We present the case of a 70-year-old never-smoking female patient with epidermal growth factor receptor (EGFR) p.L858R-mutated metastatic non-small cell lung cancer (NSCLC). After three months of first-line treatment with erlotinib, progression occurred and platinum/pemetrexed was initiated, followed by a response for more than two years. After the progression, the molecular testing of a vertebral metastasis revealed a ROS proto-oncogene 1 (ROS1) translocation and a human epidermal growth factor receptor 2 (HER2) p.S310F mutation, in addition to the known EGFR p.L858R mutation. Crizotinib then led to a durable response of 17 months. The molecular retesting of the tumour cells obtained from the recurrent pleural effusion revealed the absence of the ROS1 translocation, whereas the EGFR and HER2 mutations were still present. Afatinib was added to the crizotinib, and the combination treatment resulted in another durable response of more than two years. The patient died more than 7 years after the initial diagnosis of metastatic NSCLC. This case demonstrates that the repeated molecular testing of metastatic NSCLC may identify new druggable genomic alterations that can impact the patient management and improve the patient outcome.

Primary lung cancer is the leading cause of mortality worldwide. The major sites of lung cancer metastasis are the bones, liver, brain, lung, and adrenal glands. However, secondary localizations in the genital tract are extremely rare.
UNASSIGNED: The authors report the case of a 36-year-old woman who consulted for a right scapular swelling evolving for 4 months associated with a chronic cough. Clinical examination showed a hard fixed right scapular mass with any inflammatory signs. The extension assessment followed by histological analysis concluded in a secondary ovarian location of a lung adenocarcinoma. A very high serum procalcitonin level unrelated to sepsis was detected in the patient along with a substantial hematological paraneoplastic disease. The patient died after 6 months of palliative chemotherapy.
UNASSIGNED: Ovarian localization is found in only 0.4% of metastatic ovarian tumors, which is extremely low, the differentiation between primary and secondary ovarian adenocarcinoma is fundamental since the treatment and prognosis are very different. The serum procalcitonin can be elevated in lung adenocarcinoma.
UNASSIGNED: This case report highlights the interest to encourage doctors to look for ovarian metastasis during the clinical course of lung cancer, and explain the elevation of serum procalcitonin during lung adenocarcinoma.

Of the many genetic alterations that occur in cancer, relatively few have proven to be suitable for the development of targeted therapies. Mutations in isocitrate dehydrogenase (IDH) 1 and -2 increase the capacity of cancer cells to produce a normally scarce metabolite, D-2-hydroxyglutarate (2-HG), by several orders of magnitude. The discovery of the unusual biochemistry of IDH mutations spurred a flurry of activity that revealed 2-HG as an \'oncometabolite\' with pleiotropic effects in malignant cells and consequences for anti-tumour immunity. Over the next decade, we learned that 2-HG dysregulates a wide array of molecular pathways, among them a large family of dioxygenases that utilise the closely related metabolite α-ketoglutarate (α-KG) as an essential co-substrate. 2-HG not only contributes to malignant transformation, but some cancer cells become addicted to it and sensitive to inhibitors that block its synthesis. Moreover, high 2-HG levels and loss of wild-type IDH1 or IDH2 activity gives rise to synthetic lethal vulnerabilities. Herein, we review the biology of IDH mutations with a particular focus on acute myeloid leukaemia (AML), an aggressive disease where selective targeting of IDH-mutant cells is showing significant promise.

Recent decades have seen a dramatic rise of in the number of initiatives designed to promote precision oncology, a domain that has played a pioneering role in the implementation of post-genomic approaches and technologies such as innovative clinical trial designs and molecular profiling. In this paper, based on fieldwork carried out at the Memorial Sloan-Kettering Cancer Center from 2019 onwards, we analyze how a world-leading cancer center has adapted, responded, and contributed to the challenge of \"doing\" precision oncology by developing new programs and services, and building an infrastructure that has created the conditions for genomic practices. We do so by attending to the \"organizing\" side of precision oncology and to the nexus between these activities and epistemic issues. We situate the work that goes into making results actionable and accessing targeted drugs within the larger process of creating a precision medicine ecosystem that includes purpose-built institutional settings, thus simultaneously experimenting with bioclinical matters and, reflexively, with organizing practices. The constitution and articulation of innovative sociotechnical arrangements at MSK provides a unique case study of the production of a large and complex clinical research ecosystem designed to implement rapidly evolving therapeutic strategies embedded in a renewed and dynamic understanding of cancer biology.

BACKGROUND: Early palliative care integration into the oncologic treatment pattern is recognized and strongly recommended to anticipate end-of-life issues and avoid disproportionate care. Targeted therapies (TTs), with their very rapid onset of action and relatively good tolerance, may have an effect on cancer-related symptoms, which could be beneficial in the context of palliative care.
METHODS: Data were extracted from a cohort of all patients hospitalized in an acute palliative care unit between 03.04.2019 and 07.04.2020. Data for all consecutive patients for which a decision on a TT was made during hospitalization were retrospectively analyzed.
RESULTS: Forty-two patients were identified. Thirty-one patients were currently receiving TT on admission. For 19/31 (61.3%) patients, the treatment was discontinued. The remaining 12 patients had TT after discharge from the palliative care unit (continuation of the same TT or modification of the TT during the stay), with an average duration of 208 days and an average of 46 days between the last TT and death. TT was introduced or reintroduced in 7 patients of the 11 patients hospitalized without treatment at admission. In this group, the average duration of treatment was 28 days, with an average of 28 days between the last TT and death. Five of the patients who received re-challenged TT experienced a subjective improvement of their symptom.
CONCLUSIONS: TT was discontinued in the majority of our patients. However, in some cases, the treatment was maintained because it was effective on cancer-related symptoms even at the end of life. However, this should not overshadow the palliative process. The continuation or introduction of a specific oncological treatment requires close cooperation between oncologists and palliative care physicians and an honest and clear explanation to patients and their families.

Neuroendocrine breast cancer (NEBC) is a rare entity accounting for <0.1% of all breast carcinomas and <0.1% of all neuroendocrine carcinomas. In most cases treatment strategies in NEBC are empirical in absence of prospective trial data on NEBC cohorts. Herein, we present two case reports diagnosed with anaplastic and small cell NEBC. After initial therapies failed, comprehensive tumor profiling was applied, leading to individualized treatment options for both patients. In both patients, targetable alterations of the PI3K/AKT/mTOR pathway were found, including a PIK3CA mutation itself and an STK11 mutation that negatively regulates the mTOR complex. The epicrisis of the two patients exemplifies how to manage rare and difficult to treat cancers and how new diagnostic tools contribute to medical management.

BACKGROUND: NTRK (neurotrophic tyrosine receptor kinase)-rearranged spindle cell neoplasms are a new group of tumors included in the new 5th edition of the World Health Organization (WHO) classification of soft Tissue and Bone Sarcomas. These tumors are characterized by NTRK gene fusions and show a wide spectrum of histologies and clinical behavior. Several targeted therapies have recently been approved for tumors harboring NTRK fusions, including STS.
METHODS: A 26-year-old male with advanced, pretreated NTRK rearranged spindle cell neoplasm and liver, lung and bone metastases was treated with larotrectinib on a continuous 28-day schedule, at a dose of 100 mg twice daily. An 18FDG-PET/CT scan performed after 7 days of treatment showed tumor shrinkage in both visceral and bone lesions. There was no drug-related toxicity. Subsequent evaluations confirmed continued tumor regression in disease sites. The patient is well and continues treatment.
CONCLUSIONS: The clinical and radiological response of our patient with an uncommon TPM4 (exon 7)-NTRK1 (exon 12) gene fusion tumor treated with a first-generation TRK inhibitor could contribute to a better understanding of the biology of this new STS entity and help to improve patient management.

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More than 40 tyrosine kinase inhibitors (TKIs) have received hematological or oncological indications over the past 20 years, following the approval of imatinib, and many others are currently being tested in clinical and preclinical level. Beyond their common toxicities, no certain agent from this large class of molecularly targeted therapies was strongly associated with \"off-target\" impairment of neuromuscular transmission, and although myasthenia gravis (MG) is a well-characterized autoimmune disorder, only few sporadic events proven by serologically detected causative autoantibodies and/or by positive electrophysiological tests are reported in the literature. Herein, we present the first case of anti-MUSK (+) MG in a woman with metastatic BRAF-mutant melanoma after long-term treatment with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor). Triggered by this report, a systematic literature review was conducted, summarizing all other cancer cases that developed MG, after exposure to any type of targeted agent and regardless of the underlying malignancy. All available data on the clinical diagnosis, the potential of administered TKIs to induce a seropositive myasthenic syndrome, the immune and non-immune-mediated pathogenesis of postsynaptic damage, and the challenging management of this neuromuscular toxicity were collected and discussed. In the presented case, MG was confirmed by both autoantibodies and nerve-conduction tests, while its reactivation after TKIs rechallenge supports a more than coincidental association. The following review identified 12 cancer cases with TKI-related MG in six case reports and one case series. In most of them, the myasthenia diagnosis was challenging, since the clinical symptomatology of fatigable weakness was not corroborating with consistent laboratory and electrophysiological findings. In fact, anti-AchR titers were positive in five and anti-MuSK only in the abovementioned individual. The symptomatology corresponded to TKI discontinuation and standard treatment with pyridostigmine and prednisolone; intravenous immunoglobulin was added only in three, and two required mechanical ventilation. In an era where TKIs will be prescribed more frequently for various malignancies, even in combinations with immune-checkpoint inhibitors, this report synthesizes their risk for neuromuscular complications and increases the clinicians\' awareness in order to extend the on-treatment and overall survival of TKI-treated cancer patients.

BACKGROUND: Pneumatosis intestinalis (PI) is a rare entity which refers to the presence of gas within the wall of the small bowel or colon which is a radiographic sign. The etiology and clinical presentation are variable. Patients with PI may present either with chronic mild non-specific symptoms or with acute abdominal pain with peritonitis. Some cases of intestinal pneumatosis have been reported as adverse events of new oncological treatments such as targeted therapies that are widely used in multiple tumors.
METHODS: A 59-year-old caucasian female with radioactive iodine-refractory metastatic thyroid papillary carcinoma with BRAFV600E mutation was treated with dabrafenib and trametinib as a compassionate use. After 4 months treatment, positron emission tomography-computed tomography (PET-CT) showed PI. At the time of diagnosis, the patient was asymptomatic without signs of peritonitis. The initial treatment was conservative and no specific treatment for PI was needed. Unfortunately, after dabrafenib-trametinib withdrawal, the patient developed tumor progression with significant clinical worsening.
CONCLUSIONS: This case report is, in our knowledge, the first description of PI in a patient treated with dabrafenib-trametinib. Conservative treatment is feasible if there are no abdominal symptoms.