Real-world outcomes with durvalumab after chemoradiotherapy in patients with unresectable stage III NSCLC: interim analysis of overall survival from PACIFIC-R.

BACKGROUND: Based on the findings of the PACIFIC trial, consolidation durvalumab following platinum-based chemoradiotherapy (CRT) is a global standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC). An earlier analysis from the ongoing PACIFIC-R study (NCT03798535) demonstrated the effectiveness of this regimen in terms of progression-free survival (PFS). Here, we report the first planned overall survival (OS) analysis. PATIENTS AND METHODS: PACIFIC-R is an observational/non-interventional, retrospective study of patients with unresectable, stage III NSCLC who started durvalumab (10 mg/kg intravenously every 2 weeks) within an AstraZeneca-initiated early access program between September 2017 and December 2018. Primary endpoints are OS and investigator-assessed PFS, estimated using the Kaplan-Meier method. RESULTS: By 30 November 2021, the full analysis set included 1154 participants from 10 countries (median follow-up in censored patients: 38.7 months). Median OS was not reached, and the 3-year OS rate was 63.2% (95% confidence interval 60.3% to 65.9%). Three-year OS rates were numerically higher among patients with programmed death-ligand 1 (PD-L1) expression on ≥1% versus <1% of tumor cells (TCs; 67.0% versus 54.4%) and patients who received concurrent CRT (cCRT) versus sequential CRT (sCRT) (64.8% versus 57.9%). CONCLUSIONS: PACIFIC-R data continue to provide evidence for the effectiveness of consolidation durvalumab after CRT in a large, diverse, real-world population. Better outcomes were observed among patients with PD-L1 TCs ≥1% and patients who received cCRT. Nevertheless, encouraging outcomes were still observed among patients with TCs <1% and patients who received sCRT, supporting use of consolidation durvalumab in a broad population of patients with unresectable, stage III NSCLC.

Zirconia crown performance in primary maxillary anterior teeth: a retrospective photographic and radiographic cohort study.

PURPOSE: This retrospective cohort observational study evaluated marginal integrity, gingival health and aesthetics of zirconia crowns (ZC) placed on primary maxillary anterior teeth at 6- to over 30-month follow-up visits. METHODS: Two independent raters evaluated radiographic and photographic findings in 131 ZC placed in 36 children aged 24.8-62.2 months (median = 40.6) who had at least one recall visit 6 months after placement. Follow-up periods were stratified into three levels: long, intermediate and short. Associations between crown performance and crown brands, follow-up periods, treatment performed under general anaesthesia or sedation and previous pulpotomy were investigated by ordinal logistic regression. RESULTS: Follow-up ranged from 6 to 33.8 months (average: 13.5 months). Marginal integrity was highly rated in 82.4% of the teeth. No gingivitis was found in 35% of the teeth, 58% showed mild gingivitis and 7% showed moderate gingivitis (p = 0.06). Colour match and crown contour were rated very high in 55% of the cases. Marginal integrity and periodontal health differed between cases performed under general anaesthesia and those performed under sedation (p = 0.03 and p = 0.003, respectively). Pulpotomized teeth showed worse colour matching with the adjacent teeth than non-pulpotomized teeth (p = 0.03). CONCLUSIONS: Our findings suggest that ZC comprise a satisfactory treatment option for carious primary maxillary incisors, presenting good overall marginal integrity, gingival health, and aesthetics.

A randomised controlled clinical trial comparing pure Portland cement and formocresol pulpotomies followed from 2 to 4 years.

PURPOSE: The purpose of the present prospective randomised clinical control trial was to evaluate the long-term clinical and radiographic success rate of pulpotomies in primary molars using pure Portland cement versus formocresol. Pure Portland cement has shown a high rate of success in pulpotomy treatments, with no side effects. METHODS: Healthy 3- to 11-year-old children were treated with pulpotomies on primary molars as part of their scheduled dental treatment. Pulp dressing alternated randomly between pure Portland cement and formocresol. Data were analysed at follow-up periods up to 48 months. RESULTS: 68 (50%) teeth with pure Portland cement and 68 (50%) teeth with formocresol in 136 healthy children (59 boys and 77 girls) were followed. The overall success rate of the pulpotomies in this study was 95.6%. Pure Portland cement was successful in 100% of the cases (68 out of 68), and formocresol in 91.1% (62 out of 68). No association was found between success and type of tooth or time range from treatment to last follow-up. CONCLUSION: Based on this study's results, it can be concluded that there is no superiority of one material over the other and pure Portland cement can be used in primary molar pulpotomies.

Clinical activity of brigatinib in ROS1-rearranged non-small cell lung cancer.

BACKGROUND: Brigatinib is a potent ROS1 inhibitor. The existing data on its clinical activity in ROS1-rearranged non-small cell lung cancer (NSCLC) are limited to four cases. METHODS: Six patients with ROS1-rearranged advanced NSCLC treated with brigatinib were identified through search of the internal databases of four participating cancer centers. Four additional patients were selected by PubMed and Google Scholar search. The objective response rate (ORR), progression-free survival (PFS) (RECIST v.1.1), duration of treatment (DOT), and safety were assessed. RESULTS: Of eight patients evaluable for response assessment (crizotinib naive-1, crizotinib resistant -7), three patients demonstrated a partial response (ORR-37%). One crizotinib-naive patient had an ongoing response at 21.6 months. Of seven crizotinib-resistant patients, two patients demonstrated a partial response (ORR-29%), and one patient (14%) had stable disease. PFS, available in four crizotinib-resistant patients, was 7.6 + , 2.9, 2.0, and 0.4 months. In crizotinib-resistant patients, DOT was 9.7 + , 7.7 + , 7.6 + , 4.0, 2.0, 1.1, 0.4 months, and was not reported in two patients. Genomic profiling in one responder revealed no ROS1 alteration, suggesting that the response was attributable to "off-target" brigatinib activity. In two patients with progressive disease, genomic profiling demonstrated a cMET exon 14 mutation + KRAS G12A mutation in one case, and a persisting ROS1-CD74 fusion + TP53 K139N, FGFR2 E250G, ATM G2695D, and NF1 R2258Q mutations in the other. No grade 3-5 toxicity was observed. CONCLUSION: Brigatinib demonstrated modest activity in crizotinib-resistant ROS1-rearranged NSCLC. Its intracranial and systemic activity should be assessed in correlation with the underlying molecular mechanism of crizotinib resistance.

Our series is the first to describe brigatinib activity in ROS1-altered NSCLC. In crizotinib-resistant patients, ORR with brigatinib was 29%. PFS with brigatinib was 7.6+, 2.9, 2.0, and 0.4 months. DOT with brigatinib was 9.7+, 7.7+, 7.6+, 4.0, 2.0, 1.1, 0.4 months. The correlation between response and molecular resistance needs further exploration.

Attitudes of EAPD members toward using the "knee-to-knee" position.

AIM: This survey assessed the attitude of paediatric dental EAPD members toward using "knee-to-knee" positioning for dental examinations and minor procedures in infants and toddlers. METHODS: An anonymous electronic online questionnaire was distributed among EAPD members. The survey consisted of 12 questions and assessed demographic characteristics, professional experience and attitudes toward the use of the "knee-to-knee" position. RESULTS: Of the 162 respondents, 148 (91%) reported using "knee-to-knee" positioning for dental examination. In addition, 97 (63%) reported performing other procedures in the "knee-to-knee" position. Fluoride application and oral hygiene instructions were the most common procedures performed in the "knee-to-knee" position. CONCLUSIONS: Most of the paediatric dentists who responded to this survey reported performing dental examinations in toddlers up to 2 years old using the "knee-to-knee" position. Majority of respondents also used this position to instruct parents regarding oral hygiene and to apply fluoride varnish.

Long-term clinical performance of heat-cured high-viscosity glass ionomer class II restorations versus resin-based composites in primary molars: a randomized comparison trial.

OBJECTIVE: To evaluate the long-term clinical performance of heat-cured high-viscosity glass ionomer (GIC) and posterior composite resin (CR) restorations in primary molars over a 3-year period. METHODS: Photographs and radiographs of EQUIA GIC and Filtek™ P60 restorations were assessed. Study sample is comprised of healthy preschool/school children with proximal surface caries in primary molars. RESULTS: 70 GI restorations were placed in 45 patients (aged 78 months ± 25) and were evaluated at 33 months ± 7. 61 composite resin restorations were placed in 42 patients (age 82 months ± 19) and were evaluated at 39 months ± 13. GI restorations failure was 17.1%, a significantly greater rate compared with 4.9% in the CR group. GI failures were due to either significant loss of the restoration or to loss of marginal ridge integrity. CR failures were due to loss of marginal ridge integrity. CONCLUSION: Both GI and CR restorations were clinically successful during a 3-year period. GI restorations may be considered as an intermediate-lasting restoration option for proximal lesions in primary molars, with 83% of the restorations functioning up to 36 months. CR restorations showed a higher success rate than GIC during the same period.

"Knee-To-Knee" Position for Minor Procedures in Infants and Toddlers- Dentists Attitudes.

OBJECTIVE: The objective of this survey was to assess attitudes of pediatric dentists in Israel toward using "knee-to-knee" positioning for dental examinations and for minor procedures in infants and toddlers. STUDY DESIGN: An anonymous questionnaire was distributed among specialists in pediatric dentistry. Eleven questions accessed demographic data, professional experience and attitudes toward the use of the "knee-to-knee" position. RESULTS: Of 68 respondents, 66 (97%) reported using "knee-to-knee" positioning for dental checkups. In addition, 52 (76%) reported performing other procedures in the "knee-to-knee" position. Fluoride application and oral hygiene instructions are the most common procedures performed in the "knee-to-knee" position. CONCLUSIONS: "Knee-to-knee" positioning was found very convenient for dental examinations and other simple procedures in very young children.

Combined cancer patient-reported symptom and health utility tool for routine clinical implementation: a real-world comparison of the ESAS and EQ-5D in multiple cancer sites.

Background: We assessed whether the presence and severity of common cancer symptoms are associated with the health utility score (hus) generated from the EQ-5D (EuroQol Research Foundation, Rotterdam, Netherlands) in patients with cancer and evaluated whether it is possible pragmatically to integrate routine hus and symptom evaluation in our cancer population. Methods: Adult outpatients at Princess Margaret Cancer Centre with any cancer were surveyed cross-sectionally using the Edmonton Symptom Assessment System (esas) and the EQ-5D-3L, and results were compared using Spearman correlation coefficients and regression analyses. Results: Of 764 patients analyzed, 27% had incurable disease. We observed mild-to-moderate correlations between each esas symptom score and the hus (Spearman coefficients: -0.204 to -0.416; p < 0.0001 for each comparison), with the strongest associations being those for pain (R = -0.416), tiredness (R = -0.387), and depression (R =-0.354). Multivariable analyses identified pain and depression as highly associated (both p < 0.0001) and tiredness as associated (p = 0.03) with the hus. The ability of the esas to predict the hus was low, at 0.25. However, by mapping esas pain, anxiety, and depression scores to the corresponding EQ-5D questions, we could derive the hus using partial esas data, with Spearman correlations of 0.83-0.91 in comparisons with direct EQ-5D measurement of the hus. Conclusions: The hus derived from the EQ-5D-3L is associated with all major cancer symptoms as captured by the esas. The esas scores alone could not predict EQ-5D scores with high accuracy. However, esas-derived questions assessing the same domains as the EQ-5D-3L questions could be mapped to their corresponding EQ-5D questions to generate the hus, with high correlation to the directly measured hus. That finding suggests a potential approach to integrating routine symptom and hus evaluations after confirmatory studies.

The incidence and nature of complaints against dentists for the treatment of children in Israel from 1992-2011.

OBJECTIVES: Medical literature lacks information about complaints against dentists who treat children. The present study aimed to evaluate the reports filed to Medical Consultant International (MCI) regarding paediatric dentistry in 1992-2011. BASIC RESEARCH DESIGN: Most dentists in Israel (85%) are obliged by their professional liability insurance policy to report adverse events to MCI. Reports were analysed using a structured form that included demographic details of the treating dentist, patients and parents, type of treatment, the result and the dentist's attitude. MCI dental consultants' decisions were evaluated by two specialists in paediatric dentistry. RESULTS: The number of complaints per year is increasing. Complaints involved maltreatment (33%), case mismanagement (25%) and complications that required additional treatment (26%). Communication was problematic in 60% of cases. Only 16.7% of complaints developed into an actual lawsuit. Most complaints were against female general practitioners and against dentists who worked in community dental clinics located in peripheral areas. Treating permanent teeth increased to 3.6 times the probability of developing into a lawsuit. 59% of event records had missing data. Seventy-five percent of the cases rose from elective treatments while 25% concerned emergency treatments. One third of the cases required additional treatment in a hospital i.e. abscess drainage, foreign body swallowing or other physical damages. CONCLUSIONS: Better case selection and documentation, better training of dentists who treat children and more appropriate attitude toward patients and parents, are likely to reduce the number of complaints.

Conservative management for an entero-adnexal fistula at initial presentation of advanced ovarian carcinoma.

Gastrointestinal fistulae can occur in ovarian cancer patients, usually in the setting of advanced relapsed disease. Treatment typically involves immediate surgery.Here, we describe a case of an abscess resulting from an intestinal fistula as the first manifestation of advanced epithelial ovarian cancer, and we review the current literature on this subject. The patient was successfully treated with a combination of chemotherapy, antibiotics, and delayed surgery. Optimal debulking was achieved without a need for bowel resection.This report is the first of conservative management of a fistula in an ovarian cancer patient in the chemotherapy-naïve setting.

Rabeprazole for the prevention of pathologic and symptomatic relapse of erosive or ulcerative gastroesophageal reflux disease. Rebeprazole Study Group.

OBJECTIVE: We evaluated the effectiveness and safety profile of 10 and 20 mg of rabeprazole, a new proton pump inhibitor, once daily versus placebo in preventing endoscopic and symptomatic relapse for up to 1 yr among patients with healed erosive or ulcerative gastroesophageal reflux disease (GERD). METHODS: The 52-wk trial used a multicenter, randomized, double-blind, parallel-group design in which 209 men and women were assigned to 10 or 20 mg of rabeprazole once daily in the morning or placebo. RESULTS: Both rabeprazole doses were significantly superior to placebo in preventing endoscopic relapse (p < 0.001), and 20 mg was significantly more effective than 10 mg (p < 0.04). Both doses were also significantly superior to placebo in reducing the frequency and severity of heartburn relapse (p < 0.001). When adjusted for differences in exposure to study medication, no significant differences were found in the incidence of adverse events. No clinically significant changes were found regarding clinical laboratory parameters, vital signs, electrocardiograms, ophthalmological evaluations, body weight, serum gastrin, and enterochromaffin-like cell histology. CONCLUSIONS: Once-daily therapy with 10 or 20 mg of rabeprazole effectively prevents pathological and symptomatic GERD relapse. The 20-mg dose is significantly more effective than the 10-mg dose in preventing endoscopic recurrence. Treatment was well tolerated, and no clinically significant safety findings emerged. Our findings support rabeprazole's efficacy in preventing GERD recurrence with excellent tolerability and a short-term favorable safety profile.

[Testicular cancer--self-awareness and testicular self-examination in soldiers and physicians in the Israeli army].

Testicular cancer is the most common malignancy in young men. To evaluate knowledge and awareness of that cancer, and of the practice of testicular self-examination (TSE), we developed a questionnaire which was distributed to 717 male soldiers and 200 of their military physicians. 21% of the soldiers had received some explanation of the importance of TSE, but only 16% were actually instructed how to perform TSE, and only 2% practiced it regularly. 24% had never examined their testicles before, 185 only rarely, and 6% often. With increased age, TSE frequency increased, but previous education, type of military unit, and ethnic origin had no affect. 99% of military physicians had been taught how to examine breasts, but only 70% had been taught routine testicular examination. 22% performed it, but 27% never did. 84% had never taught their soldiers the importance of TSE, although 51% taught female soldiers breast self-examination. There was a significant lack of awareness of the importance of regular practice of TSE among both soldiers and their army physicians.

Primary peritonitis due to group A streptococcus.

Primary peritonitis is a rare condition occurring, by definition, in patients without underlying causes, such as perforated viscus, pre-existing ascites, or nephrosis. We report a case of primary peritonitis and shock due to group A beta-hemolytic streptococcus, a rare etiology. A review of the world's literature shows a predilection for women to have this condition. The entry site is obscure in most cases. Asymptomatic genital tract colonization may be a portal of entry in some women. Shock or toxic shock syndrome often accompany the abdominal findings. Laparotomy to exclude a perforated viscus may be unavoidable. Despite the significant morbidity, expeditious and appropriate antibiotic therapy is curative.

The management of drooling problems in children with neurological dysfunction: a review and case report.

Drooling in children with neurological dysfunction indicates neurogenic failure to coordinate the muscles of the tongue, soft palate, and face which act in the first stage of swallowing. This causes excessive pooling of saliva in the anterior part of the mouth and consequent overspill. Treatment for drooling includes behavioral, pharmacological, and surgical modalities. Correcting a malocclusion has also been reported to help eliminate drooling. This paper describes the treatment of a child with neurofibromatosis, psychomotor, developmental, and neurologic retardation, and difficulty with speech. The patient was referred to our clinic to correct his drooling. Simple orthodontic treatment succeeded in eliminating the drooling and improving his speech.

[Percutaneous feeding gastrostomy].

In the past 3 years 71 procedures for insertion of a percutaneous gastrostomy for enteral feeding were performed under X-ray control. The indication for gastrostomy was inability or refusal of the patient to swallow food, in the absence of mechanical obstruction of the gastrointestinal tract. The age range was 66-93 years (mean 82). Most patients had suffered strokes and some had dementia or Parkinson's disease. The procedure was successful in 69/71 patients (97%). 9 (12.6%) died within 30 days of causes related to their underlying condition, rather than to the procedure; 1 developed peritonitis and 6 (8.4%) developed minor infections at the site of entry of the gastrostomy tube. This is the first account of this technique to appear in the Hebrew medical literature. In our opinion the technique should be adopted as the preferred method for forming a gastrostomy, as it is quicker, safer and cheaper than the operative method, and even easier to perform than endoscopic percutaneous gastrostomy.

Different types of sleeve anastomosis.

Microvascular techniques are important in making routine anastomoses quicker and difficult anastomoses easier. The authors have developed three types of sleeve anastomoses for different size vessels: a three-stitch sleeve anastomosis, four-stitch sleeve anastomosis, and sidecut sleeve anastomosis. Arteriography, in vivo observation, pulsed ultrasound Doppler hemodynamic study, histology, and ultrastructural examination with scanning electron microscopy at 2 to 90 days demonstrated that all three groups of sleeve anastomoses do not stenose, do not show hemodynamically significant vasospasm, and are not complicated by aneurysm formation by 90 days. The hemodynamics were comparable to control sutured anastomoses at 2 to 4 hr postoperatively. The sleeve anastomoses left no suture material within the vessel lumen. Reendothelialization was comparable with controls at 14 days, and the long-term patency rates were similar (p > 0.05). The operative times for all three types of sleeve anastomoses were significantly shorter than sutured control anastomoses (p < 0.001). Although limited by available vessel length and diameter, the sleeve anastomosis is a useful technique for the microsurgeon.

Transient postoperative stenosis in small-vessel anastomoses.

Using a newly developed Doppler probe, we have found that a standard suture anastomosis in a rat femoral artery is accompanied by significant (30-60%) cross-sectional area stenosis, which dissipates to baseline levels within 24 hours. We hypothesized that spasm, deposition of coagulation products, or the suture technique itself was responsible. Topical vasodilators (papaverine, sodium nitroprusside, lidocaine) and intravenous thromboxane A2 synthetase inhibitor and receptor blocking agent (Ridogrel, 4 mg/ml), anticoagulants heparin and SC4992 (an experimental platelet inhibitor/arginine-glycine-aspartic acid analogue), were administered. No drug had any significant effect on preventing postoperative stenosis. Varied suture bites affected stenosis measurements. Scanning electron microscopy and light microscopy displayed "bunching" of vessel wall in the suture ties. This was confirmed with methyl methacrylate corrosion casts and microangiography. "Sham" anastomoses also produced stenosis, which was relieved when sutures were removed. We conclude that suture anastomosis of small vessels is accompanied by significant cross-sectional stenosis caused by the physical action of tensioned sutures. This effect dissipates over a 24-hour postoperative period. The mechanism behind these changes and the clinical importance of this effect are still under investigation.

Hemodynamic study of different angled end-to-side anastomoses.

This study assessed the postoperative microvascular hemodynamics in end-to-side arterial anastomoses of varied angles in order to determine whether the angle of the anastomosis affects arterial flow. Thirty male rats were divided into three groups of ten. Carotid to carotid end-to-side anastomoses were performed with anastomotic angles of 45, 90, and 135 degrees. Postoperative flow was assessed using high frequency pulsed Doppler ultrasound (HFPDU) at 30 and 120 min postoperatively. Measurements at 30 min demonstrated significant differences in flow, with the 45 degrees grafted vessels utilizing 56.5% of total carotid flow, and the 90 degrees and 135 degrees anastomoses appropriating 46.5% and 43.2% of flow, respectively (comparing 45 degrees to both 90 degrees, P < 0.05, and 135 degrees, P < 0.002). The change from baseline in 45 degrees and 90 degrees groups dissipated over a 2 hr postoperative period, but flow in the grafted vessels in the 135 degrees group continued well below 50% at 39.9% (comparing to both 45 degrees and 90 degrees, P < 0.001), thereby displaying a significant difference in the postoperative arterial flow of varied angled microanastomoses.

Microvascular anastomoses utilizing new intravascular stents.

Evolving microsurgical technique has allowed for the anastomosis of smaller diameter vessels. Standard suture anastomoses cause a measure of stenosis and intimal damage during application and therefore cannot be dependably used in the anastomosis of very small vessels. We developed and tested a fibrin glue-based anastomosis applied over a meltable stent made of mono- di- and tri-glycerides. In vivo rodent studies using the 0.35 mm diameter inferior epigastric artery have shown immediate and short-term patency rates better than those associated with suture technique. The stent technique is significantly faster and easier than the suture technique. The glyceride stent method suffers from decreased late patency due to aneurysm formation. In addition, we developed a glyceride-coated polyethylene glycol-based stent for use in lasered anastomoses. Work on both projects is ongoing.