Perceptual omission errors in positron emission tomography and computed tomography reporting.

BACKGROUND: Omission errors in medical imaging can lead to missed diagnosis and harm to patients. The subject has been studied in conventional imaging, but no data is available for functional imaging in general and for PET/CT in particular. In this work, we evaluated the frequency and characteristics of perceptual omission errors in the PET component of oncologic PET/CT imaging, and we analyzed the hazardous scenarios prone to such modality-specific errors. METHODS: Perceptual omission errors were collected in one tertiary center PET/CT clinic during routine PET/CT reporting over a 26-month period. The omissions were detected either in reporting follow-up PET/CT studies of the same patient or during multidisciplinary meetings. RESULTS: Significant omission errors were found in 1.2% of the 2100 reports included in the study. The most common omissions were bone metastases and focal colon uptake. We identified six PET-specific causative factors contributing to the occurrence of omissions, and we propose solutions to minimize their influence. CONCLUSIONS: The data presented here can help to promote the awareness of interpreting physicians to body areas that require higher attention and to implement reading strategies for improving the accuracy of PET/CT interpretation.

[FDG PET/CT FOR TREATMENT RESPONSE ASSESSMENT IN CANCER].

INTRODUCTION: FDG PET/CT (fluorodeoxyglucose (FDG)-positron emission tomography (PET) computed tomography (CT)) imaging reflects functional-metabolic changes occurring within the malignant process in response to therapy. Since these changes usually precede anatomic alterations, this imaging technique is highly valuable in assessing response during and after therapy and is superior to CT. FDG PET/CT following initiation of cancer therapy has a prognostic value, predicting progression free survival and overall survival. In some malignancies FDG PET/CT can guide personalized medicine by tailoring therapy in accordance with the metabolic cancer response in the individual patient. In lymphoma patients, including Hodgkin's disease (HD) and diffuse large B-cell lymphoma (DLBCL), FDG PET/CT is useful for monitoring response and guiding therapy, both after and early during therapy. Various quantitative and visual criteria systems are used for assessing cancer response to therapy by FDG PET/CT. Acquaintance with these interpretation methods and their adjustment to new anti-cancerous mechanisms such as in immunotherapy, is important for accurate imaging and meaningful interpretation. Large prospective meticulously performed studies, using standardized methodology, are required to further establish and expand the use of FDG PET/CT for the assessment of response to therapy in various malignancies.

Limiting surveillance imaging for patients with lymphoma in remission: a mixed methods study leading to a Choosing Wisely recommendation.

BACKGROUND: Under the 'Choosing Wisely' (CW) framework, professional organisations internationally have advocated limiting imaging for asymptomatic patients following curative cancer therapy, based on limited value and high cost. F18-fluorodeoxyglucose (FDG) positron emission tomography-CT (PET/CT) was widely adopted locally for surveillance lymphoma imaging after 2004. OBJECTIVES: Prior to ratification of a local CW recommendation to limit surveillance imaging in lymphoma, we aimed to assess: (A) performance characteristics of surveillance FDG-PET/CT; (B) rates, clinical consequences and costs of false positives (FP); and (C) patients and professionals' attitudes towards overuse. METHODS: Mixed methods (quantitative and qualitative) study. We analysed surveillance FDG-PET/CT results of two patient cohorts (n1=215 Hodgkin lymphoma and non-Hodgkin lymphoma; n2=203 Hodgkin lymphoma only). FPs were defined by negative biopsy or clinical follow-up. We held focus group discussions and in-depth interviews eliciting attitudes of 26 patients and 11 clinicians, respectively. RESULTS: FPs were observed in 25.1% (95% CI 20.5 to 30.5) per scan-cohort 1, and 41.7% (95% CI 37.9 to 45.6) per patient-cohort 2, engendering frequent additional testing. Specific characteristics and location of findings altered the FP rate. The estimated cost per relapse detected was $50 000 (cohort 2). Patients sought reassurance via surveillance imaging, which they considered highly accurate, yet stressful. Aware of radiation risks, they were largely unconcerned about consequences of FPs. Confidence in the treating physicians was an important factor in patients' acceptance of forgoing imaging. Clinicians, frequently under patient pressure to order imaging, generally believed that it did not affect prognosis (with important exceptions), welcomed professional guidelines, but rejected regulatory restrictions on its use. CONCLUSION: Acceptance of CW recommendations to limit overuse may be enhanced by quantitative data on consequences and costs of surveillance imaging, supplemented by qualitative data on patient and physician attitudes.

Posttreatment FDG-Avid Splenic Lesions in DLBCL and HD: Clinical and Radiographic Characteristics for Risk Assessment.

Residual end of treatment (EOT) FDG-avid lesions are often due to infectious or inflammatory process and not due to refractory lymphoma. Nonetheless, such lesions prompt diagnostic and therapeutic interventions. We evaluate clinical and radiological characteristics of patients with EOT FDG-avid splenic lesions. Comparing metabolic volume (MV) ratio between EOT to interim, showed a marked difference between false positive and true positive lesions (0.5 vs 3.6, P = 0.02). EOT SUVmax was also significantly different between the groups (7 vs. 19, P = 0.02). We suggest EOT/interim-MV ratio as a tool to identify patients at low risk of refractory disease allowing non-invasive surveillance.

Gamma Radiation Imaging System via Variable and Time-Multiplexed Pinhole Arrays.

Biomedical planar imaging using gamma radiation is a very important screening tool for medical diagnostics. Since lens imaging is not available in gamma imaging, the current methods use lead collimator or pinhole techniques to perform imaging. However, due to ineffective utilization of the gamma radiation emitted from the patient's body and the radioactive dose limit in patients, poor image signal to noise ratio (SNR) and long image capturing time are evident. Furthermore, the resolution is related to the pinhole diameter, thus there is a tradeoff between SNR and resolution. Our objectives are to reduce the radioactive dose given to the patient and to preserve or improve SNR, resolution and capturing time while incorporating three-dimensional capabilities in existing gamma imaging systems. The proposed imaging system is based on super-resolved time-multiplexing methods using both variable and moving pinhole arrays. Simulations were performed both in MATLAB and GEANT4, and gamma single photon emission computed tomography (SPECT) experiments were conducted to support theory and simulations. The proposed method is able to reduce the radioactive dose and image capturing time and to improve SNR and resolution. The results and method enhance the gamma imaging capabilities that exist in current systems, while providing three-dimensional data on the object.

Chemo-Radiotherapy of Oligometastases of Colorectal Cancer With Pegylated Liposomal Mitomycin-C Prodrug (Promitil): Mechanistic Basis and Preliminary Clinical Experience.

Hypo-fractionated radiotherapy and stereotactic body radiotherapy are viable options for treatment of oligometastases. A prodrug of mitomycin-C is under clinical testing as a pegylated liposomal formulation (Promitil) with an improved safety profile over mitomycin-C. Promitil was offered to two patients with oligometastases from colorectal cancer as radiosensitizer. Each derived durable clinical benefit from Promitil administered immediately prior to and following irradiation. Transient toxicity to normal tissues of moderate to severe degree was observed. Promitil appears to have potential clinical value in this setting. HIGHLIGHTS - Delivery of radio-sensitizing drugs with pegylated (long-circulating) liposomes is a pharmacologically rational approach which remains largely clinically untested.- A mitomycin-c prodrug delivered by pegylated liposomes (Promitil) is activated by thiol groups, which are produced in excess by radiation-damaged cells, thus potentiating the radio-sensitizing effect of Promitil.- Two durable clinical responses in patient with colorectal oligometastases to Promitil and radiotherapy suggest that this approach may be of value in cancer chemo-radiotherapy.

Modification of initial therapy in early and advanced Hodgkin lymphoma, based on interim PET/CT is beneficial: a prospective multicentre trial of 355 patients.

This multicentre study evaluated 5-year progression-free (PFS) and overall survival (OS) in early and advanced Hodgkin lymphoma (HL), where therapy was individualized based on initial prognostic factors and positron emission tomography-computed tomography performed after two cycles (PET-2). Between September 2006 and August 2013, 359 patients aged 18-60 years, were recruited in nine Israeli centres. Early-HL patients initially received ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) ×2. Depending on initial unfavourable prognostic features, PET-2-positive patients received additional ABVD followed by involved-site radiotherapy (ISRT). Patients with negative PET-2 and favourable disease received ISRT or ABVD ×2; those with unfavourable disease received ABVD ×2 with ISRT or, alternatively, ABVD ×4. Advanced-HL patients initially received ABVD ×2 or escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone; EB) ×2 based on their international prognostic score (≤2 or ≥3). PET-2-negative patients further received ABVD ×4; PET-2-positive patients received EB ×4 and ISRT to residual masses. With a median follow-up of 55 (13-119) months, 5-year PFS was 91% and 69% for PET-2-negative and positive early-HL, respectively; 5-year OS was 100% and 95%, respectively. For advanced-HL, the PFS was 81% and 68%, respectively (P = 0·08); 5-year OS was 98% and 91%, respectively. PET-2 positivity is associated with inferior prognosis in early-HL, even with additional ABVD and ISRT. Advanced-HL patients benefit from therapy escalation following positive PET-2. EB can be safely de-escalated to ABVD in PET-2-negative patients.

MEK inhibitor treatment is effective in a patient with metastatic carcinoma of the ampulla of Vater with BRAF and NRAS mutations shown by next-generation sequencing.

Here, we present a case of an 84-year-old woman who developed obstructive jaundice and was diagnosed with nonoperable adenocarcinoma originating from the ampulla of Vater, a lethal disease with a median overall survival of less than a year. Her tumor was examined by next-generation sequencing, which showed BRAF and NRAS mutations. To target these mutations, a MEK inhibitor was chosen for treatment. The patient has been treated with a MEK inhibitor for the last 12 months since diagnosis, with clinical and laboratory improvement and manageable side effects. PET-computed tomography imaging has shown stable disease or improvement in the primary and metastatic lesions. This is the first case report of an ampulla of a Vater cancer patient with NRAS and BRAF mutations, identified in next-generation sequencing, and treated successfully with a MEK inhibitor.

Added Value of SPECT/CT in the Evaluation of Benign Bone Diseases of the Appendicular Skeleton.

Bone scintigraphy is a sensitive technique to detect altered bone mineralization but has limited specificity. The use of SPECT/CT has improved significantly the diagnostic accuracy of bone scintigraphy, in patients with cancer as well as in evaluation of benign bone disease. It provides precise localization and characterization of tracer-avid foci, shortens the diagnostic workup, and decreases patient anxiety. Through both the SPECT and the CT components, SPECT/CT has an incremental value in characterizing benign bone lesions, specifically in the appendicular skeleton, as illustrated by present case series.

FDG PET/CT for assessing the resectability of NSCLC patients with N2 disease after neoadjuvant therapy.

OBJECTIVE: Neoadjuvant chemoradiotherapy (CMRT) is the most effective treatment of stage III non-small-cell lung cancer (NSCLC). The present study aimed at assessing FDG PET/CT for defining the response of N2 disease to neoadjuvant CMRT, as surgical resection after such therapy significantly improves 5-year survival in responding N2 disease. METHODS: Forty-five patients with locally advanced NSCLC underwent both pre-neoadjuvant therapy FDG PET/CT and post-neoadjuvant therapy FDG PET/CT followed by anatomical resection of lung and ipsilateral mediastinal lymph nodes (LN). Seventeen of these patients who had PET/CT studies in our institution and were operated after CMRT were retrospectively included in the study group (12 males, ages 43-78 years; stage IIIA: 14 patients, stage IIIB: 3 patients). PET/CT response in N2 was visually scored per-lymph node station and per patient. Quantitative N2 response was evaluated by SUVmax and total lesion glycolysis (TLG) measurements after therapy alone and in comparison with pre-therapy values. PET/CT N2 response was confirmed at surgery. RESULTS: Seventeen NSCLC patients with 29 metastatic N2 lymph nodes (LN) were assessed. Histopathology confirmed 14 responders and 3 non-responders, and was available in 20/29 metastatic LN, showing complete response in 17 and residual disease in 3 LN. LN-based visual analysis of N2 response on PET/CT defined 3 TP, 16 TN and 1 FP, for sensitivity, specificity, accuracy, negative and positive predictive values (NPV and PPV) of 100, 94, 95, 100 and 75%, respectively. Patient-based visual analysis defined 3 TP, 13 TN and 1 FP study, for sensitivity, specificity, accuracy, NPV and PPV of 100, 93, 94, 100 and 75%, respectively. Nodal-based quantitative analysis of FDG uptake in N2 nodes revealed a significant difference between responding and non-responding LN only of SUVmax post-therapy (2.5 ± 1.21 vs. 3.5 ± 2.36, P = 0.04). CONCLUSION: FDG PET/CT after neoadjuvant therapy accurately defined response in metastatic N2 nodes of NSCLC patients, presenting very high sensitivity and NPV for detecting responding nodes. PET/CT may enable selection of candidates for curative resection of stage III NSCLC. Mediastinoscopy may not be mandatory in patients with a negative PET/CT after neoadjuvant therapy.

Integration of CT-Based Measurements into Surveillance PET/CT in Patients with Diffuse Large B Cell Lymphoma.

BACKGROUND: Despite the lack of clinical studies supporting the use of routine surveillance FDG-positron emission tomography (PET) in patients with diffuse large B cell lymphoma (DLBCL) who achieved remission, many centers still use this strategy, especially in high risk patients. Surveillance FDG-PET computed tomography (CT) is associated with a high false positive (FP) rate in DLBCL patients. OBJECTIVES: To investigate whether use of specific CT measurements could improve the positive predictive value (PPV) of surveillance FDG-PET/CT. METHODS: This retrospective study included DLBCL patients treated with CHOP or R-CHOP who achieved complete remission and had at least one positive surveillance PET. CT-derived features of PET-positive sites, including long and short diameters and presence of calcification and fatty hilum within lymph nodes, were assessed. Relapse was confirmed by biopsy or consecutive imaging. The FP rate and PPV of surveillance PET evaluated with/without CT-derived measurements were compared. RESULTS: Seventy surveillance FDG-PET/CT scans performed in 53 patients were interpreted as positive for relapse. Of these studies 25 (36%) were defined as true-positive (TP) and 45 (64%) as FP. Multivariate analysis found long or short axis measuring ≥ 1.5 and ≥ 1.0 cm, respectively, in PET-positive sites, International Prognostic Index (IPI) ≥ 2, lack of prior rituximab therapy and FDG uptake in a previously involved site, to be independent predictors of true positive surveillance PET (odds ratio 5.4, 6.89, 6.6, 4.9, P < 0.05 for all). CONCLUSIONS: PPV of surveillance PET/CT may be improved by its use in selected high risk DLBCL patients and combined assessment of PET and CT findings.

Endovascular infection following inferior vena cava (IVC) filter insertion.

Inferior vena cava filter (IVC) placement is increasing significantly. However, due to low retrieval rates, many filters are left in place indefinitely thereby exposing patients to long-term filter-related complications. This study reports a series of three patients with IVC filter infection. Cases were identified during retrospective review of medical records of all patients undergoing an IVC filter insertion at a single tertiary care university hospital between 2009 and 2013. Clinical presentation, radiological features and management are discussed. Two patients presented within days of filter placement, while the other one presented 1 year later. In two patients, fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) was found to be a sensitive method to diagnose IVC filter infection. Endovascular infection of IVC filter is a rare event. In patients with IVC filter in place and fever of unknown origin or persistent bacteremia, this complication should be suspected. FDG PET/CT has a diagnostic value in this challenging diagnosis.

A deep penetrating facial congenital melanocytic tumor with bone involvement and ipsilateral eye blindness.

Bone involvement has been described in tumors with melanocytic differentiation such as melanotic neuroectodermal tumor of infancy, and very rarely in cellular blue nevi and neurocristic cutaneous hamartoma. We present an unusual case of facial congenital melanocytic tumor that involved the underlying bones and maxillary sinus and led to unilateral blindness. A newborn with a large red bluish patch with peripheral brown and black macules overlying marked swelling on the left side of his face was presented. The tumor was shown by magnetic resonance imaging, scintigraphy, and histopathology to invade the underlying bones and maxillary sinus and to compress the left eyeball resulting in blindness. Histopathology, immunohistochemistry, morphometric computerized microscopy, molecular genetic mutation analysis, and fluorescent in situ hybridization studies were more congruent with a melanocytic nevus. An 8.5-year follow-up was uneventful, with spontaneous partial shrinkage of the tumor.

Hodgkin lymphoma patients in first remission: routine positron emission tomography/computerized tomography imaging is not superior to clinical follow-up for patients with no residual mass.

There is no consensus regarding optimal follow-up mode for Hodgkin lymphoma (HL) patients that achieve complete remission following chemotherapy or combined chemo- and radiation therapy. Several studies demonstrated high sensitivity of positron emission tomography/computerized tomography (PET/CT) in detecting disease progression; however, these techniques are currently not recommended for routine follow-up. This retrospective study conducted in two Israeli (N = 291) and one New Zealand academic centres (N = 77), compared a group of HL patients, followed-up with routine imaging every 6 months during the first 2 years after achieving remission, once in the third year, with additional dedicated studies performed due to symptoms or physical findings (Group I) to a group of patients without residual masses who underwent clinically-based surveillance with dedicated imaging upon relapse suspicion (Group II). Five-year overall survival (OS) was 94% and median time to relapse was 8·6 months for both modes. Relapse rates in Groups I and II were 13% and 9%, respectively. During the first 3 years of follow-up, 47·5 and 4·7 studies were performed per detected relapse in Groups I and II, respectively. The current study demonstrated no benefit in either progression-free survival (PFS) or OS in HL patients followed by routine imaging versus clinical follow-up. The cost was 10 times higher for routine imaging.

Targeted therapy with low doses of 131I-MIBG is effective for disease palliation in highly refractory neuroblastoma.

BACKGROUND: Palliative treatment ore remains a significant clinical problem. OBJECTIVES: To retrospectively determine the clinical response to 131I-MIBG therapy at low doses in patients with refractory neuroblastoma. METHODS: We performed a retrospective chart review of 10 patients with neuroblastoma treated with 1311-MIBG at Rambam Health Care Campus from 1994 to 2012. Clinical data, number of 131I-MIBG courses delivered, toxicities, and clinical responses were reviewed. MIBG scan was performed after each course. RESULTS: Twenty-one courses of 131I-MIBG were delivered to 10 patients (3 girls, 7 boys). Their mean age was 3.8 years (range 1.5-6 years). All patients received several protocols of chemotherapy including the high dose form. Three patients received three courses of 131I-MIBG with a minimum of 6 weeks between each course, five patients received two courses, and two patients received only one course. An objective response to the first course was obtained in nine patients and to the second course in six of eight, and in three children who underwent the third course the pain decreased. One patient has no evidence of disease, four are alive with disease, and five died of the disease. No unanticipated toxicities were observed. CONCLUSIONS: Low dose 131I-MIBG is an effective and relatively non-toxic treatment in neuroblastoma disease palliation. Rapid and reproducible pain relief with 131I-MIBG was obtained in most of the children. Treatment with systemic radiotherapy in the form of low dose 131I-MIBG was easy to perform and effective in cases of disseminated neuroblastoma, demonstrating that this primary therapy can be used for palliative purposes.

Strikingly high false positivity of surveillance FDG-PET/CT scanning among patients with diffuse large cell lymphoma in the rituximab era.

Predictive value (PV) of surveillance fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy-rituximab (R) versus chemotherapy only, remains unclear. The aim of the current study was to compare the performance of surveillance PET in DLBCL patients receiving CHOP (cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, and prednisone) alone versus CHOP-R. Institutional database was retrospectively searched for adults with newly diagnosed DLBCL, receiving CHOP or CHOP-R, who achieved complete remission and underwent surveillance PETs. Follow-up (FU) PET was considered positive for recurrence in case of an uptake unrelated to physiological or known benign process. Results were confirmed by biopsy, imaging and clinical FU. One hundred nineteen patients, 35 receiving CHOP and 84 CHOP-R, who underwent 422 FU-PETs, were analyzed. At a median PET-FU of 3.4 years, 31 patients relapsed (17 vs. 14, respectively; P = 0.02). PET detected all relapses, with no false-negative studies. Specificity and positive PV (PPV) were significantly lower for patients receiving CHOP-R vs. CHOP (84% vs. 87%, P = 0.023; 23% vs. 74%, P < 0.0001), reflecting a higher false-positive (FP) rate in subjects receiving CHOP-R (77% vs. 26%, P < 0.001). In the latter group, FP-rate remained persistently high up to 3 years post-therapy. Multivariate analysis confirmed rituximab to be the most significant predictor for FP-PET. In conclusion, routine surveillance FDG-PET is not recommended in DLBCL treated with rituximab; strict criteria identifying patients in whom FU-PET is beneficial are required.

A 10-year experience with treatment of high and standard risk Hodgkin disease: six cycles of tailored BEACOPP, with interim scintigraphy, are effective and female fertility is preserved.

Therapy of Hodgkin lymphoma (HL) is designed to prolong survival and minimize toxicity. A total of 124 patients with newly diagnosed HL and adverse prognostic factors were prospectively studied between July, 1999 and August, 2005. Patients with early unfavorable and advanced disease were eligible for the study. Patients were assigned to therapy based on international prognostic score (IPS). Those with IPS ≥ 3 received three cycles of escalated BEACOPP (EB). All others received two cycles of standard BEACOPP (SB). Subsequent therapy was prospectively assigned according to early interim GA(67) or positron emission tomography (PET)/computerized tomography (CT). Four cycles of EB or SB were administered following a positive or negative scan, respectively. Complete remission rate, 10-year progression free (PFS), and overall survival (OS) were 97, 87, and 88%, respectively, at a median follow-up of 89 months (5-144). PFS and OS were similar in both groups. Fertility status was assessed in 38 females aged <40 years; 94% of females younger than 40 years preserved their cyclic ovarian function. Nineteen conceived during follow-up for 30 pregnancies, delivering 24 babies. Deliveries were reported up to 7 years from diagnosis. Predictive value of negative interim Ga(67) or PET/CT was 87 and 93%, respectively. Six cycles of tailored BEACOPP, for patients with adverse prognostic factors, provide encouraging long-term PFS and OS, and fertility is preserved in most females.