Gene-Guided Treatment Decision-Making in Non-Small Cell Lung Cancer - A Systematic Review

Decision-making in cancer treatment is part of clinicians' everyday work, and it is especially challenging in non-small cell lung cancer (NSCLC) patients, for whom decisions are clearly dependent on gene alterations or the lack of them. The multimodality of treatments, involvement of gene alterations in defining systemic cancer therapies, and heterogeneous nature of tumors and their responsiveness provide extra challenges. This article reviews the existing literature to 2021 with extra effort to explore the role of genes and gene-driven therapies as part of decision-making. The process and elements in this decision-making participation are recognized and discussed comprehensively. Genetic health literacy aids are provided as a part of the review. Our systematic review, data extraction and analysis found that with current methods and broad gene panels, patients benefit from early molecular testing of liquid biopsy samples. An estimated 79% of liquid biopsy samples showed somatic mutations based on 8 original studies included in the systematic review. When both liquid biopsy samples and tissue samples are evaluated, the sensitivity to detect targetable mutations in NSCLC increases. We recommend early testing with liquid biopsy. Additional effort is needed for the logistics of obtaining and evaluating samples, and tissue samples should be saved and stored for tests that are not possible from liquid biopsy.</p

Denitrifying microbial communities along a boreal stream with varying land-use

Streams have an important role in regulating nitrogen (N) transportation from terrestrial ecosystems to downstream waters. Here, we examined how catchment land-use affects potential denitrification rates and the function and composition of denitrifier communities in boreal stream sediments, using stable isotope incubations and qPCR and 454-pyrosequencing targeted on nirS, nirK and nosZ genes. Although land-use influenced the water chemistry as higher nitrite+nitrate (NOx)-concentration at the agriculture-affected sampling point, sediment organic matter content was found to be the key factor in regulating potential denitrification rates. However, the abundance as well as the diversity and community composition of denitrifying microbes, and genetic N2O production potential (the ratio between nirS+nirK and nosZ gene abundances) were connected to both NOx- and sediment quality. Overall, our results suggest that catchment land-use-driven changes in N and carbon availability affect the denitrification rates, and possibly N-2:N2O production ratio, in boreal streams, through altering denitrifier abundance and community composition.Peer reviewe

Current challenges in applying gene-driven therapies in clinical lung cancer practice

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Metastatic Rectal Carcinoma with Long-Term Remission due to Modern Multimodality Treatment

In the era of personalized medicine, systemic treatment with chemotherapy in combination with targeted drugs, tailored according to RAS and BRAF status, has improved the survival of patients with metastatic colorectal cancer (mCRC), but curative resection of metastases provides the only chance of cure. Here, we present a 40-year-old male with rectal adenocarcinoma and multiple bilateral synchronous liver metastases who has achieved long-term remission with multimodal treatment without resection of all metastatic lesions. This case emphasizes the need of repeated multidisciplinary team assessments and change of treatment intent if extraordinary responses are seen. The initial therapy consisted of short-course radiotherapy and surgery of the primary tumor followed by oxaliplatin-based combination chemotherapy and panitumumab with disease control intent. A complete radiologic response in >20 liver metastases in segments II–VIII was obtained. A biopsy-verified relapse of 3 liver metastases occurred at 9 months of treatment pause. Subsequently, major liver resection of 8 lesions was performed (4 with adenocarcinoma and 4 with cicatrix showing the challenge of disappearing lesions), followed by 6 months of adjuvant-like therapy. No relapse in MRI, PET, or CT has been noted since liver resection 6 years ago. Comprehensive genomic profiling of the primary tumor and liver metastases had similar driver mutations representing a low level of gene alteration and low diversity, possibly explaining the exceptional treatment response.</p

DPYD-geenitestaus kliinisessä käytössä

Vertaisarvioitu.Eri syöpien hoidossa laajasti käytettyihin fluoropyrimidiini-lääkkeisiin (kapesitabiini, tegafuuri ja 5-fluorourasiili) liittyy vakavien haittavaikutusten mahdollisuus. Niistä tyypillisimpiä ovat ripuli, suun ja suolen limakalvojen haavaumat, luuydinlama, hermotoksisuus sekä sydänhaitat. Yksi syy haittoihin on dihydropyrimidiinidehydrogenaasi-entsyymin (DPD) vajaus ja toimimattomuus, joka johtaa fluorourasiilin aineenvaihduntahäiriöön ja kertymiseen elimistöön. Vuonna 2020 Euroopan lääkevirasto (EMA) antoi suosituksen, jonka mukaan DPD-entsyymin toimimattomuus tulee selvittää ennen fluoropyrimidiinien antamista. Testaus voidaan tehdä tutkimalla potilaan verinäytteestä tunnettuja kliinisesti merkittäviä DPYD-geenivariantteja. Fluoropyrimidiinejä ei tule antaa potilaalle ollenkaan, mikäli hänellä todetaan täydellinen DPD-entsyymin puutos. Osittaisessa DPD-entsyymin puutostilassa hoito aloitetaan pienennetyllä annoksella, mikä pohjautuu kansainvälisiin annossuosituksiin.Peer reviewe

DPYD-geenitestaus kliinisessä käytössä

Vertaisarvioitu.Eri syöpien hoidossa laajasti käytettyihin fluoropyrimidiini-lääkkeisiin (kapesitabiini, tegafuuri ja 5-fluorourasiili) liittyy vakavien haittavaikutusten mahdollisuus. Niistä tyypillisimpiä ovat ripuli, suun ja suolen limakalvojen haavaumat, luuydinlama, hermotoksisuus sekä sydänhaitat. Yksi syy haittoihin on dihydropyrimidiinidehydrogenaasi-entsyymin (DPD) vajaus ja toimimattomuus, joka johtaa fluorourasiilin aineenvaihduntahäiriöön ja kertymiseen elimistöön. Vuonna 2020 Euroopan lääkevirasto (EMA) antoi suosituksen, jonka mukaan DPD-entsyymin toimimattomuus tulee selvittää ennen fluoropyrimidiinien antamista. Testaus voidaan tehdä tutkimalla potilaan verinäytteestä tunnettuja kliinisesti merkittäviä DPYD-geenivariantteja. Fluoropyrimidiinejä ei tule antaa potilaalle ollenkaan, mikäli hänellä todetaan täydellinen DPD-entsyymin puutos. Osittaisessa DPD-entsyymin puutostilassa hoito aloitetaan pienennetyllä annoksella, mikä pohjautuu kansainvälisiin annossuosituksiin.Peer reviewe

DPYD-geenitestaus kliinisessä käytössä

publishedVersionPeer reviewe

Genetic and Environmental Controls on Nitrous Oxide Accumulation in Lakes

We studied potential links between environmental factors, nitrous oxide (N2O) accumulation, and genetic indicators of nitrite and N2O reducing bacteria in 12 boreal lakes. Denitrifying bacteria were investigated by quantifying genes encoding nitrite and N2O reductases (nirS/nirK and nosZ, respectively, including the two phylogenetically distinct clades nosZ(I) and nosZ(II)) in lake sediments. Summertime N2O accumulation and hypolimnetic nitrate concentrations were positively correlated both at the inter-lake scale and within a depth transect of an individual lake (Lake Vanajavesi). The variability in the individual nirS, nirK, nosZ(I), and nosZ(II) gene abundances was high (up to tenfold) among the lakes, which allowed us to study the expected links between the ecosystem's nir-vs-nos gene inventories and N2O accumulation. Inter-lake variation in N2O accumulation was indeed connected to the relative abundance of nitrite versus N2O reductase genes, i.e. the (nirS+nirK)/nosZ(I) gene ratio. In addition, the ratios of (nirS+ nirK)/nosZ(I) at the inter-lake scale and (nirS+ nirK)/nosZ(I+II) within Lake Vanajavesi correlated positively with nitrate availability. The results suggest that ambient nitrate concentration can be an important modulator of the N2O accumulation in lake ecosystems, either directly by increasing the overall rate of denitrification or indirectly by controlling the balance of nitrite versus N2O reductase carrying organisms.Peer reviewe