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-based regimens or the modified FOLFIRINOX regimen (mFFX). While mFFX has been shown to be more effective than gemcitabine-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 AI-signatures were obtained by combining Independent Component Analysis, Least Absolute Shrinkage and the Selection Operator-Random Forest approach. We integrated a previously developed gemcitabine 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 HR: 0.31; 95% 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 gemcitabine sensitive group when treated with gemcitabine. 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 gemcitabine.

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.

[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.

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.

[The German Society of Orthopedics and Traumatology study: pathogen spectrum and resistance status]. / DGOT-Studie: Erregerspektrum und Resistenzlage.

In the scope of a DGOT Study various aspects and evaluations of the bacterial spectrum of wound infections are reviewed and the frequency of resistance is presented. The study is based on 3700 wound healing protocols. Our results suggest that the bacterias involved in the field of orthopaedic surgery and traumatology are for the most part known germs. This should be decisive for the type of antibiotic therapy being possibly required. The main organisms are Staphylococci, Enterococci and Pseudomonades; available agents of choice are penicillinase-resistant and -susceptible Penicillins, Ampicillins and Cephalosporins of the first and second generation.

[Curettage of giant cell tumors with temporary implantation of bone cement]. / Die Kürettage von Riesenzelltumoren mit temporärer Implantation von Knochenzement.

Curettage with simultaneous bone transplantation is followed by a recurrence rate of 20-60%. In a follow-up of own cases up to 36 years after treatment recurrence was roughly 50%. In the last 10 years we changed to on other treatment procedure, namely optical controlled curettage with temporary cementation. To prevent further damage to the preexisting destabilization of the periarticular cortical bone, tumor excision is done through a small bone window, using a cold lighted mirror to achieve complete curettage. The cavity is then filled with bone cement, which is left in place for 3 months. When at that time there are no signs for tumor persistence, the cement is removed and bone reconstruction performed. An analysis of 17 cases treated this way showed a clearly smaller recurrence rate of 6%; this difference was statistically significant when applying the Kaplan-Meier test.

[Giant cell tumor of bone. An analysis of 69 cases]. / Der Riesenzell-Tumor des Knochens. Eine Analyse von 69 Fällen.

1. The tumor stage of the giant cell tumor is an indicator for the prognosis and the need for adjuvant therapy. 2. Intralesional excisions without an adjuvant result in high rates of recurrence. 3. Polymethyl methyl acrylate (PMMA) largely prevents recurrences, provides stability and makes early functional treatment possible. 4. Broad excisions should only be performed in bone which is dispensable. 5. Recurrences frequently manifest themselves by pain. They can be removed intralesionally, as in primary therapy.

[Ventral stabilization of primary tumors and metastases of the spine with vertebral body implant and palacos]. / Die ventrale Stabilisierung von primären Tumoren und Metastasen der Wirbelsäule mit dem Wirbelkörperimplantat und Palacos.

The authors report on the clinical course of 31 patients with primary tumors or metastases of the spine which were treated with the vertebral body implant and Palacos, i.e., composite osteosynthesis. The goal of therapy is to relieve the spinal cord and the nerve roots and to restore the supporting function of the spine. Subjective and objective improvement was found in 64% of the patients; the result was unchanged in 23%, and further symptoms developed in 13%. The tumor-specific breakdown revealed that overall survival was somewhat more than two years in plasmocytoma cases and ten months in metastasis cases. In almost all cases in which an improvement in initial symptoms was achieved postoperatively, this improvement was permanent. With the surgical technique applied here spinal stability can be restored and the patients can also be mobilized quickly.

[Other nosocomial infections]. / Andere nosokomiale Infektionen.

Besides wound infections we postoperatively are also facing the problems of other nosocomial infections, e.g. urinary tract infections, bronchopneumonia and sepsis caused by the use of intravenous devices. A preliminary survey was performed among 4008 patients in a multicentre study. After orthopaedic surgery we found the incidence of urinary tract infections to be 4.8%. Because of non satisfactory documentation the postoperatively acquired respiratory tract infections could not be evaluated properly. Sepsis due to the use of central or peripheral venous cannulas has been observed in 0.2%. Serious problems of nosocomial infections are discussed.

[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.

[The diagnostic value of wound secretion analysis]. / Die diagnostische Wertigkeit der Wundsekretanalyse.

Wound exudation is commonly produced by damaged tissue particles after surgery and by repairing mechanisms initiated by the body. The early postoperative analysis of normal visual, chemical and corpuscular composition of wound exudation reveals a characteristic distribution in normal wound healing. Typical changes in the visual aspect and the corpuscular distribution permit a sooner recognition of wound infection. Thus, instant special management becomes possible being frequently decisive for the final outcome. Our results show a positive correlation between the prolonged decrease of the white blood cell concentration in the wound exudation and established wound infection. The serum analysis of CRP and ESR does not show unequivocal changes. The visual and corpuscular analysis of wound exudation is an important contribution to early diagnostics of wound infection. By means of chemical analysis admixtures to wound exudation can be clearly identified, e.g. the presence of liquor is recognized by the determination of total wound exudation protein.

[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.

[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.

[The value of nuclear magnetic resonance tomography in staging of bone and soft tissue sarcomas]. / Der Stellenwert der Kernspintomographie im Staging von Knochen- und Weichteilsarkomen.

The prognosis of survival in bone and soft-tissue sarcomas is definitely correlated with compartmental tumor extension at the time of surgery and with the surgical margins achieved by resection. Preoperative planning and selection of an adequate surgical treatment procedure require a maximum of information on the tumor size, compartmental extension, proximity to the physis, skin layers, and the vessels and nerves. This information is indispensable and can only be obtained by a combination of several diagnostic investigations, MRI being of utmost importance. Whereas CT is superior in illustrating the bone structure, MRI outclasses CT in outlining the intraosseous tumor extension and the extraosseous tumor components. The latter aspects are especially important in planning and performing tumor resection. With the combined use of gradient echo sequences and Gadolinium DTPA with MRI, appreciation of the tumor margin and response to polychemotherapy may be possible in the future.

The cytogenesis of macrophages and osteoclast-like giant cells in bone tumors with special emphasis on the so-called fibrohistiocytic tumors.

Recent investigations have suggested that osteoclasts and osteoblasts belong to different cell systems: osteoclasts originate from hemopoietic stem cells, most probably via precursors of the mononuclear phagocyte system. Osteoblasts, however, arise from local mesenchyme. The present classification of bone tumors issued by the WHO, however, is still based on the assumption of osteoclasts and osteoblasts being merely different manifestations or differentiations of the same basic cell type. Consequently, histiocytes or macrophages as well as osteoclast-like giant cells are interpreted in most bone tumors as an autochthonous component of the tumor. In the present study, this theory is contradicted by histological immunohistological, electron microscopic, and autoradiographic-electron microscopic results on a larger number of osteosarcomas, chondromas, chondrosarcomas, chondroblastomas, aneurysmal bone cysts, giant cell tumors of bone, malignant fibrous histiocytomas, fibrosarcomas, desmoplastic fibromas, Ewing's sarcomas, fibrous dysplasias, nonossifying fibromas, and malignant hemangioenkdotheliomas of bone. In order to elucidate the role of macrophages and osteoclast-like giant cells, different monoclonal antibodies were applied to bone tumor specimens as markers of mononuclear macrophages and giant cells. The concept of what is called fibrohistiocytic tumors should be reconsidered. Immunohistological studies have shown that in malignant fibrous histiocytoma as well as in giant cell tumors of bone only a certain portion of macrophages will react with the highly specific antibodies, whereas the majority of tumor cells are negative. This finding alone suggests that the infiltration of macrophages is a reactive phenomenon. It is in agreement with earlier autoradiographic and electron microscopic investigations on giant cell tumors of bone, confirming that only the fibroblast-like tumors are actually proliferating. These data were verified in the present study with the aid of double labeling immunohistological techniques, using antibodies against mature tissue macrophages and others against a proliferation-associated nuclear antigen. Only the fibroblast-like cells, which do not react with the macrophage-specific antibody, will express the proliferation-associated nuclear antigen. Analogous results were obtained in malignant fibrous histiocytoma. We may infer from these results that the majority of these tumors must be neoplasms of local mesenchyme, mostly in fibroblastic differentiation, while the considerable number of macrophages is seen as a reactive phenomenon.(ABSTRACT TRUNCATED AT 400 WORDS)