Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre: chemotherapy, haematopoietic stem cell transplantation, molecular targeted therapies, and immune checkpoint inhibitors.

The purpose of this review is to familiarise radiologists with the spectrum of hepatic toxicity seen in the oncology setting, in view of the different systemic therapies used in cancer patients. Drug-induced liver injury can manifest in various forms, and anti-neoplastic agents are associated with different types of hepatotoxicity. Although chemotherapy-induced liver injury can present as hepatitis, steatosis, sinusoidal obstruction syndrome, and chronic parenchymal damages, molecular targeted therapy-associated liver toxicity ranges from mild liver function test elevation to fulminant life-threatening acute liver failure. The recent arrival of immune checkpoint inhibitors in oncology has introduced a new range of immune-related adverse events, with differing mechanisms of liver toxicity and varied imaging presentation of liver injury. High-dose chemotherapy regimens for haematopoietic stem cell transplantation are associated with sinusoidal obstruction syndrome. Management of hepatic toxicity depends on the clinical scenario, the drug in use, and the severity of the findings. In this article, we will (1) present the most common types of oncological drugs associated with hepatic toxicity and associated liver injuries; (2) illustrate imaging findings of hepatic toxicities and the possible differential diagnosis; and (3) provide a guide for management of these conditions.

MDCT and clinicopathological features of small bowel gastrointestinal stromal tumours in 102 patients: a single institute experience.

OBJECTIVE: Small bowel (SB) is the second most common site of gastrointestinal stromal tumours (GISTs). We evaluated clinical presentation, pathology, imaging features and metastatic pattern of SB GIST. METHODS: Imaging and clinicopathological data of 102 patients with jejunal/ileal GIST treated at Dana-Farber Cancer Institute and Brigham and Women's Hospital (Boston, MA) between 2002 and 2013 were evaluated. Imaging of treatment-naive primary tumour (41 patients) and follow-up imaging in all patients was reviewed. RESULTS: 90/102 patients were symptomatic at presentation, abdominal pain and lower gastrointestinal blood loss being the most common symptoms. On pathology, 21 GISTs were low risk, 17 were intermediate and 64 were high risk. The mean tumour size was 8.5 cm. On baseline CT (n = 41), tumours were predominantly well circumscribed, exophytic and smooth/mildly lobulated in contour. Of 41 tumours, 16 (39%) were homogeneous, whereas 25 (61%) were heterogeneous. Of the 41 tumours, cystic/necrotic areas (Hounsfield units < 20) were seen in 16 (39%) and calcifications in 9 (22%). CT demonstrated complications in 13/41 (32%) patients in the form of tumour-bowel fistula (TBF) (7/41), bowel obstruction (4/41) and intraperitoneal rupture (2/41). Amongst 102 total patients, metastases developed in 51 (50%) patients (27 at presentation), predominantly involving peritoneum (40/102) and liver (32/102). 7/8 (87%) patients having intraperitoneal rupture at presentation developed metastases. Metastases elsewhere were always associated with hepatic/peritoneal metastases. At last follow-up, 28 patients were deceased (median survival, 65 months). CONCLUSION: SB GISTs were predominantly large, well-circumscribed, exophytic tumours with or without cystic/necrotic areas. Complications such as TBF, bowel obstruction and intraperitoneal perforation were visualized at presentation, with patients with perforation demonstrating a high risk of metastatic disease. Exophytic eccentric bowel wall involvement and lack of associated adenopathy are useful indicators to help differentiate GISTs from other SB neoplasms. ADVANCES IN KNOWLEDGE: SB GISTs are predominantly large, well-circumscribed, exophytic tumours, and may present with complications. They often are symptomatic at presentation, are high risk on pathology and metastasize to the peritoneum more commonly than the liver.

Imaging of uncommon esophageal malignancies.

Malignant esophageal neoplasms other than squamous cell carcinoma and adenocarcinoma are uncommon and include endocrine tumors, lymphoid malignancies, melanoma, malignant stromal tumors, and secondary tumors (metastases). Imaging, though not diagnostic in many cases, helps in selecting the appropriate treatment strategy by determining the anatomic extent of the tumor and locoregional and distant spread. In this article, we provide a comprehensive review of the imaging features of these uncommon esophageal malignancies.

Multidetector-row CT of tumour-bowel fistula: Experience at a tertiary cancer centre.

AIM: To study the clinical and multidetector computed tomography (MDCT) features of tumour-bowel fistula (TBF). MATERIALS AND METHODS: Fifty-one patients (27 women; mean age 57.4 years, range 30-77years) with TBF presenting to our institution between January 2005 and February 2012 were identified retrospectively from the radiology database. MDCT images before, at, and subsequent to diagnosis of TBF were reviewed by three radiologists in consensus; clinical presentation, management, and outcome were documented from electronic medical records. RESULTS: Of 51 patients, small bowel (n = 22) was the most common site with gastrointestinal stromal tumour (GIST) being the most common sarcoma subtype (n = 10). TBF was treatment-associated (TTBF) in 40 patients [78%; 22 of whom had received molecular targeted therapy (MTT)], and spontaneous (STBF) in 11 patients (22%). Thirty-one patients (61%) were symptomatic at the time of TBF detection. TTBF was more often asymptomatic (19/40 versus 1/11; Fisher's exact test p = 0.03). In the TTBF group, 16 had a partial response, seven had stable disease, and 17 had progressive disease. Treatment was discontinued or changed to an alternative regimen in 27/40 patients, and 13/40 patients continued with the same regimen. TBF persisted in 27/33 patients (82%) who underwent CT follow-up. Thirty-one of the 51 patients were deceased at the time of analysis. Time from diagnosis of TBF to death was shorter with STBF (1.8 months) than with TTBF (6.4 months). CONCLUSION: TBF is often associated with MTT and can be seen with treatment response or progression. TTBF is more frequently asymptomatic. TBF is usually managed conservatively by discontinuing treatment, but often persists on CT follow-up.

Radiologic assessment of earliest, best, and plateau response of gastrointestinal stromal tumors to neoadjuvant imatinib prior to successful surgical resection.

BACKGROUND: To determine the timing of earliest, best and plateau response to neoadjuvant imatinib in patients with GIST. MATERIALS AND METHODS: In this IRB-approved retrospective study, we included all 20 patients (10 women; mean age 61 years, range 30-83 years) with KIT-positive primary GIST who received neoadjuvant imatinib and underwent surgery between January 2001 and December 2012. Earliest (earliest time to partial response), best (percentage reduction in longest axial diameter [LAD] and volume correlated with RECIST 1.1 and volumetric criteria) and plateau (time point when there was <10% change in treatment response between two consecutive scans beyond best response) responses were analyzed on review of imaging. RESULTS: Median tumor size at baseline was 7.2 cm (range, 3.0-31.4 cm). Median duration of neoadjuvant imatinib was 32 weeks (IQR, 16-36 weeks). Partial response was noted in 16/20 patients (median interval = 16 weeks; IQR, 7-26 weeks); 4/20 had stable disease. Median time to earliest PR was 16 weeks (IQR, 7-26 weeks). At best response, median decrease in LAD and volume were 43% (IQR, 31-48%) and 83% (IQR, 63-87%), (median interval = 28 weeks; IQR, 18-37 weeks), at which point 10 tumors were resected. Plateau response (45% [IQR, 35-45%] LAD reduction) was noted in the remaining 10 patients (median interval = 34 weeks; IQR, 26-41 weeks) before resection. Tumor size, location or risk category did not correlate with best response or time to best response. CONCLUSION: Best response to neoadjuvant imatinib was seen at 28 weeks irrespective of tumor size and location. Plateau response was seen at 34 weeks, beyond which further treatment may not be beneficial.

Imaging features of primary anorectal gastrointestinal stromal tumors with clinical and pathologic correlation.

PURPOSE: To evaluate the imaging features of anorectal gastrointestinal stromal tumors (GISTs) with clinical and histopathologic correlation. MATERIALS AND METHODS: In this Institutional Review Board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study, 16 patients (12 men; mean age 66 years (30-89 years)) with pathologically proven anorectal GISTs seen at our institution from January 2001 to July 2011 were identified. Electronic medical records were reviewed to obtain clinical data. Pretreatment imaging studies (computed tomography (CT) in 16 patients, magnetic resonance imaging (MRI) in 9 patients and fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT in 8 patients) were evaluated by 2 radiologists until consensus. The location, size and imaging features of the primary tumor and metastases at presentation, if any, were recorded, and correlated with clinical data and pathologic features (histologic type, presence of necrosis, mitotic activity, risk category, immunohistochemical profile). RESULTS: The mean tumor size was 6.9 × 6.0 cm. Of the 16 tumors, 11 (68.7%) were infralevator, 4 (25%) supra and infralevator and 1 (6.3%) supralevator; 9 (56.2%) were exophytic, 6 (37.5%) both exophytic and intraluminal, and 1 (6.3%) was intraluminal. The tumors were iso- to minimally hypoattenuating to muscle on CT, iso- to minimally hypointense on T1-weighted images, hyperintense on T2-weighted images and showed variable enhancement. Necrosis was seen in 4 (25%), and hemorrhage and calcification in 2 (12.5%) patients each. The tumors were FDG avid with a mean maximum standardized uptake value of 11 (8.4-16.8). All tumors were positive for KIT and CD34. Distant metastasis to liver was seen in 1 patient (6.3%) at presentation. CONCLUSION: Anorectal GISTs are well-circumscribed, non-circumferential, predominantly infralevator, intramural or exophytic, FDG-avid, hypoattenuating masses, and present without lymphadenopathy or intestinal obstruction.

Malignant peripheral nerve sheath tumors: prognostic impact of rhabdomyoblastic differentiation (malignant triton tumors), neurofibromatosis 1 status and location.

PURPOSE: The purpose of this study was to assess the impact of rhabdomyoblastic differentiation [malignant triton tumors (MTT)], neurofibromatosis 1 (NF1) status and location on the outcome of malignant peripheral nerve sheath tumors. METHODS: In this IRB-approved, HIPAA-compliant retrospective study medical records of 84 patients with pathologically confirmed MPNST from 1999 to 2011 were retrospectively reviewed. Patient and tumor characteristics including size, location, NF1 status, absence or presence of rhabdomyoblastic differentiation (MPNST versus MTT, respectively), recurrence and metastatic patterns and outcomes were evaluated. RESULTS: Of 84 patients, 62 were MPNST and 22 were MTT. MTT occurred in older patients than MPNST (50 years versus 40.7 years, p = 0.04) and were larger (12.3 cm versus 8.1 cm, p = 0.01). While there was no difference between the location, rate of recurrent or metastasis disease, and metastatic pattern between MTT and MPNST groups, MTT had shorter metastasis-free interval (median, 1 month versus 9 months, p = 0.02) and shorter survival (median, 10 months versus 43 months, p < 0.0001). NF1 status, while associated with earlier diagnosis (mean age, 35.1 years versus 46.5 years, p = 0.008), had no impact on rate of MTT or on prognosis. Patients with primary in the torso had shorter survival than those with extremity primary (median, 15 months versus 47 months, p = 0.0004). Multivariate analysis using the Cox proportional hazard regression model yielded age (p = 0.029), size (p = 0.0001), presence of rhabdomyoblastic differentiation (MTT) (p = 0.001), and location in the torso (p = 0.01) as independent predictors of survival. CONCLUSIONS: Among patients with malignant peripheral nerve sheath tumors, rhabdomyoblastic differentiation (MTT) and location in the torso are associated with poor prognosis. NF1 status has no impact on the prognosis.

Imaging features of bowel toxicities in the setting of molecular targeted therapies in cancer patients.

Molecular targeted therapies are becoming ubiquitous in cancer treatment. These drugs may cause gastrointestinal toxicities including perforation, pneumatosis, enteritis, colitis and fistula formation. Knowledge of these complications and their management enables early radiological identification and appropriate intervention, reducing patient morbidity and mortality.

Esophageal gastrointestinal stromal tumor: report of 7 patients.

PURPOSE: To evaluate imaging features of esophageal gastrointestinal stromal tumors (GIST) with clinical and histopathologic correlation and imaging follow-up. MATERIALS AND METHODS: In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study, 14 patients with pathologically proven esophageal GIST seen from January 2001 to October 2011, 7 patients (4 women; mean age 70 years, range 56-87 years) who had imaging of primary tumor and follow-up imaging at our institution were included. Imaging studies were evaluated by 3 radiologists in consensus. Location, size and imaging features of primary tumor and metastases, if any, were recorded, and correlated with pathologic (histopathologic subtype, presence of necrosis, mitotic rate, immunohistochemical profile) and clinical (treatment-related changes, distant spread and outcome) parameters. RESULTS: Of 7 tumors, 5 were located in the lower esophagus and 2 in mid-esophagus. Four were intraluminal, 2 were exophytic, and 1 was intramural. All 7 patients underwent computed tomography (CT); tumors appeared as well-circumscribed, hypoattenuating masses showing mild enhancement, with mean size of 5.7 × 4.2 cm. Necrosis and calcification were seen in 1 tumor each. Five patients underwent fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT. GISTs were FDG avid with mean standardized uptake value (SUV)[max] of 9.5 (4.5-12.3). All tumors were positive for KIT (7/7) and CD34 (6/6). Distant metastases to liver and pleura were seen in 1 patient. On imatinib treatment, the tumors responded with decreased attenuation values and unchanged size on CT, and decreased SUV[max] of primary tumor and metastases on FDG-PET/CT. CONCLUSION: Esophageal GISTs are well-circumscribed, FDG-avid, hypoattenuating masses that can metastasize to liver and pleura, and respond to imatinib treatment with decreased attenuation value on CT and decreased SUV[max] on FDG-PET/CT.

Imaging features of primary and secondary malignant tumours of the sacrum.

Malignant tumours of the sacrum may be primary or secondary. While sacral metastases are frequently encountered, a diagnostic dilemma can present when there is a single sacral bone tumour with no history or evidence of malignancy elsewhere in the body. Familiarity with the imaging features and clinical presentations of primary malignant bone tumours is helpful in narrowing the differential. This pictorial review will illustrate with both common and uncommon malignant sacral tumours CT, MRI and positron emission tomography/CT, highlighting the specific features of each.

Spleen in haematological malignancies: spectrum of imaging findings.

Imaging morphology and metabolic activity of splenic lesions is of paramount importance in patients with haematological malignancies; it can alter tumour staging, treatment protocols and overall prognosis. CT, MRI and positron emission tomography (PET)/CT have been shown to be powerful tools for the non-invasive assessment of splenic involvement in various haematological malignancies. Since many haematological malignancies and non-neoplastic conditions can involve the spleen and imaging manifestations can overlap, imaging and clinical findings outside of the spleen should be looked for to narrow the differential diagnosis; confirmation can be obtained by pathological findings. Radiologists should be familiar with the cross-sectional imaging patterns of haematological malignancies involving the spleen as well as non-neoplastic splenic findings common in these patients to facilitate their care and follow-up. This pictorial review provides the common and uncommon imaging appearances and complications of various haematological malignancies involving the spleen on CT, MRI and PET/CT, and common pitfalls in diagnosis.

Neuropathy progression in Charcot-Marie-Tooth disease type 1A.

OBJECTIVE: To determine the rate of disease progression in Charcot-Marie-Tooth disease type 1A (CMT1A). BACKGROUND: CMT1A is the most common inherited peripheral neuropathy, affecting approximately 1:5,000 people irrespective of ethnic background or gender. There is no cure for CMT1A. Clinical trials are being initiated that use the CMT Neuropathy Score (CMTNS), a composite score based on patient symptoms, signs, and neurophysiologic abnormalities, as the primary outcome variable. The sensitivity of the CMTNS or any other score to change over time, as a measure of CMT1A progression, has yet to be determined. METHODS: We determined the CMTNS as well as the Neuropathy Impairment Score (NIS) on 72 patients followed for up to 8 years. The rate of disease progression was evaluated for the CMTNS and NIS using mixed effects linear regression models, adjusting for age and gender. RESULTS: Both CMTNS and NIS showed changes over time. The CMTNS increased an average of 0.686 points per year (95% CI 0.461 to 0.911, p

CMT1X phenotypes represent loss of GJB1 gene function.

OBJECTIVE: To investigate possible genotype-phenotype correlations and to evaluate the natural history of patients with Charcot-Marie-Tooth disease type 1X (CMT1X). BACKGROUND: CMT1X is caused by over 260 distinct mutations in the gap junction beta 1 (GJB1) gene, located on the X chromosome, which encodes the gap junction protein connexin 32 (Cx32). The natural history of CMT1X is poorly understood, and it remains unknown whether particular mutations cause more severe neuropathies through abnormal gain-of-function mechanisms. METHODS: We evaluated 73 male patients with CMT1X, who each have 1 of 28 different GJB1 mutations predicted to affect nearly all domains of Cx32. Disability was evaluated quantitatively by the CMT Neuropathy Score (CMTNS) as well as by the CMT Symptom Score (CMTSS) and the CMT Examination Score (CMTES), which are both based on the CMTNS. Patients were also evaluated by neurophysiology. RESULTS: In all patients, disability increased with age, and the degree of disability was comparable with that observed in patients with a documented GJB1 deletion. Disability correlated with a loss of motor units as assessed by motor unit number estimates. CONCLUSIONS: Taken together, these data suggest that most GJB1 mutations cause neuropathy by a loss of normal connexin 32 function. Therefore, treatment of male patients with Charcot-Marie-Tooth disease type 1X may prove amenable to gene replacement strategies.

Juvenile onset Huntington disease resulting from a very large maternal expansion.

We report a 5(1/2)-year-old girl with a maternal family history of Huntington disease (HD), who presented clinically with unbalanced gait, impaired speech, and increasing difficulty with fine motor control. Onset of symptoms began at the age of 3(1/2) years. The suspected diagnosis of juvenile HD, based upon her family history, was confirmed by DNA analysis. At age 7, the patient died secondary to complications of her underlying disorder. Juvenile-onset Huntington disease is uncommon, predominantly transmitted by fathers and is always associated with very large expansions of the CAG repeat. Interestingly, this patient inherited a large CAG size expansion from her mother, who herself had symptoms of HD at the age of 18. Molecular analysis revealed that the mother had 70 CAG repeats whereas our patient had approximately 130 CAG repeats. This is the largest reported CAG expansion from a maternal transmission that has been confirmed molecularly and it demonstrates that very large expansions can also occur through the maternal lineage.

Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A), the most frequent form of CMT, is caused by a 1.5 Mb duplication on the short arm of chromosome 17. Patients with CMT1A typically have slowed nerve conduction velocities (NCVs), reduced compound motor and sensory nerve action potentials (CMAPs and SNAPs), distal weakness, sensory loss and decreased reflexes. In order to understand further the molecular pathogenesis of CMT1A, as well as to determine which features correlate with neurological dysfunction and might thus be amenable to treatment, we evaluated the clinical and electrophysiological phenotype in 42 patients with CMT1A. In these patients, muscle weakness, CMAP amplitudes and motor unit number estimates correlated with clinical disability, while motor NCV did not. In addition, loss of joint position sense and reduction in SNAP amplitudes also correlated with clinical disability, while sensory NCV did not. Taken together, these data strongly support the hypothesis that neurological dysfunction and clinical disability in CMT1A are caused by loss or damage to large calibre motor and sensory axons. Therapeutic approaches to ameliorate disability in CMT1A, as in amyotrophic lateral sclerosis and other neurodegenerative diseases, should thus be directed towards preventing axonal degeneration and/or promoting axonal regeneration.

Charcot-Marie-Tooth disease type 1: molecular pathogenesis to gene therapy.

Charcot-Marie-Tooth disease type 1 (CMT1) is caused by mutations in the peripheral myelin protein, 22 kDa (PMP22) gene, protein zero (P0) gene, early growth response gene 2 (EGR-2) and connexin-32 gene, which are expressed in Schwann cells, the myelinating cells of the peripheral nervous system. Although the clinical and pathological phenotypes of the various forms of CMT1 are similar, including distal muscle weakness and sensory loss, their molecular pathogenesis is likely to be quite distinct. In addition, while demyelination is the hallmark of CMT1, the clinical signs and symptoms of the disease are probably produced by axonal degeneration, not demyelination itself. In this review we discuss the molecular pathogenesis of CMT1, as well as approaches to an effective gene therapy for this disease.