Diabetes insípida central como primera manifestación clínica de un carcinoma colorrectal metastásico

Metastases of systemic tumours in the hypothalamus-pituitary region are reported to be around 1% to 4% of all intra-cranial metastases. Most of them are diagnosed when the primary tumour is operated-upon, or when widespread metastases occur. The metastasic infiltration of this region is usually asymptomatic and rarely recognised ante-mortem. The metastases rarely clinically manifest, but diabetes insipidus is the most frequent. Autopsy studies have shown breast and lung cancer are the mostfrequent cause of the metastases in this region. We present a clinical case of a patient presenting diabetes insipidus as the first manifestation of a metastasic colorectal cancer.     

Pituitary stalk metastasis from breast cancer treated with systemic chemotherapy

We describe a 61-year-old woman with diabetes insipidus caused by a pituitary stalk metastasis from breast cancer. She had a medical history of breast conservation therapy for early breast cancer 5 years previously. Pituitary, lung, liver, bone and neck lymphnode metastases was revealed at the same time. She received systemic chemotherapy consisting of docetaxel and cisplatin. After chemotherapy MRI finding in pituitary gland was improved, lung and liver metastases also improved, however, symptoms of diabetes insipidus did not improve. She is alive, receiving endocrine treatment for 2 years, since onset of diabetes insipidus.     

PD-L1 Expression of Lung Cancer Cells,Unlike Infiltrating Immune Cells,Is Stable and Unaffected by Therapy During Brain Metastasis

BackgroundApproximately 50% of brain metastases originate from non–small-cell lung cancer. The median survival of patients with brain metastases is 1 month without treatment. Novel immunotherapeutic strategies, such as those targeting the programmed death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) axis, are promising in patients with advanced systemic disease but are often preferentially administered to patients with tumors showing PD-L1 positivity.Patients and MethodsSurgically resected paired primary lung adenocarcinoma and brain metastasis samples of 61 patients were analyzed. We compared the paired samples regarding the amount of peritumoral and stromal mononuclear infiltration, PD-L1 expression of tumor and immune cells, and PD-1 expression of immune cells. We investigated the effect of radiotherapy, chemotherapy, and steroid therapy on PD-L1 expression in brain metastases.ResultsThere was significant positive correlation regarding the PD-L1 expression of tumor cells between the paired primary lung adenocarcinoma and brain metastatic samples with the use of different cutoff levels (1%, 5%, 50%). We found no impact of chemotherapy or steroid therapy on the changes of PD-L1 expression of tumor cells between the 2 sites. There is no or only limited concordance of the proportion of PD-1– or PD-L1–positive tumor-associated immune cells between the paired tumor samples, which suggests that brain metastases develop their own immune environment.ConclusionWe observed a strong correlation of PD-L1 positive tumor cells between primary lung adenocarcinoma cases and their corresponding brain metastases, which is not significantly influenced by chemotherapy or steroid therapy.     

Polyuria and polydipsia in a patient with non-small-cell lung cancer

Tumor metastasis to the pituitary gland has been infrequently reported, and this is probably because only a small proportion of these patients are symptomatic. Most of the symptoms of this malady are related to diabetes insipidus. A 78-year-old man was diagnosed 2 years previously with stage IIIA adenocarcinoma of the lung and treated with sequential chemoradiation therapy and later with whole-brain radiation therapy because of newly developed brain metastasis; he was then admitted to our hospital with symptoms of polydipsia and polyuria. He was confirmed to have central diabetes insipidus that was caused by the pituitary metastasis from lung cancer. His symptoms resolved after treatment with desmopressin. Because of the rarity of this manifestation in lung cancer patients, we report on this case along with a brief review of the relevant literature.     

Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer

BackgroundThe dynamics of PD-L1 expression may limit its use as a tissue-based predictive biomarker. We sought to expand our understanding of the dynamics of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in patients with lung cancer-related brain metastases.Experimental designPaired primary lung cancers and brain metastases were identified and assessed for PD-L1 and CD3 expression by immunohistochemistry. Lesions with 5% or greater PD-L1 expression were considered positive. Agreement statistics and the χ² or Fisher's exact test were used for analysis.ResultsWe analyzed 146 paired lesions from 73 cases. There was disagreement of tumor cell PD-L1 expression in 10 cases (14%, κ = 0.71), and disagreement of TIL PD-L1 expression in 19 cases (26%, κ = 0.38). Most paired lesions with discordant tumor cell expression of PD-L1 were obtained 6 or more months apart. When specimens were categorized using a proposed tumor microenvironment categorization scheme based on PD-L1 expression and TILs, there were significant changes in the classifications because many of the brain metastases lacked either PD-L1 expression, tumor lymphocyte infiltration or both even when they were present in the primary lung cancer specimens (P = 0.009).ConclusionsWe identified that there are significant differences between the tumor microenvironment of paired primary lung cancers and brain metastases. When physicians decide to treat patients with lung cancer with a PD-1 or PD-L1 inhibitor, they must do so in the context of the spatial and temporal heterogeneity of the tumor microenvironment.     

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors as a First-Line Therapy for Never-Smokers with Adenocarcinoma of the Lung and Asymptomatic Synchronous Brain Metastasis

BackgroundAs routine initial evaluation with improved neuroimaging technique increases incidence of brain metastases in advanced/metastatic non—small-cell lung cancer, we face a dilemma to choose initial treatment for patients with asymptomatic brain metastasis. On the other hand, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib reportedly have high response rates for patients who have never smoked and have adenocarcinoma histology. Based on those findings, we studied the efficacy of the EGFR TKIs as a first-line therapy for never-smokers with metastatic adenocarcinoma of the lung and asymptomatic synchronous brain metastases.Patients and MethodsThe eligible patient should be a never-smoker with adenocarcinoma of the lung and asymptomatic synchronous brain metastases. Additional inclusion criteria are as follows: Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–3, adequate organ function, and measurable disease in both extracranial and intracranial sites. Neither previous chemotherapy nor radiation therapy, including stereotactic radiosurgery, was allowed. Treatment consisted of gefitinib 250 mg or erlotinib 150 mg orally given once daily until disease progression, unacceptable toxicity, or patient's refusal. Objective tumor responses were assessed every 2 months or clinically indicated.ResultsBetween January 2005 and August 2007, all 23 patients (median age, 60 years; male/female, 1/22; ECOG PS of 0–1/2–3, 11/12) were enrolled. Among them, 12 patients had no extrathoracic metastasis except brain. There were 15 partial responses (65.2%; 95% CI, 44.8%–81.3%), 3 stable diseases (13.0%), and 5 progressive diseases (21.7%), giving a disease control rate of 79.3%. With a median follow-up of 9 months, progression-free and overall survival was 6.4 months and 18.6 months, respectively. Among 17 patients showing progressive disease, 9 (39.1%) had to receive whole-brain radiation therapy because of the development of neurologic symptoms or signs.ConclusionsEGFR TKIs showed promising response rate as a first-line therapy for never-smokers with adenocarcinoma of the lung and asymptomatic synchronous brain metastases in both intracranial and extracranial sites, suggesting that these agents can be a treatment of choice in this clinical setting.     

Timing and Origins of Local and Distant Metastases in Lung Cancer

IntroductionMetastasis is the primary cause of lung cancer-related death. Nevertheless, the underlying molecular mechanisms and evolutionary patterns of lung cancer metastases are still elusive.MethodsWe performed whole-exome sequencing for 40 primary tumors (PTs) and 61 metastases from 47 patients with lung cancer, of which 40 patients had paired PTs and metastases. The PT-metastasis genomic divergence, metastatic drivers, timing of metastatic dissemination, and evolutionary origins were analyzed using appropriate statistical tools and mathematical models.ResultsThere were various degrees of genomic heterogeneity when comparing the paired primary and metastatic lesions or comparing metastases of different sites. Multiple metastasis-selected/enriched genetic alterations were found, such as MYC amplification, NKX2-1 amplification, RICTOR amplification, arm 20p gain, and arm 11p loss, and these results were were also featured in a meta-analysis cross-validated using an independent cohort from Memorial Sloan-Kettering Cancer Center database. To elucidate the metastatic seeding time, we applied a metastatic model and found 61.1% of the tumors were late dissemination, in which the metastatic seeding happened approximately 2.74 years before clinical detection. One exception was lymph node metastases whose dissemination time was relatively early. By analyzing the evolutionary origins, we reported that nonlymph node metastases were mainly seeded by the PT (87.5%) rather than the earlier colonized lymph node metastases.ConclusionsOur results shed light on the molecular features that potentially drive lung cancer metastases. The distinct temporospatial pattern of disease progression revealed that lung cancer was susceptible to either late dissemination or indolent early lymph node metastases, leaving a potential time window to minimize metastases by early cancer detection.     

Pembrolizumab as First-Line Palliative Therapy in PD-L1 Overexpressing (≥ 50%) NSCLC: Real-world Results with Special Focus on PS ≥ 2, Brain Metastases,and Steroids

IntroductionPembrolizumab is a highly effective standard of care in PD-L1 overexpressing (≥ 50%) non–small-cell lung cancer. However, a substantial share of patients from everyday clinical practice is treated without clear evidence from clinical trials.Patients and MethodsWe performed a retrospective multicentric study including all consecutive patients from 6 certified lung cancer centers in Berlin, Germany, having received pembrolizumab as first-line palliative therapy from January 1 until December 31, 2017. Aims were to validate published clinical trials with a special focus on efficacy and outcome in patients with reduced performance status (PS), brain metastases, and steroids.ResultsA total of 153 patients were included (median age 69 years, 58% men, 69% adenocarcinoma). Rates for PS ≥ 2, brain metastases, and steroids were 24.8%, 20.9%, and 24.2%, respectively. Median objective response rate, progression-free and overall survival were 48.5%, 8.2 and 22.0 months for all patients and 52.4%, 8.8 and 29.2 months in patients fulfilling the inclusion criteria for the KEYNOTE-024 trial. Patients with a comorbidity-defined PS ≥ 2, symptomatic brain metastases requiring upfront radiotherapy, or baseline steroids had significantly reduced survival. In contrast, durable responses occurred with a tumor-related PS ≥ 2 or asymptomatic brain metastases. Grade 3/4 and 5 immune-related adverse events affected 13.7% and 2.0% of patients.ConclusionReal-world and clinical trial efficacy with upfront pembrolizumab correspond well. Pembrolizumab may sufficiently control asymptomatic brain metastases and may improve a cancer-related reduced PS. However, the frail share of patients with a comorbidity-defined PS ≥ 2, symptomatic brain metastases, or baseline steroids derives no relevant benefit.     

Mutational Landscape and Evolutionary Pattern of Liver and Brain Metastasis in Lung Adenocarcinoma

IntroductionA comprehensive genomic analysis of paired primary tumors and their metastatic lesions may provide new insights into the biology of metastatic processes and therefore guide the development of novel strategies for intervention. To date, our knowledge of the genetic divergence and phylogenetic relationships among diverse metastatic lesions from cancer remains limited.MethodsWe performed whole-exome sequencing in 84 tissue and blood samples from 26 patients with lung adenocarcinoma having liver metastases (LiM) or brain metastases (BrM) before any systemic therapy, with the goal to molecularly characterize the metastatic process. Mutational landscape and evolutionary patterns were compared between paired primary lesions (primary lesion of LiM or BrM) and metastases (metastatic site of LiM or BrM).ResultsWe found that common driver mutations, including TP53 and EGFR, were highly consistent between paired primary and metastatic tumors. Although tumor mutational burden was comparable among groups, the LiM group had significantly higher mutational and copy number variational similarity than the BrM group between paired primary lesions and metastases (p = 0.019 and p = 0.035, respectively). Phylogenetic analysis further revealed that LiM-competent disseminations had a higher level of genetic similarity to their paired primary lesions and were genetically diverged from their primary tumors at a relatively later stage than those of BrM. These results suggest that LiM favorably followed the linear progression model, whereas BrM was more consistent with the parallel progression model.ConclusionsThis study suggests that the mutational landscape and evolutionary pattern was distinctly different between the LiM and BrM of lung adenocarcinoma.     

Bone matters in lung cancer

BackgroundBone metastases are a significant and undertreated clinical problem in patients with advanced lung cancer.DesignWe reviewed the incidence of bone metastases and skeletal-related events (SREs) in patients with lung cancer and examined the burden on patients' lives and on health care systems. Available therapies to improve survival and lessen the impact of SREs on quality of life (QoL) were also investigated.ResultsBone metastases are common in lung cancer; however, owing to short survival times, data on the incidences of SREs are limited. As with other cancers, the costs associated with treating SREs in lung cancer are substantial. Bisphosphonates reduce the frequency of SREs and improve measures of pain and QoL in patients with lung cancer; however, nephrotoxicity is a common complication of therapy. Denosumab, a recently approved bone-targeted therapy, is superior to zoledronic acid in increasing the time to first on-study SRE in patients with solid tumours, including lung cancer. Additional roles of bone-targeted therapies beyond the prevention of SREs are under investigation.ConclusionsWith increasing awareness of the consequences of SREs, bone-targeted therapies may play a greater role in the management of patients with lung cancer, with the aim of delaying disease progression and preserving QoL.     

The role of hepatectomy in the management of metastatic gastric adenocarcinoma: A systematic review

BackgroundGastric cancer has a high mortality, with many patients presenting with advanced disease. Many patients who undergo curative gastrectomy will subsequently develop metastatic disease. Hepatectomy has an established place in treating metastases from a variety of cancers but its role in gastric cancer is not clear. This review sought to systematically appraise the literature to establish the role of hepatectomy in treating gastric cancer metastases.MethodMedline and EMBASE were searched for all papers publishing data on survival of patients with metastatic gastric adenocarcinoma who underwent hepatectomy.ResultsSeventeen studies with 438 patients were included. There were no randomised controlled trials. Perioperative mortality was 2%, with morbidity between 17 and 60%. Patients with solitary metastases appeared to have better survival. Other favourable survival characteristics included unilobar disease, and metachronous presentation. No advantage was demonstrated with either adjuvant or neoadjuvant chemotherapy.DiscussionFew patients with hepatic metastases from gastric cancer are suitable for hepatectomy, but for those suitable there appears to be survival benefit. Patients with synchronous, multiple or bilobar metastases have worse survival.ConclusionThe evidence supporting the role of hepatectomy in the treatment of hepatic metastases from gastric cancer is weak. However in a selected group there appears to be a survival advantage; patients with solitary metastases had better survival outcomes than those with multiple metastases and metachronous presentation was associated with a better prognosis than synchronous presentation. Hepatectomy should be considered in these patients in the setting of a randomised trial.     

Response to afatinib in treatment-naïve patients with advanced mutant epidermal growth factor receptor lung adenocarcinoma with brain metastases

Background: Brain metastases are observable in 20–40% of non-small cell lung cancer patients, but standard treatments for such metastases may be intolerable to some. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were found to be effective against mutant-EGFR lung adenocarcinomas, but data regarding their effectiveness, especially for the second-generation EGFR-TKI afatinib, is limited. This study compared key outcomes for afatanib monotherapy versus afatinib combined with whole-brain radiotherapy (WBRT) in treatment-naïve lung adenocarcinoma patients harboring EGFR mutations.

Methods: A retrospective review of 28 brain metastatic lung adenocarcinoma patients treated between June 2014 and December 2016 was conducted; 17 were treated with WBRT and maintenance afatinib therapy, while 11 received afatinib monotherapy.

Results: The patients were predominantly female (n = 17, 60.7%) and non-smokers (78.6%). Almost all the patients (89.3%) had an Eastern Cooperative Oncology Group performance status of 0–2. The EGFR mutation type consisted of the del19 mutation in 57.1% of the patients (n = 16), while L858R mutations were found in 42.9% (n = 12). The mean number of brain metastases (6.1 ± 5.0) was higher among the patients treated with afatinib monotherapy, while the mean size of the largest brain metastasis (19.0 ± 10.5mm) was greater in the afatinib combined with WBRT group. The objective response rates for the afatinib monotherapy and combination therapy groups were 81.8% and 88.2%, respectively. However, the monotherapy group exhibited a significantly higher complete response rate for intracranial lesions (63.6% vs. 17.6%, p = 0.02), and there were no significant differences between the two treatment groups in overall survival or time to treatment failure.

Conclusion: Afatinib can provide therapeutic efficacy and a good response rate in treatment-naïve mutant-EGFR lung adenocarcinoma patients with brain metastases regardless of whether or not they also receive radiotherapy.     

Survival benefit of combined curative resection of the stomach (D2 resection) and liver in gastric cancer patients with liver metastases

BackgroundThe benefit of surgical resection of liver metastases from gastric cancer has not been well established. The aim of this study was to evaluate the rationale for hepatic resection in patients with hepatic metastases from gastric cancer.MethodsAmong 10 259 patients diagnosed with gastric adenocarcinoma in the Yonsei University Health System from 1995 to 2005, we reviewed the records of 58 patients with liver-only metastases from gastric cancer who underwent gastric resection regardless of hepatic surgery.ResultsThe overall 1-year, 3-year, and 5-year survival rates of 41 patients who underwent hepatic resection with curative intent were 75.3%, 31.7%, and 20.8%, respectively, and three patients survived >7 years. Of the 41 patients, 22 had complete resection and 19 had palliative resection. Between the curative and palliative resections, survival rates after curative intent were not different. The number of liver metastasis (solitary or multiple) was a marginally significant prognostic factor for survival.ConclusionsSurgery for liver metastases arising from gastric adenocarcinoma is reasonable if complete resection seems feasible after careful preoperative staging, even if complete resection is not actually achieved. Hepatic resection should be considered as an option for gastric cancer patients with hepatic metastases.     

Expression of Chemokine Receptor CCR6 as a Molecular Determinant of Adrenal Metastatic Relapse in Patients With Primary Lung Cancer

BackgroundRecent studies suggest that chemokines are involved in organ-specific metastatic relapse. We evaluated the potential implications of chemokine receptors in the development of adrenal metastasis after complete resections of primary non–small-cell lung cancer.Patients and MethodsWe studied a unique cohort of 21 primary lung cancers with matched adrenal metastases for the expression of CX3CR1, CXCR4, CCR6, and CCR7, using immunohistochemistry.ResultsAlthough CXCR4, CX3CR1, and CCR7 were independently expressed in primary and corresponding metastases, CCR6 was clearly overexpressed in adrenal metastases, compared with corresponding primary tumors. Moreover, CCL20, the ligand of CCR6, was preferentially expressed in adrenal tissues that developed metastases.ConclusionWe report for the first time (to the best of our knowledge) a potential role for the CCR6 receptor in the organ orientation of the development of metastases in lung cancer. We demonstrated a statistically significant overexpression of CCR6 in adrenal metastases compared with primary lung tumors, indicating that the increased production of CCL20 in adrenal glands might contribute to the selective recruitment of CCR6-expressing cancer cells in lung cancer. This study, in concordance with the data obtained in animal models, suggests that the chemokine receptor family constitutes a biologic support of the “seed and soil” theory.     

Evidence That Established Lung Cancer Mortality Disparities in American Indians Are Not Due to Lung Cancer Genetic Testing and Targeted Therapy Disparities

BackgroundAmerican Indians and Alaska Natives (AI/AN) continue to experience extreme lung cancer health disparities. The state of Minnesota is home to over 70,000 AI/AN, and this population has a 2-fold increase in lung cancer mortality compared to other races within Minnesota. Genetic mutation testing in lung cancer is now a standard of high-quality lung cancer care, and EGFR mutation testing has been recommended for all adenocarcinoma lung cases, regardless of smoking status. However, genetic testing is a controversial topic for some AI/AN.Patients and MethodsWe performed a multisite retrospective chart review funded by the Minnesota Precision Medicine Grand Challenge as a demonstration project to examine lung cancer health disparities in AI/AN. We sought to measure epidemiology of lung cancer among AI receiving diagnosis or treatment in Minnesota cancer referral centers as well as rate of EGFR testing. The primary outcome was the rate of EGFR mutational analysis testing among cases and controls with nonsquamous, non–small-cell lung cancer. We secured collaborations with 5 health care systems covering a diverse geographic and demographic population.ResultsWe identified 200 cases and 164 matched controls from these sites. Controls were matched on histology, smoking status, sex, and age. In both groups, about one third of subjects with adenocarcinoma received genetic mutation testing.ConclusionThere was no significant difference in mutation testing in AI compared to non-AI controls at large health care systems in Minnesota. These data indicate that other factors are likely contributing to the higher mortality in this group.     

The comparison of Lobe-Specific or Systematic Mediastinal Lymph Node Dissection for Early-Stage Lung Adenocarcinoma With Consolidation Tumor Ratio Over 0.5

IntroductionSurgery is the most effective treatment for early-stage lung cancer. This study will propose a personalized plan for mediastinal lymph node dissection in early-stage lung adenocarcinoma to reduce the risk of surgery and improve the quality of life.MethodsThis study retrospectively analyzed the patients underwent lobectomy and lymph node dissection in the Department of Thoracic Surgery, Zhongshan Hospital, Fudan University. Clinical stage I lung adenocarcinoma patients with solid component ratio (CTR) between 0.5 and 1 were included. Patients were divided into systematic (S-MLND) and lobe-specific (L-MLND) mediastinal lymph node dissection groups. The days of hospitalization, the presence or absence of complications, the recurrence-free survival rate, and the overall survival rate were calculated to evaluate the postoperative quality and operation risk of the patients.Results210 patients (138 L-MLND and 72 S-MLND) were included. 2 lymph node metastases appeared in the S-MLND group while none in the L-MLND group (P = .049). No differences were shown in age, tumor site, size, solid component, degree of tumor invasion, and stage. The proportion of patients with severe postoperative cough and the length of hospital stay in the L-MLND group decreased. The 5-year OS of the entire cohort was 98.1%, 98.6% in L-MLND, compared with 97.2% in S-MLND; RFS was 94.8%, 95.7% in L-MLND, compared with 93.0% in S-MLND.ConclusionFor cIA lung adenocarcinoma, according to the Thin-slice CT within 1 month before the operation, if the main lesion was less than 3 cm and CTR over 0.5, L-MLND is as effective as S-MLND.     

Pancreatic involvement in small cell lung cancer

Background

Few data are available concerning incidence, clinical picture, and prognosis for pancreatic metastases of small cell lung carcinoma. In this paper we review the related literature available in English language.

Conclusions

Although pancreatic metastases are generally asymptomatic, they can rarely produce clinical symptoms or functional abnormalities. The widespread use of multi-detector computerised tomography (CT) in contemporary medical practice has led to an increased detection of pancreatic metastases in oncology patients. Tissue diagnosis is imperative because radiological techniques alone are incapable of differentiating them from primary pancreatic tumours. Pancreatic metastases occur in the relative end stage of small cell lung cancer. The main complications of these lesions, although rare, are acute pancreatitis and obstructive jaundice. Early chemotherapy can provide a survival benefit even in patients with mild acute pancreatitis or extrahepatic biliary obstruction.