Keyanoosh Hosseinzadeh

CT of Nonneoplastic Hepatic Vascular and Perfusion Disorders

The unique dual blood supply of the liver (75% portal venous, 25% hepatic arterial) makes multiphase helical computed tomography (CT) a highly suitable technique for hepatic evaluation with imaging in two (arterial and portal venous) or more phases. Multiphase helical CT has become an important tool in the detection and characterization of hepatic tumors. In some situations, hemodynamic changes might mimic neoplastic or inflammatory lesions and evoke diagnostic uncertainty. To confidently identify hepatic conditions such as venous outflow obstruction (Budd-Chiari syndrome), arterioportal shunts, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome), peliosis hepatis, passive congestion, and hepatic infarction, radiologists must be familiar with the disease-specific CT appearances and related clinical manifestations.

Imaging of Posttransplantation Lymphoproliferative Disorder after Solid Organ Transplantation

Posttransplantation lymphoproliferative disorders (PTLDs) are a heterogeneous group of diseases that represent uncommon complications of transplantation and can lead to significant morbidity and mortality. PTLD is most prevalent during the first year following transplantation and occurs most frequently in multiorgan transplant recipients, followed by bowel, heart-lung, and lung recipients. It may involve any of the organ systems, with disease manifestation and the anatomic pattern of organ involvement being highly dependent on the type of transplantation. The current classification system includes four subtypes that have different prognoses requiring different treatment strategies. Tissue sampling is necessary for diagnosis and further subcategorization. The majority of cases are characterized by B-cell proliferation and are related to infection from Epstein-Barr virus. Knowledge of the distribution and radiologic features of PTLD allows the radiologist to play a pivotal role in making an early diagnosis and in guiding biopsy.

Gallbladder Carcinoma Update: Multimodality Imaging Evaluation, Staging, and Treatment Options

OBJECTIVE The purpose of this article is to review the epidemiology, multimodality imaging findings, differential diagnosis, pathologic staging, and current treatment options of gallbladder carcinoma. CONCLUSION Understanding the characteristic appearances of primary gallbladder carcinoma at multiple imaging modalities can facilitate diagnosis and enable more accurate staging for triage to extended resection or an alternate therapy.

MRI of Pregnancy-Related Issues: Abnormal Placentation

OBJECTIVE In this article, we review the clinical significance of abnormal placentation and the role of MRI in diagnosis and management of this potentially morbid condition. We present our clinical perspective on diagnosing this challenging problem with MRI and review the imaging findings that can lead to a correct diagnosis. CONCLUSION As abnormal placentation becomes more prevalent, in large part due to the markedly rising rates of cesarean delivery, there is a need for accurate antenatal diagnosis of this condition to prevent maternal morbidity and mortality. Maternal and fetal outcomes can be optimized through multidisciplinary planning to achieve accurate diagnosis and anticipation of the extent of abnormal placentation in the antenatal period. Imaging findings of abnormal placentation have been described for both ultrasound and MRI, although limitations exist for each technique. Although ultrasound remains the primary screening modality for the detection of abnormal placentation, MRI is a complementary technique that should be considered when ultrasound is inconclusive or incomplete. Familiarity with MRI techniques to assess the placenta, MRI appearance of normal placenta, and imaging findings that suggest abnormal placentation can help radiologists contribute to a successful maternal outcome.

Adult Bile Duct Strictures: Role of MR Imaging and MR Cholangiopancreatography in Characterization

Bile duct strictures in adults are secondary to a wide spectrum of benign and malignant pathologic conditions. Benign causes of bile duct strictures include iatrogenic causes, acute or chronic pancreatitis, choledocholithiasis, primary sclerosing cholangitis, IgG4-related sclerosing cholangitis, liver transplantation, recurrent pyogenic cholangitis, Mirizzi syndrome, acquired immunodeficiency syndrome cholangiopathy, and sphincter of Oddi dysfunction. Malignant causes include cholangiocarcinoma, pancreatic adenocarcinoma, and periampullary carcinomas. Rare causes include biliary inflammatory pseudotumor, gallbladder carcinoma, hepatocellular carcinoma, metastases to bile ducts, and extrinsic bile duct compression secondary to periportal or peripancreatic lymphadenopathy. Contrast material-enhanced magnetic resonance (MR) imaging with MR cholangiopancreatography is extremely helpful in the noninvasive evaluation of patients with obstructive jaundice, an obstructive pattern of liver function, or incidentally detected biliary duct dilatation. Some of these conditions may show characteristic findings at MR imaging-MR cholangiopancreatography that help in making a definitive diagnosis. Although endoscopic retrograde cholangiopancreatography with tissue biopsy or surgery is needed for the definitive diagnosis of many of these strictures, certain MR imaging characteristics of the narrowed segment (eg, thickened wall, long-segment involvement, asymmetry, indistinct outer margin, luminal irregularity, hyperenhancement relative to the liver parenchyma) may favor a malignant cause. Awareness of the various causes of bile duct strictures in adults and familiarity with their appearances at MR imaging-MR cholangiopancreatography are important for accurate diagnosis and optimal patient management.

Imaging of the Female Perineum in Adults

The female perineum is a diamond-shaped structure inferior to the pelvic diaphragm and between the symphysis pubis and coccyx. The perineum is divided into the anterior urogenital triangle and the posterior anal triangle; the vulva represents the external genitalia. A wide array of diseases affect the female perineum in adults. Vulvar trauma, infection (including Fournier gangrene), developmental lesions, and thrombophlebitis can be investigated with various imaging modalities; vulvar malignancies are best imaged with magnetic resonance (MR) imaging to identify local-regional extent of disease. MR imaging is also the modality of choice for imaging of the distal urethra, although imaging of a urethral diverticulum also includes voiding cystourethrography and ultrasonography. The distal vagina at the level of the introitus is best imaged with MR imaging for assessment of Bartholin gland cysts and malignancies. Diseases encountered in the anus include anal carcinoma, fistula-in-ano, and anovaginal fistula, which can all be imaged with various modalities offering different sensitivities and fields of view. Lastly, musculoskeletal neoplasms affecting the perineum and vulva include mesenchymal, lipomatous, nerve sheath, and osseous neoplasms. These neoplasms can be imaged with both computed tomography and MR imaging, although the latter provides higher soft-tissue contrast and greater anatomic detail for diagnosis and determination of the extent of necessary surgery. Familiarity with the anatomy of the female perineum and appropriate selection of imaging modalities facilitate prompt and accurate diagnosis and treatment.

Pre- and Postoperative Evaluation of Urethral Diverticulum

OBJECTIVE The purpose of this article is to review the diagnostic imaging findings, differential diagnosis, complications, and postoperative imaging appearance of urethral diverticulum. CONCLUSION With increased clinical awareness and advanced imaging techniques, diagnoses of urethral diverticula are more frequent, and radiologists need to be aware of the pre- and postoperative imaging appearances of this disorder.

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial

BACKGROUND Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. METHODS In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0-1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m2, leucovorin at 400 mg/m2, irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. FINDINGS Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m2. The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4-19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250-602). Two patients enrolled at a higher dose of 1000 mg/m2, and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3-4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3-4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1-3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. INTERPRETATION A maximum tolerated dose of CPI-613 was established at 500 mg/m2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. FUNDING Comprehensive Cancer Center of Wake Forest Baptist Medical Center.Background Pancreatic cancer statistics are dismal, with a five-year survival of less than 10%, and over 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma, including aerobic glycolysis, oxidative phosphorylation, glutaminolysis, lipogenesis and lipolysis, autophagic status, and anti-oxidative stress. CPI-613 is a novel anti-cancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumor cells, causing changes in mitochondrial enzyme activities and redox status which lead to apoptosis, necrosis and autophagy of tumor cells. Methods This is a phase 1 study to determine the maximum-tolerated dose (MTD) of CPI-613 when used in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m2 and irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus and 2400 mg/m2 over 46 h) in combination with CPI-613 in patients with newly diagnosed metastatic pancreatic adenocarcinoma with good bone marrow, liver and kidney function and good performance status (NCT01835041 – closed to recruitment). A two-stage dose-escalation scheme (single patient and traditional 3+3 design) was applied. In the single patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m2/day; the dose level was then escalated by doubling the previous dose if there was no toxicity greater than Grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxicity attributed as probably or definitely related to CPI-613 was ≥ Grade 2. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as used in the last cohort of the single patient dose-escalation stage. Secondary objectives were safety, preliminary efficacy, and tissue collection for future analyses. Response rates, progression-free survival and overall survival data were assessed in the patients treated at the MTD. Findings Twenty patients were enrolled April 22, 2013 – January 8, 2016. The MTD of CPI-613 was 500 mg/m2. The median number of treatment cycles administered at the MTD was 11 (interquartile range, 4–19). Two patients enrolled at a higher dose (1000 mg/m2) both experienced a DLT (dose limiting toxicity). There were 2 unexpected serious adverse events (SAEs), both for the first patient enrolled: 1) possible leaching due to infusion of CPI-613 via non-PVC tubing, and 2) the patient re- accessed her port at home after accidental de-access. Neither incident resulted in a negative clinical outcome. Expected SAEs were: thrombocytopenia, anemia and lymphopenia (all for Patient #2, with anemia and lymphopenia being a DLT); hyperglycemia (Patient #7); hypokalemia, hypoalbuminemia and sepsis (Patient #11); and neutropenia (Patient #20). There was no grade 5 toxicity. For the 18 patients treated at the MTD, the most common Grade 3–4 toxicities were hypokalemia (6/18, 33%), diarrhea (5/18, 28%) and abdominal pain (4/18, 22%). Sensorial neuropathy (17/18, 94%) was managed with dose de-escalation or discontinuation per standard of care. None of the patients experienced grade 4 or 5 neuropathy. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Among the 18 patients treated with the MTD, there were 3 patients with a complete response (CR), 1 with a non-CR/non-progressive disease, 7 with a partial response (PR), 3 with stable disease, and 4 with PD. The partial + complete response rate was 61% (11/18). Interpretation The treatment was well tolerated and all end points were met. The intriguing signal of efficacy will require validation in a phase 2 study. Funding Comprehensive Cancer Center of Wake Forest Baptist Medical Center

Imaging of hepatobiliary disorders complicating pregnancy.

OBJECTIVE A variety of uncommon, but potentially devastating, hepatobiliary disorders may complicate pregnancy. Because of their rarity, such disorders may elude diagnosis and treatment may be delayed. Although some of these disorders can be diagnosed clinically, imaging plays an important role in the diagnosis of several pregnancy-related hepatobiliary disorders. CONCLUSION The radiologist should be familiar with the imaging findings of hepatobiliary diseases that complicate pregnancy and can result in significant maternofetal morbidity and mortality.

MR imaging of the retrorectal–presacral tumors: an algorithmic approach

Abstract The retrorectal–presacral space is located posterior to the mesorectum and anterior to the sacrum, and can harbor a heterogeneous group of uncommon masses. Retrorectal–presacral tumors may be classified as congenital, neurogenic, osseous, and miscellaneous. Magnetic resonance imaging (MRI) plays a crucial role in directing appropriate management through accurate diagnosis, detection of complications and anatomic extent. MRI aids in the selection of optimal surgical approach such as anterior, posterior, or combined—based on the lesion extent and relationship to adjacent structures. This article reviews the anatomy of the retrorectal–presacral space and the related tumors, optimal MRI protocol, MRI-based approach to differential diagnosis, and finally pertinent reporting pointers and implications of MR imaging findings for surgical management.