Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors.

BACKGROUND: Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic properties of GDC-0575 alone and in combination with gemcitabine. Antitumor activity and Chk1 pathway modulation were assessed. PATIENTS AND METHODS: In this phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose. Patients in arm 2 received either i.v. gemcitabine 1000 mg/m2 (arm 2a) or 500 mg/m2 (arm 2b), followed by GDC-0575 (45 or 80 mg, respectively, as RP2D). Stage II enrolled disease-specific cohorts. RESULTS: Of 102 patients treated, 70% were female, the median age was 59 years (range 27-85), and 47% were Eastern Cooperative Oncology Group PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2 hours of dosing, and half-life was ∼23 hours. No pharmacokinetic drug-drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were four confirmed partial responses, three occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2. CONCLUSION: GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine; however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary antitumor activity was observed but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine. CLINICAL TRIAL NUMBER: NCT01564251.

CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer.

BACKGROUND: A phase I/II study and subsequent phase III study (MPACT) reported significant correlations between CA19-9 decreases and prolonged overall survival (OS) with nab-paclitaxel plus gemcitabine (nab-P + Gem) treatment for metastatic pancreatic cancer (MPC). CA19-9 changes at week 8 and potential associations with efficacy were investigated as part of an exploratory analysis in the MPACT trial. PATIENTS AND METHODS: Untreated patients with MPC (N = 861) received nab-P + Gem or Gem alone. CA19-9 was evaluated at baseline and every 8 weeks. RESULTS: Patients with baseline and week-8 CA19-9 measurements were analyzed (nab-P + Gem: 252; Gem: 202). In an analysis pooling the treatments, patients with any CA19-9 decline (80%) versus those without (20%) had improved OS (median 11.1 versus 8.0 months; P = 0.005). In the nab-P + Gem arm, patients with (n = 206) versus without (n = 46) any CA19-9 decrease at week 8 had a confirmed overall response rate (ORR) of 40% versus 13%, and a median OS of 13.2 versus 8.3 months (P = 0.001), respectively. In the Gem-alone arm, patients with (n = 159) versus without (n = 43) CA19-9 decrease at week 8 had a confirmed ORR of 15% versus 5%, and a median OS of 9.4 versus 7.1 months (P = 0.404), respectively. In the nab-P + Gem and Gem-alone arms, by week 8, 16% (40/252) and 6% (13/202) of patients, respectively, had an unconfirmed radiologic response (median OS 13.7 and 14.7 months, respectively), and 79% and 84% of patients, respectively, had stable disease (SD) (median OS 11.1 and 9 months, respectively). Patients with SD and any CA19-9 decrease (158/199 and 133/170) had a median OS of 13.2 and 9.4 months, respectively. CONCLUSION: This analysis demonstrated that, in patients with MPC, any CA19-9 decrease at week 8 can be an early marker for chemotherapy efficacy, including in those patients with SD. CA19-9 decrease identified more patients with survival benefit than radiologic response by week 8.

Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody-drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer.

BACKGROUND: MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody-drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). PATIENTS AND METHODS: This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3-3.2 mg/kg) or weekly (Q1W, 0.8-1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken. RESULTS: Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC. CONCLUSIONS: DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required. CLINICAL TRIAL NUMBER: NCT01335958.

A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors.

Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors.

BACKGROUND: This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity. PATIENTS AND METHODS: A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle. RESULTS: Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug-drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%). CONCLUSIONS: This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.

Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial.

BACKGROUND: Pyrexia is a frequent adverse event with combined dabrafenib and trametinib therapy (CombiDT), but little is known of its clinical associations, etiology, or appropriate management. PATIENTS AND METHODS: All patients on the BRF133220 phase I/II trial of CombiDT treated at the standard dose (150/2) were included for assessment of pyrexia (n = 201). BRAF and MEK inhibitor-naïve patients (n = 117) were included for efficacy analyses. Pyrexia was defined as temperature ≥38°C (≥100.4(°)F) or related symptoms. RESULTS: Fifty-nine percent of patients developed pyrexia during treatment, 24% of which had pyrexia symptoms without a recorded elevation in body temperature. Pyrexia was grade 2+ in 60% of pyrexia patients. Median time to onset of first pyrexia was 19 days, with a median duration of 9 days. Pyrexia patients had a median of two pyrexia events, but 21% had three or more events. Various pyrexia management approaches were conducted in this study. A trend was observed between dabrafenib and hydroxy-dabrafenib exposure and pyrexia. No baseline clinical characteristics predicted pyrexia, and pyrexia was not statistically significantly associated with treatment outcome. CONCLUSIONS: Pyrexia is a frequent and recurrent toxicity with CombiDT treatment. No baseline features predict pyrexia, and it is not associated with clinical outcome. Dabrafenib and metabolite exposure may contribute to the etiology of pyrexia. The optimal secondary prophylaxis for pyrexia is best studied in a prospective trial.

Intermittent dosing of axitinib combined with chemotherapy is supported by (18)FLT-PET in gastrointestinal tumours.

BACKGROUND: We evaluated week-on/week-off axitinib dosing plus chemotherapy in patients with gastrointestinal tumours, including tumour thymidine uptake by fluorine-18 3'-deoxy-3'-fluorothymidine positron emission tomography ((18)FLT-PET). METHODS: During a lead-in period, patients received twice daily (b.i.d.) axitinib 7 mg (n=3) or 10 mg (n=18) for 7 days followed by a 7-day dosing interruption; serial (18)FLT-PET scans were performed before day 1 and on days 7, 10, and 14. Axitinib plus FOLFIRI or FOLFOX was then administered in 2-week cycles; axitinib was interrupted on day 10 of each cycle for 7 days. RESULTS: The maximum tolerated dose of axitinib was 10 mg b.i.d., in a week-on/week-off schedule, combined with FOLFIRI or FOLFOX. Common all-causality grade 3 adverse events were neutropenia (38%), hypertension (33%), and fatigue (29%). Of 21 patients, 2 (10%) had a partial response and 12 (57%) had stable disease. Following 7 days of continuous axitinib dosing, tumour (18)FLT uptake decreased -49% from baseline and recovered to -28% and -17% from baseline, respectively, after 3 and 7 days of axitinib interruption. CONCLUSION: Axitinib administered in a week-on/week-off schedule combined with FOLFIRI or FOLFOX is supported by (18)FLT-PET data and was well tolerated in patients with gastrointestinal tumours.

Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies.

BACKGROUND: We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics. METHODS: Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m(-2))/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate. RESULTS: Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months). CONCLUSIONS: Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m(-2) in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance.

A phase I/II study of lenalidomide in combination with sunitinib in patients with advanced or metastatic renal cell carcinoma.

BACKGROUND: This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide plus sunitinib in metastatic renal cell carcinoma (RCC) patients. PATIENTS AND METHODS: Patients with histologically confirmed, metastatic RCC were treated with 10 mg/day lenalidomide plus 37.5 mg/day sunitinib, orally in 21-day cycles. Doses were escalated to determine the MTD in phase I, with additional patients planned at this dose in phase II. Primary end points were MTD and response rate. RESULTS: Sixteen patients received a median of 2, 3, and 5 cycles in cohort 1 [lenalidomide 10 mg (days 1-21) and sunitinib 37.5 mg (days 1-21)], cohort 2 [lenalidomide 10 mg (days 1-21) and sunitinib 37.5 mg (days 1-14)], and cohort 3 [lenalidomide 15 mg (days 1-21) and sunitinib 37.5 mg (days 1-14)], respectively. Median treatment durations were 41, 63, and 97 days for lenalidomide; and 41, 57, and 97.5 days for sunitinib. The MTD was found to be continuous dosing of lenalidomide 10 mg/day plus sunitinib 37.5 mg/day for 14 of 21 days. Dose-limiting toxicities included neutropenia, leukopenia, thrombocytopenia, asthenia, atrial fibrillation, and increased transaminases. The most frequent grade 3-4 treatment-emergent adverse events were hematologic, including neutropenia and leukopenia. One patient achieved partial response, and seven had stable disease of which three were confirmed at subsequent tumor assessments. B cells and several T-cell subsets were modulated versus baseline. CONCLUSION: The dose schedules of lenalidomide and sunitinib evaluated in this study were not well tolerated; cumulative toxicity precluded enrollment at the MTD.

A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors.

BACKGROUND: Tivantinib (ARQ 197) is an orally available, non-adenosine triphosphate competitive, selective c-MET inhibitor. The primary objective of this study was to evaluate the safety, tolerability and to establish the recommended phase II dose (RP2D) of tivantinib and gemcitabine combination. PATIENTS AND METHODS: Patients with advanced or metastatic solid tumors were treated with escalating doses of tivantinib (120-360 mg capsules) in combination with gemcitabine (1000 mg/m(2) weekly for 3 of 4 weeks). Different schedules of administration were tested and modified based on emerging preclinical data. Tivantinib was given continuously, twice a day (b.i.d.) for 2, 3 or 4 weeks of a 28-day cycle or on a 5-day on, 2-day off schedule (the day before and day of gemcitabine administration). RESULTS: Twenty-nine patients were treated with gemcitabine and escalating doses of tivantinib: 120 mg b.i.d. (n = 4), 240 mg b.i.d. (n = 6) and 360 mg b.i.d. (n = 19). No dose-limiting toxicities were observed in escalation. The RP2D was 360 mg b.i.d. daily, and 45 additional patients were enrolled in the expansion cohort. Grade ≥3 treatment-related toxicities were observed in 54 of 74 (73%) patients with the most common being neutropenia (43%), anemia (30%), thrombocytopenia (28%) and fatigue (15%). There was one treatment-related death due to neutropenia. Administration of gemcitabine did not affect tivantinib concentration. Fifty-six patients were assessable for response. Eleven (20%) patients achieved a partial response and 26 (46%) had stable disease (SD), including 15 (27%) who achieved SD for over 4 months. Ten of 37 patients with clinical benefit had prior exposure to gemcitabine. CONCLUSION: The combination of tivantinib at its monotherapy dose and standard dose gemcitabine was safe and tolerable. Early signs of antitumor activity may warrant further development of this combination in nonsmall-cell lung cancer, ovarian, pancreatic and cholangiocarcinoma. CLINICALTRIALSGOV IDENTIFIER: NCT00874042.

Determination of fundic accommodation in gastric emptying scintigraphy. Evaluation of its clinical usefulness.

AIM: Gastric emptying scintigraphy is used to assess patients with symptoms of dyspepsia or gastroparesis. An alteration of fundus accommodation may explain these symptoms. The aim of this study was to determine the accommodation in gastric emptying scintigraphy studies performed in our institution. MATERIAL AND METHODS: 50 patients (43 children) referred for gastric emptying assessment were evaluated. After fasting for 8 h, and following international guidelines, egg labeling was performed with 37 mBq of [99mTc]Tc-DTPA and administration of standardized food. Areas of interest were defined in the stomach at different times, and the corresponding retention percentages were calculated. Considering the image at time zero, gastric accommodation was qualitatively and quantitatively assessed, calculating the ratio between proximal stomach counts and total counts. RESULTS: Of the 50 patients studied, 32 had normal emptying, 10 had slowed emptying and 8 had accelerated emptying. Within the group of patients with normal emptying, 8 had altered accommodation (25%) and another 8 in the group with abnormal emptying (44%). Applying the ROC curve analysis to quantitative values, the most appropriate cut-off value was 0.785 with p < 0.001, sensitivity 82.4% and specificity 100%. CONCLUSION: Gastric emptying scintigraphy in addition to determining motility, made it possible to assess both qualitatively and quantitatively the distribution of the radiotracer in the stomach and thus, indirectly, the accommodation in the fundus. It provided added diagnostic information in a simple manner, without protocol changes and allowing more specific treatments to be assessed.

Utility of gastrointestinal transit scintigraphy in the evaluation of chronic constipation.

AIM: Chronic constipation is a common pathology in clinical practice. In the absence of response to treatment, assessment of gastrointestinal function is recommended. This can be performed by scintigraphy, although its use is not widespread. The aim of this paper was to assess the utility of gastrointestinal transits scintigraphy in patients with chronic constipation. MATERIAL AND METHODS: Twenty patients (13 children) sent for scintigraphy for chronic constipation refractory to treatment, syringomyelia, rectocele or abdominal migraine were evaluated. All underwent clinical assessment, analytical determination, radiological imaging and/or rectal biopsy. A complete study protocol was performed, including gastric emptying, small bowel and colonic transits scintigraphy. For this, a dose of [111In]In-DTPA diluted in water (37MBq) was administered together with standardized food. Following international guidelines, regions of interest were defined in the stomach, terminal ileum and different regions of the large intestine to calculate the geometric center as a measure of progression. RESULTS: Of the 13 pediatric patients, 10 had abnormal gammagraphic patterns, with treatment being modified in 8 of them. Most of the children showed no alterations on radiological explorations. In adult patients, the results of the test changed the therapeutic management in all of them. CONCLUSIONS: Scintigraphic study provided useful information in the study of chronic constipation, influencing the diagnosis and therapeutic management of the patient. The physiological and quantitative information it provides allows both global and regional of gastrointestinal transit time determination.

Prognostic value of PERCIST and PET/CT metabolic parameters after neoadjuvant treatment in patients with esophageal cancer.

AIM: To assess the clinical utility of PERCIST criteria and changes in [18F]FDG PET/CT quantitative parameters as prognostic factors for progression-free survival and cancer-specific survival (CSS) in patients with esophageal cancer treated by chemoradiotherapy. MATERIAL AND METHODS: Fifty patients (48 men) diagnosed with esophageal cancer were retrospectively evaluated over a 7.5-year interval. PERCIST criteria were used to assess response to neoadjuvant therapy. Variations in the metabolic parameters maximum SUV (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) between pre- and post-treatment PET/CT studies were also determined. ROC curves, Kaplan-Meier method and Cox regression model were used for the analysis of prognostic factors and survival curves. RESULTS: The average follow-up was 26.8 months, with 40 recurrences-progressions and 41 deaths. Survival analysis showed statistically significant differences in CSS curves for PERCIST criteria and variation of MTV and TLG. PERCIST criteria were the only independent predictor in the multivariate analysis. Neither SUVmax nor tumor size were predictors for any of the assessment criteria. CONCLUSION: Application of PERCIST criteria as well as change in MTV and TLG from PET/CT studies proved to be prognostic factors for CSS in patients in our setting treated for esophageal cancer. The results could help to personalize treatment.

Baseline 18F-FDG PET/CT quantitative parameters as prognostic factors in esophageal squamous cell cancer.

AIM: To determine the utility of [18F]FDG PET/CT quantitative parameters as prognostic factors for the response to neoadjuvant treatment, progression-free survival (PFS) and cancer-specific survival (CSS) in patients with esophageal squamous cell carcinoma (SCC). MATERIAL AND METHODS: Thirty patients (29 men) diagnosed with SCC were retrospectively evaluated over a 6-year interval. Metabolic parameters were determined: maximum SUV (SUVmax), mean SUV (SUVmed), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) from baseline PET/CT study. After treatment with chemotherapy and/or radiotherapy, response to treatment and patient survival were assessed. The comparison of parameters between groups of responders and non-responders was carried out using a Mann-Whitney U test ROC curves and the Kaplan-Meier method were used for analysis of prognostic factors and survival curves. RESULTS: The average follow-up was 22.4 months, with 22 recurrence-progressions and 25 deaths. Significant differences were demonstrated between responders and non-responders with respect to tumor size, MTV and TLG. Survival analysis found significant differences for SCE and CSS depending on these three parameters. CONCLUSION: Metabolic parameters MTV and TLG, and tumor size were prognostic factors for neoadjuvant treatment response, PFS, and CSS in patients diagnosed with SCC. Neither SUVmax nor SUVmed were predictive for any of the evaluation criteria. Results could help to personalize patient treatment.

Baseline 18F-FDG PET/CT quantitative parameters as prognostic factors in esophageal squamous cell cancer. / Parámetros cuantitativos de la PET/TC basal con 18F-FDG como factores pronósticos en el carcinoma de células escamosas de esófago.

AIM: To determine the utility of 18F-FDG PET/CT quantitative parameters as prognostic factors for the response to neoadjuvant treatment, progression-free survival (PFS) and cancer-specific survival (CSS) in patients with esophageal squamous cell carcinoma (SCC). MATERIAL AND METHODS: Thirty patients (29 men) diagnosed with SCC were retrospectively evaluated over a 6-year interval. Metabolic parameters were determined: maximum SUV (SUVmax), mean SUV (SUVmed), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) from baseline PET/CT study. After treatment with chemotherapy and/or radiotherapy, response to treatment and patient survival were assessed. The comparison of parameters between groups of responders and non-responders was carried out using a Mann-Whitney U test. ROC curves and the Kaplan-Meier method were used for analysis of prognostic factors and survival curves. RESULTS: The average follow-up was 22.4months, with 22 recurrence-progressions and 25 deads. Significant differences were demonstrated between responders and non-responders with respect to tumor size, MTV and TLG. Survival analysis found significant differences for SCE and CSS depending on these three parameters. CONCLUSION: Metabolic parameters MTV and TLG, and tumor size were prognostic factors for neoadjuvant treatment response, PFS, and CSS in patients diagnosed with SCC. Neither SUVmax nor SUVmed were predictive for any of the evaluation criteria. Results could help to personalize patient treatment.

[Spinal osteoblastoma resection through radioguided surgery]. / Extirpación de un osteoblastoma vertebral mediante cirugía radiodirigida.

Osteoblastoma is an uncommon primary neoplasm of the bone, with histological manifestations similar to osteoid osteoma. Approximately 40% of them are located in the spine, usually involving the posterior structures. This location may be associated with scoliosis and neurologic manifestations. Diagnostic imaging includes simple X-ray, CT scan, MRI and radionuclide studies. Bone scintigraphy demonstrates an increased radiotracer accumulation. The standard treatment consists of open intralesional resection. Nevertheless, localization of nidus may be difficult and bone resection may be limited due to the proximity of the neural structures. We present the case of a patient with a spinal osteoblastoma in whom the use of radioguided surgery was performed through gamma probe and mini gamma camera. This technique made it possible to accurately locate the tumor and perform an effective removal of the nidus.

18F-FDG PET/CT quantitative parameters as prognostic factor in localized and inoperable lung cancer. / Parámetros cuantitativos de la PET/TC con 18F-FDG como factores pronósticos en el cáncer de pulmón localizado e inoperable.

AIM: To assess the utility of 18F-FDG PET/CT quantitative parameters as prognostic factor in patients diagnosed with localized and inoperable lung cancer treated by stereotactic body radiotherapy (SBRT). MATERIAL AND METHODS: Fifty patients (42 men) diagnosed in the last 7years with early-stage lung cancer and treated with SBRT alone were assessed by a prospective study. After PET/CT study, metabolic parameters maximum SUV (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were determined at different thresholds. The prognostic factors for overall survival (OS), cause-specific survival (CS) and disease-free survival (DFS) were analysed by Cox proportional hazards model and the survival analysis by Kaplan-Meier method. RESULTS: The average follow-up was 39.6months, with 21 recurrences and 24 dead. Univariate analysis determined MTV30 and MTV40 as predictors for OS; MTV30, MTV40, TLG30 and TLG40 for CS, and MTV2, MTV30, MTV40, TLG2, TLG30 and TLG40 for DFS. Survival analysis found statistically significant differences for CS and DFS depending on tumor size and for DFS considering the cut-off values of MTV2 and TLG2 (threshold SUVmax=2). SUVmax, age and sex were not shown to be significant factors. CONCLUSION: Pre-treatment quantitative assessment using metabolic parameters MTV2 and TLG2 as well as tumor size proved to be prognostic factors in patients diagnosed with localized and inoperable lung cancer treated by SBRT. Results could help to personalize treatment.

[Neurolymphomatosis: diagnosis of extension and assessment of response to treatment with PET-CT]. / Neurolinfomatosis: diagnóstico de extensión y valoración de la respuesta al tratamiento mediante PET-TAC.

Neurolymphomatosis is a rare neurological manifestation of non-Hodgkin's lymphoma (NHL) and it may be its first and sole manifestation. Diagnosis is often difficult and nerve biopsy is generally required. However, this it is not always possible to perform or is not conclusive. We present the case of a 66-year-old woman diagnosed with giant B-cell NHL. After 6 cycles of chemotherapy, imaging and molecular biology techniques showed complete remission. At four months after treatment, the patient complained of low back pain of radicular distribution. CT and MRI imaging showed signs of lymphoproliferative activity of L5 and also lesions to thoracic nerve roots. A PET-CT was requested in order to complete the diagnosis and plan the treatment. Imaging confirmed the presence of tumor recurrence with neurolymphomatosis and also indicated lesions on the chest and abdominal level. Thus, it was decided to start a new line of chemotherapy, without performing the histological study through biopsy. This case illustrates the important role played by PET-CT imaging in neurolymphomatosis diagnosis. This technique can help the patient avoid more aggressive procedures, such as a biopsy, and can also be useful in the follow-up and assessment of the treatment response to NHL-diagnosed patients.

Gastrointestinal transit scintigraphy in chronic constipation evaluation in pediatric age; an infrequent test. / Gammagrafía de tránsito gastrointestinal en el estudio del estreñimiento crónico en edad pediátrica; una exploración infrecuente.

AIM: Chronic constipation is a common pathology in children. The aim of this paper was to show the usefulness of gastrointestinal transit scintigraphy in pediatric patients with chronic constipation, and the advantages with respect to other imaging techniques, despite our limited experience. MATERIAL AND METHODS: We evaluated 5 patients sent to our service with a diagnosis of chronic constipation refractory to treatment. We performed a complete study protocol, including liquid gastric emptying scintigraphy and small and large bowel transit times, using a single dose of 111In-DTPA. Following international guidelines regions of interest were defined in stomach, terminal ileum and in 6 regions of the large intestine. RESULTS: All patients showed altered scintigraphy study, showing 4 of them normal radiological tests. Radioisotopic study changed diagnosis in 2 patients and in other 2 patients contributed to clarify it, since discordance between normal radiological tests and abnormal rectal biopsy. One of the patients showed concordance between each imaging modality. The results of the test changed the therapeutic management in 2 cases. CONCLUSIONS: Our limited experience coincides with published data in which scintigraphy study turns out to be a reproducible and accurate method. It provides physiological, quantitative and useful information in the study of constipation, being the unique exploration that allows both global and regional gastrointestinal transit time determination.

TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.

PURPOSE: This phase I trial evaluated the safety, pharmacokinetic profile, and antitumor activity of investigational oral TORC1/2 inhibitor TAK-228 plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. METHODS: Sixty-seven patients received TAK-228 6-40 mg via three dosing schedules; once daily for 3 days (QDx3d QW) or 5 days per week (QDx5d QW), and once weekly (QW) plus paclitaxel 80 mg/m2 (dose-escalation phase, n = 47) and with/without trastuzumab 2 mg/kg (expansion phase, n = 20). Doses were escalated using a modified 3 + 3 design, based upon dose-limiting toxicities in cycle 1. RESULTS: TAK-228 pharmacokinetics exhibited dose-dependent increase in exposure when dosed with paclitaxel and no apparent differences when administered with or 24 h after paclitaxel. Dose-limiting toxicities were dehydration, diarrhea, stomatitis, fatigue, rash, thrombocytopenia, neutropenia, leukopenia, and nausea. The maximum tolerated dose of TAK-228 was determined as 10-mg QDx3d QW; the expansion phase proceeded with 8-mg QDx3d QW. Overall, the most common grade ≥3 drug-related toxicities were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable patients, eight achieved partial response and six had stable disease lasting ≥6 months. CONCLUSION: TAK-228 demonstrated a safety profile consistent with other TORC inhibitors and promising preliminary antitumor activity in a range of tumor types; no meaningful difference was noted in the pharmacokinetics of TAK-228 when administered with or 24 h after paclitaxel. These findings support further investigation of TAK-228 in combination with other agents including paclitaxel, with/without trastuzumab, in patients with advanced solid tumors. CLINICALTRIALS. GOV IDENTIFIER: NCT01351350.