Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

Parental age and birth defects: a sibling study

European Journal of Epidemiology - Higher parental age at childbearing has generated much attention as a potential risk factor for birth disorders; however, previous research findings are mixed....     

Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Recent Advances and Ongoing Challenges

Locally advanced rectal cancer has a rising global incidence. Over the last 4 decades, advances first in surgery and later in radiotherapy and chemoradiotherapy have improved outcomes, particularly with regard to local recurrence. Unfortunately, distant metastases remain a significant problem. In clinical trials of patients with stage II and III disease, distant relapse occurs in 25% to 30% of patients regardless of the treatment approach. Recent phase 3 trials have therefore focused on intensification of systemic therapy for localized disease, with an aim of reducing the distant relapse rate. Early results of trials of total neoadjuvant therapy with combination systemic therapy provided in the neoadjuvant setting are promising; for the first time, a significant improvement in the rate of distant relapse has been noted. Longer-term follow-up is eagerly awaited. On the other hand, trimodal therapy with chemotherapy, radiotherapy, and surgery is toxic. Several trials are currently assessing the feasibility of a watch-and-wait approach, omitting surgery in those with complete response to neoadjuvant treatment, in an attempt to reduce the burden of treatment on patients. The future for rectal cancer patients is likely to be highly personalized, with more intense approaches for high-risk patients and omission of unnecessary therapy for those whose disease responds well to initial treatment. Biomarkers such as circulating tumor DNA will help to more accurately stratify patients into risk groups. Improvements in survival and quality of life are expected as the results of ongoing research become available throughout the next decade.     

COVID-19 and mental health: a longitudinal population study from Norway

European Journal of Epidemiology - Existing research has found adverse short-term effects of the COVID-19 pandemic on mental health, but longer-term effects have been less documented. Using newly...     

Komplikationen bei skleranahtfixierter Kunstlinsenimplantation

Die Sklerafixation einer Kunstlinse ist bei insuffizientem Kapselapparat eine häufig gewählte Versorgung. Als nachteilig gilt das potenzielle Komplikationsprofil. Analyse des postoperativen Komplikationsprofils. In dieser monozentrischen, retrospektiven Analyse einer konsekutiven Fallserie von Patienten mit standardisierter, skleranahtfixierter Kunstlinsenimplantation (2007 bis 2017) wurden die dokumentierten Komplikationen in „dauerhaft visusbedrohend“ (Endophthalmitis, Aderhautblutung, Ablatio retinae) und „klinisch relevant, aber nicht dauerhaft visusbedrohend“ (z. B. Blutungen, Hypotonie) kategorisiert. Zudem wurde der Zeitpunkt der erstmaligen Dokumentation der Komplikationen erfasst und in 3 Zeiträume eingeordnet (0 bis 3, 4 bis 30 und ≥31 Tage). Vorliegend handelt es sich um das bislang größte publizierte Patientenkollektiv einer Studie mit Skleranahtfixierung einer Hinterkammerlinse (HKL). Es wurden 338 Augen von 338 Patienten in die Studie eingeschlossen (Frauen: 47 %), die mediane Nachbeobachtungszeit betrug 60 Tage (min.: 1 Tag, max.: 5833 Tage). In 68 % der Fälle wurden Komplikationen dokumentiert. „Dauerhaft visusbedrohende Komplikationen“ traten bei 3 % (n = 10) der Patienten auf. Als „klinisch relevante Komplikationen“ wurden ermittelt: okuläre Hypotension auf Werte ≤10 mm Hg (n = 119; 35 %), entrundete Pupille (n = 93; 28 %), Hyphäma, Iris- oder Glaskörperblutungen (n = 34; 10 %), Sekundärglaukom (n = 32; 9 %) und Iris-Capture (n = 17; 5 %); 41 % der Komplikationen traten innerhalb der ersten 3 Tage und 70 % innerhalb der ersten 30 Tage auf. Zu Revisionsoperationen kam es bei 4,5 % (n = 15) der Patienten. Obwohl bei ca. zwei Dritteln aller Eingriffe Komplikationen auftraten, war die Zahl der dauerhaft visusbedrohenden Komplikationen gering. Die Sklerafixation der Kunstlinse ist weiterhin ein vertretbarer Eingriff.