pancreatic ductal adenocarcinoma is important to select patients for neoadjuvant treatment. The present meta-analysis aimed to compare the results of distal pancreatectomy for resectable adenocarcinoma of the pancreatic body-tail with and without splenic vessels infiltration.MethodsA systematic search was performed of PubMed, Embase and the Cochrane Library in accordance with PRISMA guidelines. The inclusion criteria were studies including patients who underwent distal pancreatectomy for pancreatic cancer with or without splenic vessels infiltration. 5-year overall survival (OS) was the primary outcomes. Meta-analysis was carried out applying time-to-event method.ResultsSix articles with 423 patients were analysed. Patients with pathological splenic artery invasion had a worse survival compared with those without infiltration (Hazard ratio 1.76, 95% CI 1.36–2.28; P < 0.0001). A similar results was found when considering pathological splenic vessels infiltration, showing that survival was significantly poorer when splenic vein infiltration was present (Hazard ratio 1.51, 95% CI 1.19–1.93; P = 0.0009).ConclusionsThis meta-analysis showed worse survival for patients with splenic vessels infiltration undergoing distal pancreatectomy for pancreatic cancer. Splenic vessels infiltration represents the stigmata of a more aggressive disease, although resectable.



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