Development and validation of AI-assisted transcriptomic signatures to personalize adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment. PATIENTS AND METHODS: We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the 'Pancreas-View' tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial. RESULTS: Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months [stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001] and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively). CONCLUSIONS: This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.

An international study to revise the EORTC questionnaire for assessing quality of life in lung cancer patients.

BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13 was the first module to be used in conjunction with the core questionnaire, the QLQ-C30. Since the publication of the LC13 in 1994, major advances have occurred in the treatment of lung cancer. Given this, an update of the EORTC QLQ-LC13 was undertaken. METHODS: The study followed phases I to III of the EORTC Module Development Guidelines. Phase I generated relevant quality-of-life issues using a mix of sources including the involvement of 108 lung cancer patients. Phase II transformed issues into questionnaire items. In an international multicenter study (phase III), patients completed both the EORTC QLQ-C30 and the 48-item provisional lung cancer module generated in phases I and II. Patients rated each of the items regarding relevance, comprehensibility, and acceptance. Patient ratings were assessed against a set of prespecified statistical criteria. Descriptive statistics and basic psychometric analyses were carried out. RESULTS: The phase III study enrolled 200 patients with histologically confirmed lung cancer from 12 centers in nine countries (Cyprus, Germany, Italy, Israel, Spain, Norway, Poland, Taiwan, and the UK). Mean age was 64 years (39 - 91), 59% of the patients were male, 82% had non-small-cell lung cancer, and 56% were treated with palliative intent. Twenty-nine of the 48 questions met the criteria for inclusion. CONCLUSIONS: The resulting module with 29 questions, thus currently named EORTC QLQ-LC29, retained 12 of the 13 original items, supplemented with 17 items that primarily assess treatment side-effects of traditional and newer therapies.

Expression of pEGFR and pAKT as response-predictive biomarkers for RAS wild-type patients to anti-EGFR monoclonal antibodies in metastatic colorectal cancers.

BACKGROUND: RAS wild-type (RASw/t) tumours have been associated with better outcomes in patients with metastatic colorectal cancer (mCRC) treated with anti-EGFR monoclonal antibodies (mAb). We investigated the expression of EGFR downstream proteins under their active phosphorylated forms as potential markers in response to these patients. METHODS: One-hundred tumour samples were collected from patients with mCRC refractory to FOLFOX and/or FOLFIRI and treated by a combination of chemotherapy with anti-EGFR mAb. The outcomes were measured on response evaluation criteria in solid tumour (RECIST), progression-free survival (PFS) and overall survival (OS). All samples were assessed for RAS and BRAF mutations, and the key phosphorylated proteins of EGFR downstream signalling were quantitatively analysed using the BioPlex Protein array. RESULTS: Among the 60 RASw/t patients, 45.0% achieved a complete or partial response when treated with anti-EGFR mAb. Expression of pAKT, pERK1/2 and pMEK1 was significantly lower in RASw/t patients (P=0.0246; P=0.004; P=0.0110, respectively). The response rate was significantly higher for RASw/t patients who express pEGFR and pAKT (P=0.0258; P=0.0277, respectively). CONCLUSIONS: Overexpression of pEGFR and pAKT may predict the response rate in RASw/t patients treated with anti-EGFR mAb. On the basis of our results, we hypothesise that the association of anti-EGFR mAb and anti-AKT therapies could be of interest.

Differentiating multi-MeV, multi-ion spectra with CR-39 solid-state nuclear track detectors.

The development of high intensity petawatt lasers has created new possibilities for ion acceleration and nuclear fusion using solid targets. In such laser-matter interaction, multiple ion species are accelerated with broad spectra up to hundreds of MeV. To measure ion yields and for species identification, CR-39 solid-state nuclear track detectors are frequently used. However, these detectors are limited in their applicability for multi-ion spectra differentiation as standard image recognition algorithms can lead to a misinterpretation of data, there is no unique relation between track diameter and particle energy, and there are overlapping pit diameter relationships for multiple particle species. In this report, we address these issues by first developing an algorithm to overcome user bias during image processing. Second, we use calibration of the detector response for protons, carbon and helium ions (alpha particles) from 0.1 to above 10 MeV and measurements of statistical energy loss fluctuations in a forward-fitting procedure utilizing multiple, differently filtered CR-39, altogether enabling high-sensitivity, multi-species particle spectroscopy. To validate this capability, we show that inferred CR-39 spectra match Thomson parabola ion spectrometer data from the same experiment. Filtered CR-39 spectrometers were used to detect, within a background of ~ 2 × 1011 sr-1 J-1 protons and carbons, (1.3 ± 0.7) × 108 sr-1 J-1 alpha particles from laser-driven proton-boron fusion reactions.

Is there a neuroscience-based, mechanistic rationale for transcranial direct current stimulation as an adjunct treatment for posttraumatic stress disorder?

It is well-known that there is considerable variation in the effectiveness of evidence-based treatments for psychiatric disorders, and a continued need to improve the real-world effectiveness of these treatments. In the last 20+ years the examination of noninvasive brain stimulation techniques for psychiatric treatment has increased dramatically. However, in order to test these techniques for effective therapeutic use, it is critical to understand (a) (what are) the key neural circuits to engage for specific disorders or clusters of symptoms, and (b) (how) can these circuits be reached effectively using neurostimulation? Here we focus on the research toward the application of transcranial direct current stimulation (tDCS) for posttraumatic stress disorder (PTSD). tDCS is a portable and inexpensive technique that lends itself well to be combined with, and thus potentially augment, exposure-based treatment for PTSD. In this review, we discuss the behavioral model of threat and safety learning and memory as it relates to PTSD, the underlying neurobiology of PTSD, as well as the current understandings of tDCS action, including its limitations and opportunities. Through this lens, we summarize the research on the application of tDCS to modulated threat and safety learning and memory to date, and propose new directions for its future research. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

[Efficient use of flash sequences in the staging of bone and soft tissue tumors]. / Rationeller Einsatz von Flash-Sequenzen im Staging von Knochen- und Weichteiltumoren.

Delineation of neoplasms from normal tissue is possible using Flash sequences. These sequences prove useful in preoperative staging of bone tumours and soft tissue tumours. However, contrast between neoplastic and surrounding normal tissue is lower than in optimal selected spin-echo sequences. Flash-90 sequence is superior to Flash-10 sequence in the demonstration of intraosseous extension of predominantly sclerotic, calcified and purely fibrous tumours. In contrast, Flash-10 sequence proves superior for the demarcation of osteolytic tumours with minimal fibrous tissue content. Delineation of extraosseous tumour masses against muscle can best be achieved using Flash-90 sequence after intravenous administration of Gadolinium-DTPA. Flash-90 sequence enables sharp demarcation of extraosseous masses of bone tumours against surrounding fat, whereas Flash-10 sequence proves useful in the delineation of non-lipomatous soft tissue tumours against normal fat.

[Treatment of soft tissue infections with gentamycin-polymethylmethacrylate bead chains]. / Die Behandlung von Weichteilinfektionen mit Gentamycin-Polymethylmethacrylat-Ketten.

Local antibiotic treatment with Septopal chains can also provide early control of soft tissue infections, provided the operative procedure is adequate. Of 80 patients treated this procedure was successful in 73% after the first operation and in 24% after reoperation. During the planning of treatment attention should be paid to the special requirements of this specific therapy; certain septic surgical methods have to be modified. Therefore limited extension of gentamycin diffusion has to be considered, and primary wound healing - if necessary by means of Epigard - should be attempted.

Treatment of infected arthrodesis of the ankle.

In arthrodesis of the ankle joint the use of external fixation can cause severe problems owing to pintrack infections. As long as infection is active, bony consolidation of the arthrodesis is delayed. In the potentially infected area a normal internal osteosynthesis is risky. Our treatment rationale comprises a two-stage procedure with treatment of infection first by implant removal, thorough debridement and implantation of Septopal beads and then secondary internal stabilization with an antibiotic-releasing bone plate. Of the 42 cases amputation had to be performed in 3; of the remaining 39, infection was cured long-term in 36. In all 39 a stable bony fusion was achieved.

Management of wound sepsis after spinal fusion surgery.

In wound sepsis after spinal surgery a first attempt to control infection without removal of the implants is justified, as implant removal after correction of scoliosis and kyphosis and in reduction of slipped vertebrae would often cause instability of the segments operated on. If the first revision is not successful, a second should not be delayed too long. Sometimes partial removal of the implants may be sufficient for infection control, thus maintaining a certain stability. We use local antibiotic treatment with Septopal chains, as suction irrigation sometimes is complicated by secondary bacterial contamination. By applying this treatment rationale we were able to control infection in 50 out of 53 patients with wound infection.

[Cystic parosteal osteosarcoma. A case treated by resection]. / Ostéosarcome parostéal "kystique". Un cas traité par résection.

A parosteal sarcoma in a twelve-year-old girl is described in which a large cystic lesion developed at the centre of the lower femoral metaphysis. Treatment was by extensive resection and reconstruction with an allograft in two stages. There was an excellent result after seven years. Only one other case was found in a review of the literature of slowly growing primary malignant tumours.

[Parosteal osteosarcoma as a cause of chronic knee pain in an athlete]. / Parossales Osteosarkom als Ursache chronischen Knieschmerzes beim Sportler.

The present case of a rare, however existing disease, which remained undetected for years, is to underline the necessity of diligent diagnosis. We report about a 23-year-old football player who complained about permanent pain in the right knee from the age of 13. In spite of repeated sports- and orthopedic-specific examinations correct diagnosis could only be established eight years after the onset of the symptoms. Differential diagnosis and the present mode of the therapy of this tumor close to the knee joint are demonstrated.

[Infection of knee endoprosthesis]. / Die Infektion bei Knieendoprothesen.

In knee arthroplasties, infection was and still is the most decisive factor with respect to the end result. Control of infection without removal of the endoprosthesis can be achieved only when an early revision is performed in the first 6 weeks after the arthroplasty. Half-hearted antibiotic medication alone is an unsuitable remedy. Therefore, an infection must be diagnosed without delay and followed up by decisive management. Clinical and laboratory data must be considered together and must supplement each other. Late infections need temporary or permanent removal of the endoprosthesis as a prerequisite for getting rid of the infection. Reimplantation and arthrodesis should be done in a two-stage procedure after the infection is healed. Reimplantation should be restricted to cases in which the infection is definitely under control and in which there is a good bone stock. Arthrodesis is still the treatment of choice, especially in patients with bony defects in the metaphysis of the femur and tibia. Arthrodesis also needs good soft tissue cover, and to prevent a reinfection in this dangerous area we suggest the use of antibiotic-releasing bone plates for stabilisation. External fixation has a high percentage of pintrack infections and often cannot be applied long enough; thus non-unions are the logical consequence.

[The importance of nosocomial infections for patients and socio-political representatives]. / Die Bedeutung von nosokomialen Infektionen für Patienten und die Solidargemeinschaft.

The importance of nosocomial infection prevention is up to now not seen in all its consequences by physicians and the social-political representatives. Do activities to analyse and prevent nosocomial infections nowadays not encounter the resistance, we know from the times of Semmelweis, the problems in this respect haven't changed a great deal, i.e. the negative sides of modern medicine are often intentionally overseen. Hospital hygiene may not be misunderstood as clinical bacteriology, it is indeed a true task for the clinician and has to deal with all complications resulting from patient treatment. Side effects from drugs and postoperative thromboembolic complications have also been followed, as they are very often in direct or indirect correlation with bacterial infections or their consequences. From the social economic point of view nosocomial infections represent a very important cost factor, which could be reduced to great deal by activities for prevention of nosocomial infection. This means, that such activities not only could be performed cost-neutral, but could render a further cost reduction in hospital medicine. Besides of the individual disasters, nosocomial infections create, this economic view could be a strong second argument for hospital hygiene in our world mostly reacting only on financial factors.

[Documentation and quality control]. / Dokumentation und Qualitätskontrolle.

Documentation and quality control in hospitals are not only required due to legal obligations, but should be a representation, how physicians see themselves. The fast changes in medical treatment procedures makes adequate techniques of information management indisposable. In the past data analysis in hospitals was characterized by a too strong restriction in variables under study, and a too sharp project orientation with the consequences, that many tasks had to be done repeatedly and an overview on the whole situation wasn't achieved either. So in recording postoperative wound sepsis many separate aspects have to be taken into consideration and microbiological results have to be stored in a way, that differentiation over time is possible. For medical data management a time oriented database structure is therefore advisable and more adequate than a relational one.

[The incidence of disorders of wound healing (results of the German Society of Orthopedics and Traumatology study)]. / Häufigkeit von Wundheilungsstörungen (Ergebnisse der DGOT-Studie).

The methods and design of the DGOT-study on nosocomial infections in orthopaedic hospital are discussed and presented. On postoperative wound healing complications two interim evaluations of the large database were performed, at different time-points of the continuing study. Wound healing complications accounted to a total of 4.5%, deep infections being present in 0.4%. Secondary wound healing was found in 2.85% and superficial infections accumulated to 1.44% of all wounds followed. When a grouping on the basis of anatomic regions was done, significant differences could be detected with the shoulder area having the lowest and the feet having the highest incidence of wound complications. On the other hand, grouping on the basis of surgical procedures didn't show any difference in the wound healing situation.

[Current problems of hospital health]. / Aktuelle Probleme der Krankenhaushygiene.

In addition to the original assignments, as prevention of bacterial infections, hospital hygiene nowadays has to be concerned with the reduction of infection risks for the medical staff. AIDS isn't only a tremendous threat to the society, but may severely influence bone and joint surgery. The indications for surgical procedures have to be thoroughly investigated just as the question, whether and under what circumstances there is a ethical obligation to perform surgery on HIV-positive patients. To further reduce the remaining risk of HIV-transmission by blood transfusions, all available techniques for decreasing intraoperative blood loss and retransfusion of the patients own blood have to be investigated and applied. Aside from blood, postoperative wound secretions hide the highest infection potential for HIV-transmission to nurses in orthopaedic wards. Therefore we have to focus our attention on the techniques and instruments of wound drainage to protect the patients from wound infections and the staff members from HIV-transmission as well. Disconnections of the drainage lines should be eliminated, at least reduced to the very minimum by using adequate drainage equipments.

[Weaknesses of conventional drainage systems]. / Schwachstellen herkömmlicher Drainagen.

Of the different drainage systems the high vacuum technique according to Redon is the procedure of choice for orthopaedic and trauma surgery. Overflow drainage should be restricted to certain special indications, when there is a risk for high blood loss. Open drainage doesn't fulfill the high sterility demands, we require in orthopaedic surgery. Aside from the positive wound healing effects, high vacuum drainage according to Redon hides some risks for complications, which aren't well known by surgeons. All openings of the drainage lines, the change of suction container as well, may lead to a reflux and thus cause retrograde wound contamination. By this procedure also aerosol formation was found, which may represent risks for the ward personnel. Changes of the suction container must have an indication and should only be performed in the presence of a blocking device at the connection tube. The vacuum indicators of most products on the market need further improvement, in order to enhance the operating safety.

Infection management in total hip replacement.

Early diagnosis and determined management of infection after hip replacement are the prerequisites for good end results. Infections that manifest themselves during the first 6 weeks after a prosthetic implant can be mastered by local debridement. The implant can thus be saved, and the functional performance as well. Infections that appear after this 6-week period may require temporary removal of the implant in order to control the infection. When the clinical aspects and laboratory data indicate the infection is under control, the hip endoprosthesis can be reimplanted with a very low rate of recurrence. The method applied for removal of implants and bone cement is of utmost importance for the final results, and a extremely diligent surgical technique is the basis for long-term management of infection and good functional performance. Resection arthroplasty is not the treatment of choice anymore for infected hip prostheses and should be restricted to special cases.

[Postoperative wound suction drainage and its effect on wound healing]. / Die postoperative Wund-Saug-Drainage und ihr Einfluss auf die Wundheilung.

The positive as well as the negative effects of wound suction drainage on wound healing are outlined and the inherent physical laws which still were unclear are subject to an experimental analysis. The findings and conclusions which had been determined resulted in a modification of the clinical application practice and evidence points to the up to now daily change of suction bottle by routine as being a significant risk. Contamination of physical conditioned secretion reverse flow while opening the wound drainage system and the proven spreading ability of the bacteria within the drainage tubes leaves the possibility of a postoperative retrograde bacteria contamination reaching up to the wound site. To prophylactically reduce these risks instrumental improvements of the wound drainage system will be presented and discussed.