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Squamous cell carcinoma of the rectum is a rare malignancy (0.3% of all rectal cancers), with no known risk factor. These tumours are assessed as rectal cancer using immunohistochemical and radiological tests, and certain criteria (localisation, relationship with neighbouring structures) have to be fulfilled to make the diagnosis. Some clinicians used to stage them with the anal cancer TNM (tumourenodeemetastasis), whereas others used the rectal cancer TNM. When localised, the tendency nowadays is to treat those tumours like squamous anal cancers with definitive chemoradiotherapy (5-fluorouracil and mitomycin) and to skip surgery. For metastatic disease there is no clearly validated regimen and treatment should be based on recommendations of squamous anal cancers because of their common histology. Concerning follow-up after a curative approach, techniques should follow those for anal cancer as well, evaluating a delayed response.

<b><i>Background:</i></b> Gastric cancer is a leading cause of cancer-related deaths worldwide. Several treatment possibilities have been investigated, but only a few show clinically meaningful results. <b><i>Summary:</i></b> Systemic treatment options for advanced gastric cancer (aGC) have evolved over the recent years, implementing the growing molecular knowledge of this heterogeneous disease. Molecular profiling (at least for HER-2-expression, microsatellite instability status, <i>Epstein-Barr virus</i> expression, and programmed death ligand-1 expression/combined positive score [CPS]) is recommended for all therapy-fit patients prior to the start of a systemic treatment and is crucial for decisions on treatment strategy and drug selection. Various examples like the application of trastuzumab in the HER-2-positive subgroup underline the benefits of this approach starting from the first-line setting. A combination of platinum and fluoropyrimidine remains the first-line chemotherapy backbone in the treatment of advanced gastric cancer. Triplet combinations adding taxanes to the doublet regimen are reserved for certain scenarios. Unfortunately, almost all patients who receive first-line treatment (with or without anti-HER-2 blockade) progress and &#x3c;70% are eligible for a second-line therapy. The addition of monoclonal antibodies has substantially improved outcomes in this setting. As such, ramucirumab has led to significant and clinically meaningful advancements in the second-line treatment. Furthermore, immuno-oncology with checkpoint inhibition and immune stimulation has evolved in the field of aGC. Recent first-line data show a significant survival benefit in aGC patients with a CPS ≥ 5 under immunochemotherapy. Nonetheless, the impact of immunotherapy combinations and immunochemotherapy remains an area of investigation. <b><i>Key Message:</i></b> In this review, we highlight recent improvements in the treatment landscape of advanced gastric cancer, the heterogeneity of this disease, and possible personalized targets.

Opinion statementCompared to liver and lung metastases, brain metastases (BMs) from colorectal cancer (CRC) are rare and remain poorly investigated despite the anticipated rise in their incidence. CRC patients bearing BM have a dismal prognosis with a median survival of 3–6 months, significantly lower than that of patients with BM from other primary tumors, and of those with metastatic CRC manifesting extracranially. While liver and lung metastases from CRC have more codified treatment strategies, there is no consensus regarding the treatment of BM in CRC, and their management follows the approaches of BM from other solid tumors. Therapeutic strategies are driven by the number and localisation of the lesion, consisting in local treatments such as surgery, stereotactic radiosurgery, or whole-brain radiotherapy. Novel treatment modalities are slowly finding their way into this shy unconsented armatorium including immunotherapy, monoclonal antibodies, tyrosine kinase inhibitors, or a combination of those, among others.This article reviews the pioneering strategies aiming at understanding, diagnosing, and managing this disease, and discusses future directions, challenges, and potential innovations in each of these domains. Highlights • With the increasing survival in CRC, brain and other rare/late-onset metastases are rising. • Distal colon/rectal primary location, long-standing progressive lung metastases, and longer survival are risk factors for BM development in CRC. • Late diagnosis and lack of consensus treatment strategies make BM-CRC diagnosis very dismal. • Liquid biopsies using circulating tumor cells might offer excellent opportunities in the early diagnosis of BM-CRC and the search for therapeutic options. • Multi-modality treatment including surgical metastatic resection, postoperative SRS with/without WBRT, and chemotherapy is the best current treatment option. • Recent mid-sized clinical trials, case reports, and preclinical models show the potential of unconventional therapeutic approaches as monoclonal antibodies, targeted therapies, and immunotherapy.

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months. Among patients who discontinued brigatinib, 100 (59.9%) received subsequent ALK-TKIs. Lorlatinib was the most common next ALK TKI (57.0%), followed by brigatinib retreatment (16.0%), alectinib (13.0%), ceritinib (10.0%), and crizotinib (4.0%). The median (95% CI) TTD of the post-brigatinib ALK TKI was 7.2 (3.9-13.8) months. In patients who received crizotinib then brigatinib, the median (95% CI) TTD of the post-brigatinib ALK TKI was 6.7 (3.7-22.2) months. In patients who received lorlatinib after brigatinib was discontinued, median (95% CI) lorlartinib TTD was 8.0 (3.9-not reached) months.Conclusions: These results indicate that brigatinib has real-world durable clinical effects for patients. Treatment with subsequent TKIs, can still bring benefit to patients after discontinuing brigatinib. More formalized prospective data are needed to establish sequencing recommendations.

In advanced non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) mutations are one of the most frequent oncogenic drivers. They confer a favorable prognosis and strongly predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Over the last decades, several EGFR genetic alterations, common and uncommon mutations, have been described in exons 18−21. Common mutations are exon 19 deletions (most frequently E746-A750) and exon 21 L858R substitution. Uncommon mutations include exon 18 G719X, exon 20 S768l, exon 21 L861Q and many other rare ones. This report describes the case of a 55-year-old woman with a newly diagnosed metastatic lung adenocarcinoma harboring two rare EGFR mutations and showing sustained response to osimertinib.

Background Rectal cancers represent 35% of colorectal cancers; 90% are adenocarcinomas, while squamous cell carcinoma accounts for 0.3% of them. Given its rarity, little is known concerning its pathogenesis, molecular profile and therapeutic management. The current treatment trend is to treat rectal squamous cell carcinoma by analogy to anal squamous cell carcinoma with definitive chemo-radiotherapy, setting aside surgery in case of local recurrence. Methods We performed an in-depth genomic analysis (next-generation sequencing, copy number variation, and human papilloma virus characterization) on 10 rectal squamous cell carcinoma samples and compared them in silico to those of anal squamous cell carcinoma and rectal adenocarcinoma. Results Rectal squamous cell carcinoma shows 100% HPV positivity. It has a mutational (PIK3CA, PTEN, TP53, ATM, BCL6, SOX2) and copy number variation profile (3p, 10p, 10q, 16q deletion and 1q, 3q, 5p, 8q, 20p gain) similar to anal squamous cell carcinoma. PI3K/Akt/mTOR is the most commonly affected signaling pathway similarly to anal squamous cell carcinoma. Most commonly gained or lost genes seen in rectal adenocarcinoma (FLT3, CDX2, GNAS, BCL2, SMAD4, MALT1) are not found in rectal squamous cell carcinoma. Conclusion This study presents the first comprehensive genomic characterization of rectal squamous cell carcinoma. We confirm the existence of this rare histology and its molecular similarity with anal squamous cell carcinoma. This molecular proximity confirms the adequacy of therapeutic management based on histology and not localization, suggesting that rectal squamous cell carcinoma should be treated like anal squamous cell carcinoma and not as a rectal adenocarcinoma.