Impact of Borderline Resectability in Pancreatic Head Cancer on Patient Survival: Biology Matters According to the New International Consensus Criteria

Background: International consensus criteria (ICC) have redefined borderline resectability for pancreatic ductal adenocarcinoma (PDAC) according to three dimensions: anatomical (BR-A), biological (BR-B), and conditional (BR-C). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumour and vessels but that biological and conditional dimensions also are important. Methods: Patients’ tumours were retrospectively defined b

A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing

Abstract Butyrophilin (BTN)–3A and BTN2A1 molecules control the activation of human Vγ9Vδ2 T cells during T cell receptor (TCR)-mediated sensing of phosphoantigens (PAg) derived from microbes and tumors. However, the molecular rules governing PAg sensing remain largely unknown. Here, we establish three mechanistic principles of PAg-mediated γδ T cell activation. First, in humans, following PAg binding to the intracellular BTN3A1-B30.2 domain, Vγ9Vδ2 TCR triggering involves the extracellular V-domain of BTN3A2/BTN3A3. Moreover, the localization of both protein domains on different chains of the BTN3A homo-or heteromers is essential for efficient PAg-mediated activation. Second, the formation of BTN3A homo-or heteromers, which differ in intracellular trafficking and conformation, is controlled by molecular interactions between the juxtamembrane regions of the BTN3A chains. Finally, the ability of PAg not simply to bind BTN3A-B30.2, but to promote its subsequent interaction with the BTN2A1-B30.2 domain, is essential for T-cell activation. Defining these determinants of cooperation and the division of labor in BTN proteins improves our understanding of PAg sensing and elucidates a mode of action that may apply to other BTN family members

Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper

Background: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2–1.0%. Summary: Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitorin

Identification of Disparities in Personalized Cancer Care—A Joint Approach of the German WERA Consortium

(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy

Electrophysiological detection of slowly conducting pyramidal tract fibres

Nur der kleine Bruchteil (10%) der Pyramidenbahnfasern des Menschen mit Leitgeschwindigkeiten größer als 30 m/s vermittelt die überschwellige, als Muskelantwort registrierbare Wirkung eines transkraniellen magnetelektrischen Reizes auf spinale Motoneurone. Die unterschwellige Wirkung der durch den transkraniellen Reiz gleichzeitig aktivierten langsamer leitenden Neurone (90%) erzeugt keine Muskelantwort, jedoch eine Bahnung von H-Reflexen. Wenn man das Intervall zwischen konditionierendem Magnetpuls und elektrischem H-Reflexreiz zwischen Δt = -5 und Δt = 35 ms variiert, so erhält man in der distalen Muskulatur bis zu 35 ms dauernde triphasische Bahnungskurven mit einem frühen und späten Maximum. Mit den aus Autopsien gewonnenen Schätzwerten der Abstände zwischen kortikalem Reizort und spinalem Wirkort und dem jeweiligen Intervall zwischen konditionierendem und Testreiz lassen sich die Geschwindigkeiten der bahnenden Komponenten des Kortikospinaltraktes berechnen. Die Maxima werden durch Komponenten gebildet, die mit 30 m/s, bzw. 15 m/s leiten, die langsamsten Komponenten mit bahnender Wirkung leiten mit 6 m/s. Im Einklang mit unserer Hypothese, dass die Abszissenwerte der Bahnungskurve den Ankunftszeiten von bahnenden kortikospinalen Erregungen unterschiedlicher Leitgeschwindigkeit entsprechen, nimmt der zeitliche Abstand zwischen den Bahnungsgipfeln, die jeweils durch Komponenten gleicher Leitgeschwindigkeiten gebildet werden, und die Dauer der Bahnung an der unteren Extremität im Vergleich zur oberen Extremität zu. Die triphasische Bahnungskurve mit einem frühen und späten Gipfel und die Gipfel trennenden intermodalen Minimum erhält man nur aus der distalen Muskulatur. Bei proximalen Antischwerkraftsmuskeln bricht die Bahnung nach dem ersten frühen Gipfel ab, um in eine Phase normaler oder gehemmter H-Reflex Erregbarkeit überzugehen. Als Erklärung können eine durch den Magnetreiz gleichzeitig aktivierte, überwiegend spinale, Hemmkomponente oder vorwiegend disynaptische kortikomotoneuronale Verbindungen langsam leitender Pyramidenbahnfasern, die für eine direkte bahnende Interaktion mit der Ia-Afferenz am Motoneuron nicht zur Verfügung stehen, dienen. Die summierende Interaktion des peripheren und zentralen Inputs am Motoneuron lässt sich durch Modelle analytisch simulieren. Aus diesen Modellen gewinnt man auch Näherungen der empirischen Beziehungen zwischen Verstärkungswirkungen und Reizstärken. Triphasische Bahnungskurven mit zwei Maxima und intermodalem Minimum erhält man, wenn man das Produkt aus Faserzahl und Faserquerschnitt, d.h. den Anteil einer bestimmten Leitgeschwindigkeitskomponente am Gesamtquerschnitt der Pyramidenbahn, über der Leitgeschwindigkeit verteilt. Die so erhaltenen Verteilungen gleichen den empirischen Verteilungen der Bahnungsstärken. Faserzahl und auch Faserdurchmesser einer Komponente des Pyramidenbahnspektrums bestimmen also ihre Bahnungsstärke.The small fraction (10%) of the pyramidal tract fibres with conduction velocities of more than 30 m/s provides the above threshold effect of the transcranial magnetic stimulation on spinal motoneurones which is measurable as a muscular response. The 90% of slow conduction pyramidal tract fibres don’t provide a muscular response after transcranial magnetic stimulation, although they facilitate H-Reflexes. Varying the interval of conditioning magnet impulse and electric H-Reflex stimulus between Δt = -5 and Δt = 35 ms results in a triphasic facilitated curve of 35ms duration with an early and a late maximum in distal muscles. On the basis of autopsies we estimated the values of the distances between the area of cortical stimulation and spinal motoneurons in the anterior horn. Together with the intervals between conditioning magnet stimulus and electric test stimulus we calculated the conduction velocities of the respective facilitating components of the pyramidal tract. The two maxima were formed of pyramidal components conducting with 30m/s, rsp. 15m/s; the slowest facilitating components conducted with 6m/s. Consistent with our hypothesis, that the x-coordinates of our facilitated curves represent arrival times of excitating corticospinal fibres of different conduction velocities, the time-lag between the two maxima representing the same conduction velocities in upper and lower extremity grows. Additionally the overall period of facilitation is longer in the lower than in the upper extremity. The triphasic curve with an early and late peak and the separative dip is only available in the distal muscles. Concerning proximal anti gravity muscles the facilitation ends after the first peak. For longer Δts the H-reflexes were unaffected or suppressed. Explanations for this could be inhibiting spinal elements activated via the magnetic impulse or disynaptic corticomotoneuronal connections in proximal muscles which are not able to facilitate the Ia-afferents at the spinal motoneurons. In analytic models the accumulative interaction of the central and peripheral input on the spinal motoneuron can be simulated. We find approximations of the empiric relations between amplifying effects and stimulus intensities based on these models. The product of number of fibres and cross sectional area gives us the fraction of a fibre group with a distinct conduction velocity in the overall cross section area of the pyramidal tract. If we administer this product evenly across the conduction velocities, the result is a triphasic curve with two maxima and a separative minimum which resemble our empiric results. That means that the number of fibres and the diameter of a component of the pyramidal tract determine their strength of facilitation

Intensified neoadjuvant chemotherapy with nab-paclitaxel plus gemcitabine followed by FOLFIRINOX in a patient with locally advanced unresectable pancreatic cancer

The prognosis of patients with locally advanced pancreatic cancer can be improved if secondary complete (R0) resection is possible. In patients initially staged as unresectable this may be achieved with neoadjuvant treatment which is usually chemoradiotherapy based. We report the case of a 46-year-old patient with an unresectable, locally advanced pancreatic cancer (pT4 Nx cM0 G2) who was treated with a sequential neoadjuvant chemotherapy regimen consisting of 2 cycles of nab-paclitaxel plus gemcitabine followed by 4 cycles of FOLFIRINOX. Neoadjuvant chemotherapy resulted in secondary resectability (R0 resection). After 2 cycles of nab-paclitaxel plus gemcitabine, the patient already had a complete metabolic remission as measured by integrated fludeoxyglucose ((18)F) positron emission tomography and computerized tomography. After a follow-up of 18 months the patient is alive without progression of disease. We propose to assess the clinical benefit of sequencing the combinations nab-paclitaxel plus gemcitabine and FOLFIRINOX as neoadjuvant therapy for patients with locally advanced and initially unresectable pancreatic cancer in a controlled clinical trial