Phase II study of capecitabine-based concomitant chemoradiation followed by durvalumab as a neoadjuvant strategy in locally advanced rectal cancer: the PANDORA trial.

BACKGROUND: This study investigated the efficacy of chemoradiotherapy (CRT) followed by durvalumab as neoadjuvant therapy of locally advanced rectal cancer. PATIENTS AND METHODS: The PANDORA trial is a prospective, phase II, open-label, single-arm, multicenter study aimed at evaluating the efficacy and safety of preoperative treatment with durvalumab (1500 mg every 4 weeks for three administrations) following long-course radiotherapy (RT) plus concomitant capecitabine (5040 cGy RT in 25-28 fractions over 5 weeks and capecitabine administered at 825 mg/m2 twice daily). The primary endpoint was the pathological complete response (pCR) rate; secondary endpoints were the proportion of clinical complete remissions and safety. The sample size was estimated assuming a null pCR proportion of 0.15 and an alternative pCR proportion of 0.30 (α = 0.05, power = 0.80). The proposed treatment could be considered promising if ≥13 pCRs were observed in 55 patients (EudraCT: 2018-004758-39; NCT04083365). RESULTS: Between November 2019 and August 2021, 60 patients were accrued, of which 55 were assessable for the study's objectives. Two patients experienced disease progression during treatment. Nineteen out of 55 eligible patients achieved a pCR (34.5%, 95% confidence interval 22.2% to 48.6%). Regarding toxicity related to durvalumab, grade 3 adverse events (AEs) occurred in four patients (7.3%) (diarrhea, skin toxicity, transaminase increase, lipase increase, and pancolitis). Grade 4 toxicity was not observed. In 20 patients (36.4%), grade 1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypothyroidism), dermatologic toxicity (skin rash), and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation). CONCLUSION: This study met its primary endpoint showing that CRT followed by durvalumab could increase pCR with a safe toxicity profile. This combination is a promising, feasible strategy worthy of further investigation.

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients - A GIRCG study.

BACKGROUND: Gastric gastrointestinal stromal tumors (GISTs) represent a subgroup of GISTs with a better prognosis than those located in other areas. In this retrospective study we performed a molecular characterization of a large series of patients with gastric GISTs in relation to clinical-pathological characteristics and prognosis. METHODS: DNA was extracted from paraffin-embedded sections from 221 gastric GIST patients submitted to surgery. Exons 9, 11, 13 and 17 of KIT, exons 12 and 18 of PDGFRA and exons 11 and 15 of BRAF were analyzed by direct sequencing. Cox regression analysis adjusted for clinical-pathological factors was performed to evaluate KIT and PDGFRA mutations in relation to the composite endpoint of relapse or death. RESULTS: KIT and PDGFRA mutations were observed in 119 (53.8%) and 56 (25.3%) patients, respectively, whereas 46 (20.8%) patients had wild type (wt) disease. Univariable analyses showed that a high Miettinen risk category and the presence of ulceration and KIT deletions were associated with increased risk of relapse or death (p < 0.001; p = 0.0389 and p = 0.002, respectively). After adjusting for Miettinen risk score, KIT deletions remained an independent prognostic factor (HRadj = 2.65, 95% CI [1.15-6.13], p = 0.023). Moreover, KIT deletions in exon 11 codons 557, 558 or 559 were associated with a higher risk of relapse or death than wt tumors (HRadj = 3.29 95% CI [1.64-6.64], p = 0.001). CONCLUSIONS: KIT deletions in exon 11, especially those involving codons 557, 558 or 559, were correlated with a more aggressive gastric GIST phenotype and increased risk of relapse or death.

Prediction bands and intervals for the scapulo-humeral coordination based on the Bootstrap and two Gaussian methods.

Quantitative motion analysis protocols have been developed to assess the coordination between scapula and humerus. However, the application of these protocols to test whether a subject's scapula resting position or pattern of coordination is "normal", is precluded by the unavailability of reference prediction intervals and bands, respectively. The aim of this study was to present such references for the "ISEO" protocol, by using the non-parametric Bootstrap approach and two parametric Gaussian methods (based on Student's T and Normal distributions). One hundred and eleven asymptomatic subjects were divided into three groups based on their age (18-30, 31-50, and 51-70). For each group, "monolateral" prediction bands and intervals were computed for the scapulo-humeral patterns and the scapula resting orientation, respectively. A fourth group included the 36 subjects (42 ± 13 year-old) for whom the scapulo-humeral coordination was measured bilaterally, and "differential" prediction bands and intervals were computed, which describe right-to-left side differences. Bootstrap and Gaussian methods were compared using cross-validation analyses, by evaluating the coverage probability in comparison to a 90% target. Results showed a mean coverage for Bootstrap from 86% to 90%, compared to 67-70% for parametric bands and 87-88% for parametric intervals. Bootstrap prediction bands showed a distinctive change in amplitude and mean pattern related to age, with an increase toward scapula retraction, lateral rotation and posterior tilt. In conclusion, Bootstrap ensures an optimal coverage and should be preferred over parametric methods. Moreover, the stratification of "monolateral" prediction bands and intervals by age appears relevant for the correct classification of patients.

Variance computations for functional of absolute risk estimates.

We present a simple influence function based approach to compute the variances of estimates of absolute risk and functions of absolute risk. We apply this approach to criteria that assess the impact of changes in the risk factor distribution on absolute risk for an individual and at the population level. As an illustration we use an absolute risk prediction model for breast cancer that includes modifiable risk factors in addition to standard breast cancer risk factors. Influence function based variance estimates for absolute risk and the criteria are compared to bootstrap variance estimates.

Neuropathy in multiple myeloma treated with thalidomide: a prospective study.

BACKGROUND: Thalidomide is effective as a first-line therapy for the treatment of multiple myeloma (MM), but its use is limited by peripheral neurotoxicity. OBJECTIVE: To study the occurrence of both myeloma-related neuropathy and thalidomide-induced neuropathy in 31 patients with newly diagnosed MM. METHODS: Clinical and electrophysiologic examinations were performed in 31 patients with newly diagnosed MM before and after 4 months of therapy with thalidomide (200 mg/day, total dose: 21 g) aimed at debulking MM, before autologous transplantation. After transplantation, the patients took thalidomide, 200 mg/day for another 3 months (total dose over three months: 18 g) and then underwent a final clinical and electrophysiologic checkup. RESULTS: At baseline, four patients presented a mild sensorimotor peripheral neuropathy related to MM, which tended to worsen slightly during treatment with thalidomide. At the end of treatment, 83% of the patients had clinical and electrophysiologic evidence of a mild sensory rather than motor, axonal, length-dependent polyneuropathy, whereas 100% of the patients showed improvement to the basic pathology (>or=partial response). CONCLUSIONS: Peripheral neuropathy, sometimes subclinical, and mild in our patients, is a common, early side effect of thalidomide therapy. The high doses (21 g) used in all patients for a relatively short time (4 months) rule out any correlations between neuropathy, total dose, and duration of treatment.