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).

A phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamics of PF-06939999 (PRMT5 inhibitor) in patients with selected advanced or metastatic tumors with high incidence of splicing factor gene mutations.

BACKGROUND: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates dysregulated in cancer, including spliceosome machinery components. PF-06939999 is a selective small-molecule PRMT5 inhibitor. PATIENTS AND METHODS: This phase I dose-escalation and -expansion trial (NCT03854227) enrolled patients with selected solid tumors. PF-06939999 was administered orally once or twice a day (q.d./b.i.d.) in 28-day cycles. The objectives were to evaluate PF-06939999 safety and tolerability to identify maximum tolerated dose (MTD) and recommended part 2 dose (RP2D), and assess pharmacokinetics (PK), pharmacodynamics [changes in plasma symmetric dimethylarginine (SDMA) levels], and antitumor activities. RESULTS: In part 1 dose escalation, 28 patients received PF-06939999 (0.5 mg q.d. to 6 mg b.i.d.). Four of 24 (17%) patients reported dose-limiting toxicities: thrombocytopenia (n = 2, 6 mg b.i.d.), anemia (n = 1, 8 mg q.d.), and neutropenia (n = 1, 6 mg q.d.). PF-06939999 exposure increased with dose. Steady-state PK was achieved by day 15. Plasma SDMA was reduced at steady state (58%-88%). Modulation of plasma SDMA was dose dependent. No MTD was determined. In part 2 dose expansion, 26 patients received PF-06939999 6 mg q.d. (RP2D). Overall (part 1 + part 2), the most common grade ≥3 treatment-related adverse events included anemia (28%), thrombocytopenia/platelet count decreased (22%), fatigue (6%), and neutropenia (4%). Three patients (6.8%) had confirmed partial response (head and neck squamous cell carcinoma, n = 1; non-small-cell lung cancer, n = 2), and 19 (43.2%) had stable disease. No predictive biomarkers were identified. CONCLUSIONS: PF-06939999 demonstrated a tolerable safety profile and objective clinical responses in a subset of patients, suggesting that PRMT5 is an interesting cancer target with clinical validation. However, no predictive biomarker was identified. The role of PRMT5 in cancer biology is complex and requires further preclinical, mechanistic investigation to identify predictive biomarkers for patient selection.

Functional outcome of total knee arthroplasty in patients with haemophilia.

INTRODUCTION: Haemophilic arthropathy (HA) is a debilitating complication of haemophilia which leads to TKA in severe cases. AIM: We conducted a prospective study of the outcome of TKA in our haemophilia cohort to define the outcomes in this population and increase the cost effectiveness of the procedure in our developing country. METHODS: We reviewed patients with haemophilia who underwent TKA between April 2010 and April 2014. Patients with at least 6 months of follow-up were included. Preoperative knee scores (KSS and WOMAC) and the scores of the quality of life were recorded. Radiographic indices were registered pre- and postoperatively. Any complications were recorded. The patients underwent TKA with medial parapatellar approach. We had a low threshold for quadriceps snip when exposure was difficult. As our routine we did not use suction drains postoperatively. RESULTS: We included 83 patients (all males, 103 knees). The mean age of the patients was 35.8 years. The mean follow-up period was 45.1 months. Three patients (3.6%) had factor inhibitors. Twenty patients (24.1%) underwent bilateral simultaneous TKA. The mean admission time was 13.87 days. We had two cases of wound infection and one case of haematoma. None of our patients needed transfusion. All knee scores were significantly improved (P < 0.000). CONCLUSION: Total knee replacement is an effective procedure in treatment of HA. Definition of standards of care for this procedure, which are tailored for resources of a developing country, can have major impact in improving outcomes while maximizing cost effectiveness of this surgery.

Simultaneous bilateral total knee arthroplasty in patients with haemophilia: a safe and cost-effective procedure?

INTRODUCTION: Haemophilic arthropathy of the knee is usually a bilateral affliction. The patients usually refer for treatment in young ages and do not have major comorbidities, being fit for bilateral simultaneous total knee arthroplasty. AIM: In this study, we assessed the safety and cost-effectiveness of simultaneous bilateral surgery in patients with haemophilia. METHODS: Between April 2010 and April 2012, eight patients (16 knees) underwent bilateral simultaneous and 19 patients (19 knees) underwent unilateral total knee arthroplasty (TKA) at our institution. We compared the range of motion and flexion contracture, KSS, WOMAC knee score and SF36 quality of life score between two groups. The duration of hospital stay, coagulation factor consumption and all inpatient costs were recorded. The average follow-up was 26 and 29 months in unilateral and bilateral groups respectively. RESULTS: At the conclusion of the study, the KSS and WOMAC and SF36 scores were not significantly different between the two groups. Mean ROM and flexion contracture did not differ significantly. The mean length of hospital stay was 15 days for bilateral patients and 12 days for unilateral patients, the difference being non-significant. None of our patients needed transfusion in any group. The cost of simultaneous bilateral TKA was about half of the expenses of staged bilateral TKA. CONCLUSION: Simultaneous bilateral TKA seems to be a safe and cost-effective approach without increasing the rate of complications in patients' bilateral haemophilic knee arthropathy. The procedure is, at least, as effective as staged unilateral knee arthroplasty in improving the patients' quality of life.

Evaluation of the sonographic features of malignant breast masses.

Breast sonography is a common technique in the assessment of breast masses. By this modality 114 patients (age 23-75 years) with breast masses were studied and 107 of them were suspected to have malignancy. The diagnosis was based on common sonographic features which included wall contour, echogenicity, echo pattern, posterior-attenuating shadow and lesion length-to-width ratio. Eighty-four and seven-tenths percents of the masses had jagged wall contour, 84.7% were echo-poor, and 76.6% had a heterogenous echo pattern. Sixty-five and eighty-tenths percent had posterior-attenuating shadows. Eighty-two and nine-tenths percent were spherically shaped or anteroposteriorly elongated. Using these features, the positive detection rate for malignancy was 91.2%. In conclusion, sonographic diagnosis of breast malignancies can be used in the assessment of breast masses.

The radiographic features of pulmonary tuberculosis observed for the western region of Saudi Arabia.

The radiographs of 714 patients (486 males, 228 females) with proved pulmonary tuberculosis (PTB) were studied. Most were between 15 and 44 years of age, and most (86.8%) exhibited the usual radiographic appearance of PTB. All had extensive bilateral lung disease, with the right upper lobe the most commonly involved. Parenchymal opacities, cavitation, and atelectasis were common. Many radiographic patterns were encountered, and these varied from one radiograph to the next and even within the same radiograph, with two or more patterns seen together. Unusual radiographic manifestations were found in 13.2% of the patients. These included isolated opacities in the lower lobe, middle lobe, or lingula; normal chest radiographs; isolated pleural effusions; isolated mediastinal or hilar lymphadenopathy, and mass-like lesions. Permanent lung damage could be avoided if the various radiographic features of pulmonary tuberculosis were promptly recognized, thus leading to early treatment.

Mobile gamma cameras and 99mTc-labelled phosphates in acute myocardial infarction.

99mTc-labelled phosphates (PyP, IDP and MDP) were compared for their usefulness for the diagnosis of myocardial infarction. The results indicated the superiority of 99mTc-labelled imidodiphosphonate over the other 99mTc-labelled phosphates. At the same time, two mobile gamma cameras were compared with respect to their instrumental characteristics and clinical versalitity and their advantages and disadvantages are reported.

Imaging: radioisotope imaging of bone.

Isotope bone scanning is here to stay: it is noninvasive, easy to perform, and economical (6 pounds per scan). The low radiation dose delivered to patients (0.03 rad/mCi to the skeleton) and the high sensitivity (less than 4 per cent of overall false positives) underline the value of this test as a screening procedure. When included in the patient's management protocol it reduces bed-occupancy time, changes the therapeutic approach to several illnesses, and substantiates general hopes that early diagnosis is the basis for progress in the treatment of benign or malignant disease.