Division of Haematology, Dept. of Hematology, Niguarda Ca' Granda Hospital, Piazza Ospedale Maggiore 3, 20162 Milan, Italy. miccaimi@tin.it
BACKGROUND AND OBJECTIVES: The incidence of invasive ...filamentous fungal infections in hematologic patients is increasing as a consequence of high dose chemotherapy and bone marrow transplant procedures. Mortality is usually very high. The diagnosis is often difficult and yet a fast, accurate diagnosis is of fundamental importance for treating the infection and planning subsequent management of the hematologic disease. We evaluated the sensitivity of computed tomography (CT)-guided percutaneous biopsy in diagnosing pulmonary fungal infections. DESIGN AND METHODS: Between 1997 and 2002 we performed 17 CT-guided percutaneous transthoracic lung biopsies in 17 hematologic patients with suspected filamentous fungi infection with negative BAL, to obtain a certain diagnosis and to know what species of fungi was responsible for infection. In all cases suspected mycosis began during the post-chemotherapy aplastic period. Patients were receiving antifungal therapy at the time of all biopsies. When the platelet count rose above 50 x 10(9)/L, CT-guided percutaneous lung biopsy with fine-needle aspiration for cytology was performed. RESULTS: Twelve of 17 patients had histologic confirmation of the fungal infection (70.5%), 8 with Aspergillus spp. 4 with Mucorales spp. Biopsies provided non-specific results in 4 cases; in 2 of these cases, clinical course and response to therapy confirmed the diagnosis of mycosis; in the last case bronchoalveolar carcinoma was found as a new diagnosis. Cultures were positive in only 6 cases, all for Aspergillus spp. The sensitivity of CT-guided percutaneous lung biopsy was 70.6% and its positive predictive value (PPV) was 100%. This procedure provided an immediate diagnosis and only one side-effect (1 pneumothorax, without complications). INTERPRETATION AND CONCLUSIONS: Histologic discrimination between aspergillosis and mucormycosis is very important for deciding secondary prophylaxis during transplant procedures, because Mucor is usually resistant to azoles.
Colorectal cancer (CRC) has the second-highest tumor incidence and is a leading cause of death by cancer. Nearly 20% of patients with CRC will have metastases (mts) at the time of diagnosis, and more ...than 50% of patients with CRC develop metastases during their disease. Unfortunately, only 45% of patients after a chemotherapy will respond to treatment. The aim of this study is to develop and validate a machine learning algorithm to predict response of individual liver mts, using CT scans. Understanding which mts will respond or not will help clinicians in providing a more efficient per-lesion treatment based on patient specific response and not only following a standard treatment. A group of 92 patients was enrolled from two Italian institutions. CT scans were collected, and the portal venous phase was manually segmented by an expert radiologist. Then, 75 radiomics features were extracted both from 7x7 ROIs that moved across the image and from the whole 3D mts. Feature selection was performed using a genetic algorithm. Results are presented as a comparison of the two different approaches of features extraction and different classification algorithms. Accuracy (ACC), sensitivity (SE), specificity (SP), negative and positive predictive values (NPV and PPV) were evaluated for all lesions (per-lesion analysis) and patients (per-patient analysis) in the construction and validation sets. Best results were obtained in the per-lesion analysis from the 3D approach using a Support Vector Machine as classifier. We reached on the training set an ACC of 81%, while on test set, we obtained SE of 76%, SP of 67%, PPV of 69% and NPV of 75%. On the validation set a SE of 61%, SP of 60%, PPV of 57% and NPV of 64% were reached. The promising results obtained in the validation dataset should be extended to a larger cohort of patient to further validate our method.Clinical Relevance- to develop a radiomics signatures predicting single liver mts response to therapy. A personalized mts approach is important to avoid unnecessary toxicity offering more suitable treatments and a better quality of life to oncological patients.
A Body Shape Index (ABSI) was specifically developed as a transformation of waist circumference (WC), statistically independent of BMI to better evaluate the relative contribution of WC to central ...obesity and clinical outcomes. Previous studies have found ABSI is associated with total mortality and cardiovascular events. However, no study has specifically evaluated the joint contribution of ABSI and BMI to cardio-metabolic outcomes (high triglycerides, low HDL, high fasting glucose and high blood pressure). With this aim, we performed a retrospective study on 6081 Caucasian adults. Subjects underwent a medical interview, anthropometric measurements, blood sampling, measurement of blood pressure, and measurement of visceral abdominal fat thickness (VAT) by ultrasound. Generalized linear models (GLM) were used to evaluate the sex and age adjusted association of ABSI with binary and continuous cardio-metabolic risk factors. Four pre-specified GLM were evaluated for each outcome: M1 = ABSI, BMI and ABSI*BMI interaction, M2 = ABSI and BMI, M3 = ABSI alone and M4 = BMI alone. Bayesian Information Criterion (BIC) was calculated and used to identify the best predictive model. ABSI and BMI contributed independently to all outcomes. Compared to BMI alone, the joint use of BMI and ABSI yielded significantly improved associations for having high triglycerides (BIC = 5261 vs. 5286), low HDL (BIC = 5371 vs. 5381), high fasting glucose (BIC = 6328 vs. 6337) but not high blood pressure (BIC = 6580 vs. 6580). The joint use of BMI and ABSI was also more strongly associated with VAT than BMI alone (BIC = 22930 vs. 23479). In conclusion, ABSI is a useful index for evaluating the independent contribution of WC, in addition to that of BMI, as a surrogate for central obesity on cardio-metabolic risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations ...restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926 ; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting.
Background
Radiomics is expected to improve the management of metastatic colorectal cancer (CRC). We aimed at evaluating the impact of liver lesion contouring as a source of variability on radiomic ...features (RFs).
Methods
After Ethics Committee approval, 70 liver metastases in 17 CRC patients were segmented on contrast-enhanced computed tomography scans by two residents and checked by experienced radiologists. RFs from grey level co-occurrence and run length matrices were extracted from three-dimensional (3D) regions of interest (ROIs) and the largest two-dimensional (2D) ROIs. Inter-reader variability was evaluated with Dice coefficient and Hausdorff distance, whilst its impact on RFs was assessed using mean relative change (MRC) and intraclass correlation coefficient (ICC). For the main lesion of each patient, one reader also segmented a circular ROI on the same image used for the 2D ROI.
Results
The best inter-reader contouring agreement was observed for 2D ROIs according to both Dice coefficient (median 0.85, interquartile range 0.78–0.89) and Hausdorff distance (0.21 mm, 0.14–0.31 mm). Comparing RF values, MRC ranged 0–752% for 2D and 0–1567% for 3D. For 24/32 RFs (75%), MRC was lower for 2D than for 3D. An ICC > 0.90 was observed for more RFs for 2D (53%) than for 3D (34%). Only 2/32 RFs (6%) showed a variability between 2D and circular ROIs higher than inter-reader variability.
Conclusions
A 2D contouring approach may help mitigate overall inter-reader variability, albeit stable RFs can be extracted from both 3D and 2D segmentations of CRC liver metastases.
BackgroundHER2 is a therapeutic target for metastatic colorectal cancer (mCRC), as demonstrated in the pivotal HERACLES-A (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification) trial ...with trastuzumab and lapatinib. The aim of HERACLES-B trial is to assess the efficacy of the combination of pertuzumab and trastuzumab-emtansine (T-DM1) in this setting.MethodsHERACLES-B was a single-arm, phase II trial, in patients with histologically confirmed RAS/BRAF wild-type and HER2+ mCRC refractory to standard treatments. HER2 positivity was assessed by immunohistochemistry and in situ hybridisation according to HERACLES criteria. Patients were treated with pertuzumab (840 mg intravenous load followed by 420 mg intravenous every 3 weeks) and T-DM1 (3.6 mg/kg every 3 weeks) until disease progression or toxicity. Primary and secondary end points were objective response rate (ORR) and progression-free survival (PFS). With a Fleming/Hern design (H0=ORR 10%; α=0.05; power=0.85), 7/30 responses were required to demonstrate an ORR ≥30% (H1).ResultsThirty-one patients, 48% with ≥4 lines of previous therapies, were treated and evaluable. ORR was 9.7% (95% CI: 0 to 28) and stable disease (SD) 67.7% (95% CI: 50 to 85). OR/SD ≥4 months was associated with higher HER2 immunohistochemistry score (3+ vs 2+) (p = 0.03). Median PFS was 4.1 months (95% CI: 3.6 to 5.9). Drug-related grade (G) 3 adverse events were observed in two patients (thrombocytopaenia); G≤2 AE in 84% of cycles (n = 296), mainly nausea and fatigue.ConclusionsHERACLES-B trial did not reach its primary end point of ORR; however, based on high disease control, PFS similar to other anti-HER2 regimens, and low toxicity, pertuzumab in combination with T-DM1 can be considered for HER2+mCRC as a potential therapeutic resource.Trial registration number2012-002128-33 and NCT03225937.
Both abdominal obesity and its visceral component are independently associated with cardiometabolic diseases. Among the non-modifiable and modifiable determinants, lifestyle plays a central role, ...while chronotype is an emerging factor. Evening type (E-Type), more active and efficient in the last part of the day, has been associated with a health-impairing style, resulting in a higher risk of obesity and cardiometabolic diseases than morning type (M-Type). However, no study has examined the contribution of chronotype to abdominal fat distribution, even considering adherence to the Mediterranean diet (MD). We conducted a cross-sectional study on 416 adults (69.5% females, 50 ± 13 years). Waist circumference (WC), visceral fat (VAT) using ultrasonography, chronotype through the reduced Morningness-Eveningness Questionnaire (rMEQ), and adherence to MD were studied. Our results showed no differences in WC and VAT between chronotypes. However, adherence to MD resulted significantly lower in the E-Types compared to M-Types. WC decreased with increasing Mediterranean score and rMEQ score, and VAT decreased with increasing rMEQ score, indicating that E-Types have +2 cm of WC and +0.5 cm of VAT compared to M-Types. In conclusion, these results showed that chronotype is independently associated with abdominal obesity and visceral fat, underlining the potential implications of the individual circadian typology on abdominal obesity.
Summary Background We previously found that dual HER2 blockade with trastuzumab and lapatinib led to inhibition of tumour growth in patient-derived xenografts of HER2 -amplified metastatic colorectal ...cancer. In this study, we aimed to assess the antitumour activity of trastuzumab and lapatinib in patients with HER2-positive colorectal cancer. Methods HERACLES was a proof-of-concept, multicentre, open-label, phase 2 trial done at four Italian academic cancer centres. We enrolled adult patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care (including cetuximab or panitumumab), an Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion. We defined HER2 positivity in tumour samples by use of immunohistochemistry and fluorescence in-situ hybridisation in accordance with our previously validated colorectal cancer-specific diagnostic criteria. Eligible patients received intravenous trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per week, and oral lapatinib at 1000 mg per day until evidence of disease progression. The primary endpoint was the proportion of patients achieving an objective response (defined as complete response or partial response), which was assessed by independent central review in the intention-to-treat population. This trial is registered with EudraCT, number 2012-002128-33. Findings Between Aug 27, 2012, and May 15, 2015, we screened 914 patients with KRAS exon 2 (codons 12 and 13) wild-type metastatic colorectal cancer and identified 48 (5%) patients with HER2-positive tumours, although two died before enrolment. Of these patients, 27 were eligible for the trial. All were evaluable for response. At the time of data cutoff on Oct 15, 2015, with a median follow-up of 94 weeks (IQR 51–127), eight (30%, 95% CI 14–50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI −3 to 11) achieving a complete response, and seven (26%, 95% CI 9–43) achieving partial responses; 12 (44%, 95% CI 25–63) patients had stable disease. Six (22%) of 27 patients had grade 3 adverse events, which consisted of fatigue in four patients, skin rash in one patient, and increased bilirubin concentration in one patient. No grade 4 or 5 adverse events were reported. We detected no drug-related serious adverse events. Interpretation The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive metastatic colorectal cancer. Funding Associazione Italiana Ricerca Cancro (AIRC), Fondazione Oncologia Niguarda Onlus, and Roche.
ERBB2 amplification occurs in 5% of RAS wild-type metastatic colorectal cancer (mCRC) and it has been shown to be a target for treatment with 2 HER2-directed combinations of trastuzumab and lapatinib ...or trastuzumab and pertuzumab. We present long-term clinical results of trastuzumab and lapatinib (HERACLES-A trial) at 6.7 years (82 months) follow-up and focus on central nervous system (CNS) recurrences.
Patients had histologically confirmed KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive mCRC. HER2 positivity was assessed by immunohistochemistry and in situ hybridization HERACLES diagnostic criteria. Patients were treated with intravenous trastuzumab 4 mg/kg loading dose, then 2 mg/kg once per week, and oral lapatinib 1000 mg per day until disease progression or toxicity. Patients who presented with symptoms or signs of CNS disease received brain computed tomography scan or magnetic resonance imaging.
A total of 35 patients received trastuzumab and lapatinib and 32 were evaluable for response. One patient (3%) achieved complete response (CR), 8 (25%) partial response, and 13 (41%) stable disease. Therefore, response rate was 28%. Median progression-free survival was 4.7 months (95% confidence interval CI 3.7–6.1). Median overall survival was 10.0 months (95% CI 7.9–15.8). One patient achieved sustained CR still maintained at 7 years of follow-up. Progression in the central nervous system (CNS) occurred in 6 (19%) of 32 patients.
Long-term (6.7 years) follow-up analysis of HERACLES-A supports using of trastuzumab and lapatinib as treatment reference for KRAS wild-type, chemorefractory HER2-positive mCRC. In this subset of patients, prolongation of survival is accompanied by CNS recurrences that will require diagnostic and therapeutic attention in future studies.
Clinicaltrials. Gov identifier: NCT 03225937.
ERBB2 amplification is a therapeutic target in 5% of patients with RAS wild-type metastatic colorectal cancer. At 6.7 years of follow-up, therapy with trastuzumab and lapatinib combination resulted in 28% objective response rate with 1 patient still in complete response, median 4.7 months progression-free survival, and 10.0 months overall survival. Progression in the central nervous system occurred in 19% of patients.
Background
Radiation dose in computed tomography (CT) has become a topic of high interest due to the increasing numbers of CT examinations performed worldwide. Hence, dose tracking and organ dose ...calculation software are increasingly used. We evaluated the organ dose variability associated with the use of different software applications or calculation methods.
Methods
We tested four commercial software applications on CT protocols actually in use in our hospital: CT-Expo, NCICT, NCICTX, and Virtual Dose. We compared dose coefficients, estimated organ doses and effective doses obtained by the four software applications by varying exposure parameters. Our results were also compared with estimates reported by the software authors.
Results
All four software applications showed dependence on tube voltage and volume CT dose index, while only CT-Expo was also dependent on other exposure parameters, in particular scanner model and pitch caused a variability till 50%. We found a disagreement between our results and those reported by the software authors (up to 600%), mainly due to a different extent of examined body regions. The relative range of the comparison of the four software applications was within 35% for most organs inside the scan region, but increased over the 100% for organs partially irradiated and outside the scan region. For effective doses, this variability was less evident (ranging from 9 to 36%).
Conclusions
The two main sources of organ dose variability were the software application used and the scan region set. Dose estimate must be related to the process used for its calculation.
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