Most targeted cancer drugs inhibit the oncogenic signals to which cancer cells are addicted. We discuss here a counterintuitive approach to cancer therapy, which consists of deliberate overactivation of the oncogenic signals to overload the stress responses of cancer cells. We discuss why such overactivation of oncogenic signaling, combined with perturbation of the stress response pathways, can be potentially effective in killing cancer cells, aiming to inspire further discussion and consideration.

PU.1-mutated agammaglobulinemia (PU.MA) represents a recently described autosomal-dominant form of agammaglobulinemia caused by mutation of the SPI1 gene. This gene codes for PU.1 pioneer transcription factor important for the maturation of monocytes, B lymphocytes, and conventional dendritic cells. Only six cases with PU.MA, presenting with chronic sinopulmonary and systemic enteroviral infections, have been previously described. Accumulating literature evidence suggests a possible relationship between SPI1 mutation, microglial phagocytic dysfunction, and the development of Alzheimer\'s disease (AD).
We present a Caucasian female patient born from a non-consanguineous marriage, who was diagnosed with agammaglobulinemia at the age of 15 years when the immunoglobulin replacement therapy was started. During the following seventeen years, she was treated for recurrent respiratory and intestinal infections. At the age of 33 years, the diagnosis of celiac-like disease was established. Five years later progressive cognitive deterioration, unstable gait, speech disturbances, and behavioral changes developed. Comprehensive microbiological investigations were negative, excluding possible infective etiology. Brain MRI, 18FDG-PET-CT, and neuropsychological testing were suggestive for a diagnosis of a frontal variant of AD. Clinical exome sequencing revealed the presence of a novel frameshift heterozygous variant c.441dup in exon 4 of the SPI1 gene. Despite intensive therapy, the patient passed away a few months after the onset of the first neurological symptoms.
We describe the first case of PU.MA patient presenting with a rapidly progressive neurocognitive deterioration. The possible role of microglial dysfunction in patients with SPI1 mutation could explain their susceptibility to neurodegenerative diseases thus highlighting the importance of genetic testing in patients with inborn errors of immunity. Since PU.MA represents a newly described form of agammaglobulinemia, our case expands the spectrum of manifestations associated with SPI1 mutation.

OBJECTIVE: Recent clinical trials have shown promising results with drugs targeting the hepatocyte growth factor receptor (c-Met) for advanced non-small cell lung cancers overexpressing c-Met. We assessed reflex testing of c-Met immunohistochemistry (IHC) at diagnosis for NSCLC in the real-world.
METHODS: We retrospectively collected clinical, pathological and molecular data of cases diagnosed with NSCLC in our institution from January 2021 to June 2023. We performed c-Met IHC (SP44 clone) and scored the expression using a H-score and a three-tier classification.
RESULTS: 391 cases with interpretable c-Met IHC staining were included. The median age at diagnosis was 70 years (range 25-89 years) including 234 males (male/female ratio 1:5). 58% of the samples came from surgical resections, 35% from biopsies and 8% from cytological procedures. 52% of cases were classified as c-Met-positive (H-score≥150) and 19% were classified as c-Methigh (≥50%, 3+). 43% of the c-Metneg presented with lymph node and/or visceral metastases at diagnosis vs 55% for c-Methigh (p=0.042). 23% of the adenocarcinomas showed c-Methigh expression vs 3% for squamous cell carcinomas (p=0.004). 27% of the c-Metneg cases had a high PD-L1 expression vs 58% of c-Methigh cases (p<0.001). MET ex14 skipping was present in 8% of the c-Methigh cases.
CONCLUSIONS: Systematic c-Met testing in daily routine for NSCLC patients is feasible, highlighting a potential correlation with clinicopathological and molecular features.

Osimertinib has demonstrated efficacy as the first- and second-line treatment for advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) gene mutations. However, EGFR-mutant NSCLC cells often acquire resistance to osimertinib. V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation (BRAF V600E) was detected in a re-biopsy (LC-SCRUM-TRY testing) of a patient with advanced lung adenocarcinoma who was resistant to osimertinib treatment. Currently, the patient is receiving dabrafenib/trametinib combination therapy and is under observation; a slight shrinking effect of cancer has been observed.

Micropapillary urothelial carcinoma (MPUC) of the renal pelvis is an upper tract urothelial carcinoma originating in the renal pelvis region. Few genetic studies are available, and the mechanism of pathogenesis of genetically driven models is unclear. We report a case of genomic alterations in MPUC of the renal pelvis and compare the results with existing literature. DNA was extracted, followed by the next-generation sequencing of 351 oncogenes and tumor suppressor genes. Targeted gene sequencing analysis revealed somatic variants in ERBB2, KMT2C, FOXA1, and germline variants in CDKN1B, ELF3, TP53, and RB1 genes. The present case study sheds light on recognizing genetic variants in high-grade MPUC of the renal pelvis. Understanding molecular mechanisms helps with better prognostication and development of more effective therapeutics and treatment.

BACKGROUND: Acrometastasis is an uncommon finding in non-small cell lung cancer and is usually a sign of multimetastatic disease. Few case reports have suggested solitary digital metastasis as the single secondary lesion of oligometastatic non-small cell lung cancer.
METHODS: This case report describes an unusual presentation of a Kirsten rat sarcoma viral oncogene homolog-mutated lung adenocarcinoma with a solitary bone metastasis in the fourth finger medial phalanx, which was also the first sign of the disease, in a 63-year-old Caucasian female patient. Digital surgical amputation was performed. After histopathological confirmation and radiological exclusion of other secondary lesions, chemoimmunotherapy in a first-line setting was initiated. A partial metabolic response in the primary lung lesion was observed after four cycles. Maintenance therapy is currently being continued.
CONCLUSIONS: Solitary digital metastasis is a rare finding in non-small cell lung cancer. Further studies are needed to investigate the mechanisms behind this particular dissemination process.

暂无摘要。

Anaplastic thyroid carcinoma (ATC) is a highly malignant tumor with invasive nature. Most patients present with locally advanced and/or distant metastatic diseases that are difficult to treat. We report a case of a previously inoperable patient with v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutated ATC. After a trial of neoadjuvant Dabrafenib/Trametinib with immunotherapy, the tumor became operable, and surgical pathology indicated a pathologic complete response (pCR). We also reviewed cases from the literature that utilized neoadjuvant BRAF-directed therapy in ATCs. These cases emphasize that BRAF-and immune-directed therapy is a feasible option in patients with inoperable ATC and may lead to improved outcomes.

Asian patients with metastatic non-small cell lung cancer (NSCLC) have a higher prevalence of epidermal growth factor receptor (EGFR) mutations compared to Caucasians, 30-50% and 15%, respectively. Osimertinib is a tyrosine kinase inhibitor approved as first-line therapy in patients with metastatic NSCLC harboring exon 19 or exon 21 EGFR mutations.
We report a 68-year-old treatment-naïve Asian male patient with metastatic NSCLC harboring an exon 19 deletion mutation of EGFR treated with osimertinib. The patient developed an osimertinib-induced syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after approximately two months of therapy. Following fluid restriction and osimertinib discontinuation, the hyponatremia improved significantly within one week. The patient was started on second-line erlotinib without any signs of hyponatremia after treatment initiation.
There is a lack of published data from randomized prospective clinical trials of osimertinib-induced SIADH in metastatic NSCLC. Further studies to evaluate the potential underlying mechanisms are warranted.

This article is a revised version of our proposal for the establishment of the legal concept of risk-adjusted prevention in the German healthcare system to regulate access to risk-reduction measures for persons at high and moderate genetic cancer risk (Meier et al. Risikoadaptierte Prävention\'. Governance Perspective für Leistungsansprüche bei genetischen (Brustkrebs-)Risiken, Springer, Wiesbaden, 2018). The German context specifics are summarized to enable the source text to be used for other country-specific healthcare systems. Establishing such a legal concept is relevant to all universal and free healthcare systems similar to Germany\'s. Disease risks can be determined with increasing precision using bioinformatics and biostatistical innovations (\'big data\'), due to the identification of pathogenic germ line mutations in cancer risk genes as well as non-genetic factors and their interactions. These new technologies open up opportunities to adapt therapeutic and preventive measures to the individual risk profile of complex diseases in a way that was previously unknown, enabling not only adequate treatment but in the best case, prevention. Access to risk-reduction measures for carriers of genetic risks is generally not regulated in healthcare systems that guarantee universal and equal access to healthcare benefits. In many countries, including Austria, Denmark, the UK and the US, entitlement to benefits is essentially linked to the treatment of already manifest disease. Issues around claiming benefits for prophylactic measures involve not only evaluation of clinical options (genetic diagnostics, chemoprevention, risk-reduction surgery), but the financial cost and-from a social ethics perspective-the relationship between them. Section 1 of this chapter uses the specific example of hereditary breast cancer to show why from a medical, social-legal, health-economic and socio-ethical perspective, regulated entitlement to benefits is necessary for persons at high and moderate risk of cancer. Section 2 discusses the medical needs of persons with genetic cancer risks and goes on to develop the healthy sick model which is able to integrate the problems of the different disciplines into one scheme and to establish criteria for the legal acknowledgement of persons at high and moderate (breast cancer) risks. In the German context, the social-legal categories of classical therapeutic medicine do not adequately represent preventive measures as a regular service within the healthcare system. We propose risk-adjusted prevention as a new legal concept based on the heuristic healthy sick model. This category can serve as a legal framework for social law regulation in the case of persons with genetic cancer risks. Risk-adjusted prevention can be established in principle in any healthcare system. Criteria are also developed in relation to risk collectives and allocation (Sects. 3, 4, 5).