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.

Evaluating skeletal dysplasias on prenatal ultrasound: an emphasis on predicting lethality.

Lethal skeletal dysplasias can be diagnosed by prenatal ultrasound (US) using several sonographic parameters. Degree of femoral shortening, lung volumes, femur length to abdominal circumference ratio, and chest circumference to abdominal circumference ratio are the most sensitive and specific predictors. Although there are more than 450 different skeletal dysplasias, only a few are lethal in the perinatal period. We review current fetal US literature and present an updated algorithmic approach to first establish lethality and, second, evaluate for hallmark sonographic features to help determine a specific diagnosis.

Quantitative Versus Qualitative Methods in Evaluation of T2 Signal Intensity to Improve Accuracy in Diagnosis of Pheochromocytoma.

OBJECTIVE: The purpose of this study was to assess T2 signal intensity (SI) of adrenal pheochromocytoma at 1.5 T using the rapid acquisitions with relaxation enhancement (RARE) sequence. We also sought to determine whether quantitative parameters can distinguish pheochromocytoma from other adrenal lesions with better accuracy than conventional qualitative methods. MATERIALS AND METHODS: MRI examinations of 74 patients (26 with pheochromocytoma, 25 with lipid-poor adenomas, 18 with malignant adrenal lesions, and five with adrenal cysts) were retrospectively reviewed. MRI sequences included single-shot fast spin-echo (n = 38) and fast-recovery fast spin-echo (n = 36) acquisitions. T2 SI of lesions was qualitatively compared with CSF. Quantitative evaluation included applying ROI measurements and calculating SI ratio of each mass to liver, spleen, paraspinal muscle, and CSF. Twoway ANOVA compared SI ratios between different adrenal lesions and between two pulse sequences. ROC analysis determined the optimal threshold SI ratio for distinguishing pheochromocytomas from other adrenal lesions. RESULTS: Sixty-nine percent of pheochromocytomas displayed isointensity to CSF (p < 0.005), resulting in 81% specificity and 69% sensitivity for differentiation of pheochromocytomas from lipid-poor adenomas and malignant lesions. Adrenal-to-muscle SI ratio was the strongest discriminator for differentiation of pheochromocytomas from other lesions. A threshold of at least 3.95 yielded 88% specificity and 81% sensitivity for distinguishing pheochromocytomas from lipid-poor adenomas and malignant adrenal lesions. CONCLUSION: Quantitative normalization of T2 SI with reference to muscle improves the sensitivity and specificity profile for differentiation of pheochromocytoma compared with qualitative assessment alone. At 1.5 T field strength, an adrenal-to-muscle SI ratio of at least 3.95 is recommended.

Endometrial Ablation: Normal Imaging Appearance and Delayed Complications.

OBJECTIVE: Nonresectoscopic endometrial ablation techniques are being used as an alternative first-line management for menorrhagia. With these techniques, patients are at risk of developing delayed complications including painful obstructed menses, such as central hematometra and cornual hematometra, and postablation tubal sterilization syndrome. Pregnancy and the detection of endometrial cancer after ablation pose challenges in management. CONCLUSION: Radiologists should recognize the normal imaging findings in patients who have undergone endometrial ablation, be aware of the causes of treatment failure, and accurately identify delayed complications associated with these procedures.

MR imaging of the retrorectal-presacral tumors: an algorithmic approach.

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.

Circumportal pancreas: imaging findings in 40 patients.

PURPOSE: To analyze the CT and MR imaging features of circumportal pancreas (CP) with emphasis on the relative frequency of variants of parenchymal fusion, ductal anatomy, and vascular anatomy. METHODS: A retrospective review of CT and MR imaging findings of 40 patients with CP was performed. CT and MR images were reviewed by two radiologists in consensus. The course of the pancreatic duct in relation to the portal vein (anteportal vs. retroportal), location of the circumvenous pancreatic parenchyma in relation to the splenic vein (suprasplenic vs. infrasplenic), presence or absence of a visible accessory duct posterior to the portal vein, presence of vascular variants, history of pancreatitis and pancreatic surgery were recorded. Cases were classified into four categories: anteportal suprasplenic, retroportal suprasplenic, anteportal infrasplenic, and retroportal infrasplenic. RESULTS: One case of suprasplenic fusion was excluded from the classification due to non-visualization of the pancreatic duct. 32/39(82%) of cases were classified as anteportal suprasplenic, 2/39(5%) as retroportal suprasplenic, 4/39(10%) as anteportal infrasplenic, and 1/39(3%) as retroportal infrasplenic. There were 12 vascular variants including nine with an intraparenchymal course (through the pancreatic head) of the common hepatic artery, one with an intraparenchymal course of the right hepatic artery, two replaced right hepatic arteries from the superior mesenteric artery, and one with an intraparenchymal course of the left gastric vein. CONCLUSION: Circumportal pancreas is an important pancreatic fusion anomaly with distinctive imaging features. The most common variant of CP is the anteportal suprasplenic subtype, with other subtypes being much less common. Intraparenchymal course of the common hepatic artery is a common variant associated with CP. Recognition of CP is important to avoid potential complications in patients who undergo pancreatic surgery.

Practical approach to MRI of female pelvic masses.

OBJECTIVE: Female pelvic masses have a broad differential diagnosis, including benign and malignant neoplasms and nonneoplastic entities. CONCLUSION: By using a systematic approach to the evaluation of a complex pelvic mass, including incorporating the clinical and surgical history, and by using multiparametric MRI to identify the anatomic origin, morphologic features, and tissue composition of a mass, a short meaningful differential diagnosis or definitive diagnosis can often be established.

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.

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.

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.

Subperitoneal adenomucinosis following proctocolectomy for ulcerative colitis.

Adenomucinosis is a rare condition characterized by accumulation of large volumes of mucin, typically related to mucinous neoplasms of the appendix within the peritoneal space. Extraperitoneal adenomucinosis is an uncommon variant where mucin accumulates outside the peritoneal space and usually arises following surgery for mucinous appendiceal neoplasms. This is a case of subperitoneal adenomucinosis resulting from retention of a small fragment of rectal mucosa following proctocolectomy for ulcerative colitis 16 years prior. The patient presented with a slow-growing boggy perineal mass. Contrast-enhanced magnetic resonance imaging (MRI) showed the mass to be localized to the pelvis, without solid enhancing components, and correctly facilitated local surgical excision without the risk of peritoneal dissemination and accurately predicted benignity.

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.

Prenatal magnetic resonance imaging (MRI) findings of a foregut duplication cyst of the tongue: value of real-time MRI evaluation of the fetal swallowing mechanism.

Foregut duplication cysts of the oral cavity or lingual choristomas have a potential risk of airway obstruction. Two cases are reported that were initially detected by screening sonography. Further imaging with both static and real-time cine magnetic resonance imaging confirmed the lingual origin, relationship of the mass to fluid-filled spaces within the oral cavity, motion of the mass with the tongue during fetal swallowing, and airway patency. The additional information provided by magnetic resonance imaging aided in planning delivery and obviated the need for an ex utero intrapartum treatment procedure because airway patency was confirmed in both cases.

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.

2D thick-slab MR cholangiopancreatography: does parallel imaging with sensitivity encoding improve image quality and duct visualization?

OBJECTIVE: Our objective was to determine whether the theoretic advantages of parallel imaging are realized when applied to 2D thick-slab single-shot fast spin-echo (SSFSE) MR cholangiopancreatography (MRCP) with respect to image quality and duct conspicuity. MATERIALS AND METHODS: Thirty-nine patients (18 men and 21 women; mean age, 51.8 years) were referred for MRCP. Multiangled thick-slab breath-hold SSFSE imaging was performed without and with integrated parallel imaging with sensitivity encoding (SENSE). Images were retrospectively reviewed. A 4-point rating scale was used to grade overall image quality and visibility of 10 ductal segments. A Wilcoxon's signed rank test compared the two techniques. Analysis of signal intensities and relative contrast of fluid-filled structures to background tissue on the basis of region of interest was calculated. Differences between the techniques were compared using a Student's t test. RESULTS: Two-dimensional thick-slab SSFSE with integrated parallel imaging showed a mild but statistically significant increase in the relative contrast (p = 0.01) of ductal segments. Image quality deteriorated slightly with parallel imaging, but the results were not statistically significant (p = 0.06). Parallel imaging improved duct conspicuity of the medial and lateral segments of the left lobe and the posterior segment of the right lobe. However, statistical improvement was achieved only for the medial segment of the left lobe (p = 0.03). The mean scores of the remaining ducts were either unchanged or worse with parallel imaging, but the differences were not significant. CONCLUSION: Although there was improvement in the relative contrast of bile to background tissue, improvement in overall image quality was not observed with parallel imaging. However, application of parallel imaging to thick-slab SSFSE may improve depiction of the smallest-caliber ducts.

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.

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.

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.

ACR Appropriateness Criteria® Pretreatment Staging of Muscle-Invasive Bladder Cancer.

Muscle-invasive bladder cancer (MIBC) has a tendency toward urothelial multifocality and is at risk for local and distant spread, most commonly to the lymph nodes, bone, lung, liver, and peritoneum. Pretreatment staging of MIBC should include imaging of the urothelial upper tract for synchronous lesions; imaging of the chest, abdomen, and pelvis for metastases; and MRI pelvis for local staging. CT abdomen and pelvis without and with contrast (CT urogram) is recommended to assess the urothelium and abdominopelvic organs. Pelvic MRI can improve local bladder staging accuracy. Chest imaging is also recommended with chest radiograph usually being adequate. FDG-PET/CT may be appropriate to identify nodal and metastatic disease. Chest CT may be useful in high-risk patients and those with findings on chest radiograph. Nonurogram CT and MRI of the abdomen and pelvis are usually not appropriate, and neither is radiographic intravenous urography, Tc-99m whole body bone scan, nor bladder ultrasound for pretreatment staging of MIBC. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Post-treatment Follow-up Prostate Cancer.

Diagnosis and management of prostate cancer post treatment is a large and complex problem, and care of these patients requires multidisciplinary involvement of imaging, medical, and surgical specialties. Imaging capabilities for evaluation of men with recurrent prostate cancer are rapidly evolving, particularly with PET and MRI. At the same time, treatment options and capabilities are expanding and improving. These recommendations separate patients into three broad categories: (1) patients status post-radical prostatectomy, (2) clinical concern for residual or recurrent disease after nonsurgical local and pelvic treatments, and (3) metastatic prostate. This article is a review of the current literature regarding imaging in these settings and the resulting recommendations for imaging. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.