ALLIANCE A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer.

Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after neoadjuvant therapy may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes. Methods: In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N+) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (+/- 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 296 evaluable patients (148 per arm) will provide statistical power of 90.5% to detect an 17% increase in cCR rate, at a one-sided alpha=0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse effects. Biospecimens including archival tumor tissue, plasma and buffy coat in EDTA tubes, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and has a current accrual of 312. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Discussion: Building off of data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed the current trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer. Trial Registration: Clinicaltrials.gov ID: NCT05610163 ; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).

Magnifying chromoendoscopy is a reliable method in the selection of rectal neoplasms for local excision.

PURPOSE: Adequate staging of early rectal neoplasms is essential for organ-preserving treatments, but magnetic resonance imaging (MRI) frequently overestimates the stage of those lesions. We aimed to compare the ability of magnifying chromoendoscopy and MRI to select patients with early rectal neoplasms for local excision. METHODS: This retrospective study in a tertiary Western cancer center included consecutive patients evaluated by magnifying chromoendoscopy and MRI who underwent en bloc resection of nonpedunculated sessile polyps larger than 20 mm, laterally spreading tumors (LSTs) [Formula: see text] 20 mm, or depressed-type lesions of any size (Paris 0-IIc). Sensitivity, specificity, accuracy, and positive and negative predictive values of magnifying chromoendoscopy and MRI to determine which lesions were amenable to local excision (i.e., [Formula: see text] T1sm1) were calculated. RESULTS: Specificity of magnifying chromoendoscopy was 97.3% (95% CI 92.2-99.4), and accuracy was 92.7% (95% CI 86.7-96.6) for predicting invasion deeper than T1sm1 (not amenable to local excision). MRI had lower specificity (60.5%, 95% CI 43.4-76.0) and lower accuracy (58.3%, 95% CI 43.2-72.4). Magnifying chromoendoscopy incorrectly predicted invasion depth in 10.7% of the cases in which the MRI was correct, while magnifying chromoendoscopy provided a correct diagnosis in 90% of the cases in which the MRI was incorrect (p = 0.001). Overstaging occurred in 33.3% of the cases in which magnifying chromoendoscopy was incorrect and 75% of the cases in which MRI was incorrect. CONCLUSION: Magnifying chromoendoscopy is reliable for predicting invasion depth in early rectal neoplasms and selecting patients for local excision.

Serologic and histologic findings in patients with capsular contracture after breast augmentation with smooth silicone gel implants: is serum hyaluronan a potential predictor?

BACKGROUND: In this study, breast implant capsular tissues and blood samples from 25 cases were studied to characterize the relationship between capsular findings and serum analysis. The serum fibrosis indexes hyaluronan and the aminoterminal propeptide of procollagen type III (PIIINP) are fairly well correlated in several other studies with the inflammation grade and fibrosis in patients with progressive fibrotic disorders such as liver cirrhosis. METHODS: The study enrolled 25 female patients (average age, 40 +/- 12 years) with capsular contracture after bilateral cosmetic breast augmentation using smooth silicone gel implants (Mentor). The implants were placed in a submuscular position through an incision in the inframammary fold. The implant removals were prompted by development of capsular fibrosis (Baker grades 1-4). Samples of capsular tissue were obtained from all the patients for standard histologic and immunohistochemical analyses. Blood samples were drawn from all the patients immediately before surgery. Sera from 20 healthy female patients (average age, 34 +/- 9 years) who had undergone plastic surgery for reduction mammaplasty were used as controls. RESULTS: Histology. Capsular tissue was significantly thicker in patients with grades 3 and 4 contracture than in women with grade 2 contracture according the classification by Baker. There was a moderate (n = 15) or severe (n = 10) chronic inflammatory reaction in the capsules around the implants. Fibroblasts and macrophages represented the major cell population found in the fibrous capsules. In addition, activated CD4+ cells were detected. An inner layer with synovia-like metaplasia and multinucleated giant cells was found. Fibroblast-like cells formed the most common cell type in the capsules, along with macrophages, scattered polymorphonuclear leukocytes, lymphocytes, plasma cells, and mast cells. Serum analysis. There was a significantly higher level (p < 0.05) of hyaluronan serum concentration in patients with capsular contracture (26 +/- 14 microg/l) than in control subjects (12 +/- 6 microg/l). There was a positive correlation between the grade of capsular contracture (Baker 1-4) and the hyaluronan serum concentration (Baker 1-2: 15 +/- 3 microg/l; Baker 3-4: 35 +/- 12 microg/l) (r2 = 0.73; p < 0.05). CONCLUSION: : In this study, serum hyaluronan levels were significantly elevated in patients with constrictive fibrosis after breast augmentation, and there was a positive correlation with the stage of capsular contracture. Serum hyaluronan concentration may help in defining patients at risk for capsular fibrosis. If treatment with new drugs can be started as a preventive measure, it may be possible to reduce the rate of patients who require surgical intervention.

Is high PEEP low volume ventilation in burn patients beneficial? A retrospective study of 61 patients.

In burn care lung damage by inhalation injury is a major cause of mortality in burn patients. In the field of intensive care medicine ventilation strategies to reduce lung injury caused by ventilation are under investigation. The promising results of the application of pressure controlled high PEEP low volume (HPLV) ventilation prompted us to use this ventilation strategy in our burn ICU. To establish whether this ventilation regime is beneficial the charts of 61 consecutive patients needing artificial respiration were reviewed. A scoring system for PEEP level and tidal volume was developed and treatment groups with high PEEP and low volume and low PEEP high volume regimes were compared. No statistically significant differences could be found when comparing treatment versus mortality, the number of pulmonary complications or incidence of pneumothoraces. However, the trend showed a benefit in mortality for patients with an ABSI scoring up to 9, but at the same time pulmonary complications increase. The Horovitz oxygenation index showed no advantage for the HPLV Group. In a separate analysis we found a significant correlation between absolute PEEP and mortality. The correlation between PEEP level and mortality is a dynamic factor predicting outcome, This not been described yet and can be an addition to the static ABSI score. Differences between ventilation strategies were not as evident as expected in this retrospective study, so prospective randomized studies are needed.

[Karl Jaspers: a critique and an alternative]. / Karl Jaspers: kritika i alternativa.

Karl Jaspers, psychiatrist and philosopher, with his giant opus created a major influence on spiritual atmosphere of this century. In this essay we will explore implications of his philosophy on psychiatry and psychiatrists, with a special focus on the first of his books--"General psychopathology". One of the very first Jaspers' explorations were prejudices in psychiatry. After he had explained mechanisms of their formation, Jaspers analyzes them one by one, selecting six most typical and most important. Based on Jaspers' insight on six prejudices in psychiatry, author of this essay tries to unearth and analyze six tyrannies which threaten psychiatrists and their patients. Tyranny of experience, tyranny of theory, tyranny of matter, tyranny of reason, tyranny of metaphor and tyranny of diagnosis are more than sufficient elements which could turn psychiatry--characterized by openness and broadness--into petrified and sclerotic dogma. We could easily recognize reductionism in background, in which we recklessly rush into and even more stay in.