Search

This study investigated the association between lung cancer and waterpipe smoking, which is an emerging global public health concern. Multicentre case-control study. This study included 627 cases and 3477 controls from the Iranian Study of Opium and Cancer (IROPICAN) study, which was conducted between 2017 and 2020. One frequency-matched control for each lung cancer patient was selected by age, gender and residential place; however, this study used controls of four cancer types in the analyses. The multivariable logistic regression model estimated the odds ratio (OR) and 95% confidence intervals (CIs). Additional analyses were performed among 181 lung cancer cases and 2141 controls who were not cigarette smokers or opium or nass/pipe users. The odds of lung cancer were higher among waterpipe smokers than never-smokers (OR = 1.3, 95% CI: 1.0–1.7). Results showed a higher OR of lung cancer for those who smoked the waterpipe daily (OR = 2.1, 95% CI: 1.4–3.0), smoked more than two heads per day (OR = 2.7, 95% CI: 1.8–4.0), had smoked for >20 years (OR = 1.9, 95% CI: 1.3–2.7), smoked more than 20 head-years (OR = 2.8, 95% CI: 1.9–4.1) and initiated smoking before the age of 30 years (OR = 1.7, 95% CI: 1.1–2.5). The association was only statistically significant for squamous cell carcinomas (OR = 1.8, 95% CI 1.2–2.7). Furthermore, this study observed a higher OR of lung cancer among exclusive waterpipe smokers (OR = 2.3, 95% CI: 1.6, 3.5). Waterpipe smoking was associated with an increased risk of lung cancer. The association was stronger with higher frequency, duration and intensity of exposure to waterpipe smoking. The association increases in exclusive waterpipe smokers, which is likely due to controlling for residual confounding by cigarette smoking and opium consumption, and higher exposure levels in this subpopulation. [ABSTRACT FROM AUTHOR]

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but highly aggressive ovarian malignant neoplasm lacking a unified clinical management process. Most patients are diagnosed at an advanced stage and have an extremely poor prognosis with an overall probability of survival less than 10 %. Here, we describe the case of a patient with advanced SCCOHT achieved a survival of over 5 years after receiving multiple cycles of immunotherapy combined with anti-angiogenic therapy or CDK4/6 inhibitors. At the same time, we also summarized the case reports and clinical trials of immunotherapy in SCCOHT. [ABSTRACT FROM AUTHOR]

The current guidelines for the treatment of non-small cell lung cancer encourage local curative treatment for selected patients with oligometastases. This study evaluated the surgical results of total en bloc spondylectomy (TES) for isolated spinal metastases originating from lung cancer in carefully selected patients. We retrospectively reviewed 14 patients (7 men and 7 women) who underwent TES for spinal metastases originating from lung cancer between 2000 and 2017. The primary outcome measure was the postoperative overall survival time. The histological types included adenocarcinoma (n = 12), pleomorphic carcinoma (n = 1), and small cell lung carcinoma (SCLC) (n = 1 patient). We assessed postoperative survival using Kaplan–Meier analysis and the log-rank test. The median postoperative survival time was 83.0 months (6–162 months) in 13 patients with non-small cell lung carcinoma (NSCLC) and 6 months in 1 patient with SCLC. The 3-, 5-, and 10-year overall survival rates in patients with NSCLC were 61.5%, 53.8%, and 15.4%, respectively. Poor postoperative performance status (PS) and Frankel grade, and preoperative irradiation to the vertebrae to be resected were significantly associated with short-term survival after TES in patients with NSCLC (p < 0.05). The surgical results of TES for spinal metastases of lung cancer were relatively favorable among carefully selected patients. TES may be indicated for spinal metastases of lung cancer in patients with controlled primary lung cancer, NSCLC histology, prospect of good postoperative PS, and preferably no irradiation to the target vertebrae. [ABSTRACT FROM AUTHOR]

Lung cancer is the second most common cancer worldwide, yet the distribution by histological subtype remains unknown. We aimed to quantify the global, regional, and national burden of lung cancer incidence for the four main subtypes in 185 countries and territories. In this population-based study, we used data from Cancer Incidence in Five Continents Volume XI and the African Cancer Registry Network to assess the proportions of adenocarcinoma, squamous cell carcinoma, small-cell carcinoma, and large-cell carcinoma among all lung cancers by country, sex, and age group and subsequently applied these data to corresponding national (GLOBOCAN) estimates of lung cancer incidence in 2020. Unspecified morphologies were reallocated to specified subtypes. Age-standardised incidence rates were calculated using the world standard population to compare subtype risks worldwide, adjusted for differences in age composition between populations by country. In 2020, there were an estimated 2 206 771 new cases of lung cancer, with 1 435 943 in males and 770 828 in females worldwide. In males, 560 108 (39%) of all lung cancer cases were adenocarcinoma, 351 807 (25%) were squamous cell carcinoma, 163 862 (11%) were small-cell carcinoma, and 115 322 (8%) were large-cell carcinoma cases. In females, 440 510 (57%) of all lung cancer cases were adenocarcinoma, 91 070 (12%) were squamous cell carcinoma, 68 224 (9%) were small-cell carcinoma, and 49 246 (6%) were large-cell carcinoma cases. Age-standardised incidence rates for adenocarcinoma, squamous cell carcinoma, small-cell carcinoma, and large-cell carcinoma, respectively, were estimated to be 12·4, 7·7, 3·6, and 2·6 per 100 000 person-years in males and 8·3, 1·6, 1·3, and 0·9 per 100 000 person-years in females worldwide. The incidence rates of adenocarcinoma exceeded those of squamous cell carcinoma in 150 of 185 countries in males and in all 185 countries in females. The highest age-standardised incidence rates per 100 000 person-years for adenocarcinoma, squamous cell carcinoma, small-cell carcinoma, and large-cell carcinoma, respectively, for males occurred in eastern Asia (23·5), central and eastern Europe (17·5), western Asia (7·2), and south-eastern Asia (11·0); and for females occurred in eastern Asia (16·0), northern America (5·4), northern America (4·7), and south-eastern Asia (3·4). The incidence of each subtype showed a clear gradient according to the Human Development Index for male and female individuals, with increased rates in high and very high Human Development Index countries. Adenocarcinoma has become the most common subtype of lung cancer globally in 2020, with incidence rates in males exceeding those of squamous cell carcinoma in most countries, and in females in all countries. Our findings provide new insights into the nature of the global lung cancer burden and facilitates tailored national preventive actions within each world region. None. [ABSTRACT FROM AUTHOR]

Primary ovarian small cell carcinoma of pulmonary type (SCCOPT) is a rare ovarian tumor with a poor prognosis. The platinum-based chemotherapy is the standard treatment. However, there is little research on the clinical characteristics of SCCOPT and the potential benefits of other treatments due to its low incidence. The study aims to investigate clinicopathological characteristics and treatment of SCCOPT. We summarized the clinical, imaging, laboratorical and pathological characteristics of 37 SCCOPT cases, in which 6 cases were admitted to the Gansu Provincial Hospital from the year of 2008 to 2022 and 31 cases reported in 17 English and 3 Chinese literatures. The median age of the studied SCCOPT cases (n =37) was 56.00 (range, 22–80) years. Almost 80% of them had a stage III or IV tumor. All patients underwent an operation and postoperative chemotherapy. Nevertheless, all cases had a poor prognosis, with a median overall survival time of 12 months. Immunohistochemically, the SCCOPT of all patients showed positive expressions of epithelial markers, such as CD56 and sex-determining region of Y chromosome-related high-mobility-group box 2 (SOX-2), and negative expressions of estrogen receptor, progesterone receptor, vimentin, Leu-7, and somatostatin receptor 2. The tumor of above 80% cases expressed synaptophysin. Only a few cases expressed neuron-specific enolase, chromogranin A, and thyroid transcription factor-1. SCCOPT had a poor prognosis. SOX-2 could be a biomarker to be used to diagnose SCCOPT. [ABSTRACT FROM AUTHOR]

Small cell carcinoma of the cervix is a rare but poor prognosis pathological type of cervical cancer, for which advice in clinical guidelines is unspecific. We therefore aimed to investigate the factors and treatment methods that affect the prognosis of patients with small cell carcinoma of the cervix. In this retrospective study, we collected data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries cohort and a Chinese multi-institutional registry. The SEER cohort included females diagnosed with small cell carcinoma of the cervix between Jan 1, 2000, and Dec 31, 2018, whereas the Chinese cohort included women diagnosed between Jun 1, 2006, and April 30, 2022. In both cohorts, eligibility was limited to female patients older than 20 years with a confirmed diagnosis of small cell carcinoma of the cervix. Participants who were lost to follow-up or those for whom small cell carcinoma of the cervix was not the primary malignant tumour were excluded from the multi-institutional registry, and those with an unknown surgery status (in addition to those for whom small cell carcinoma of the cervix was not the primary malignant tumour) were excluded from the SEER data. The primary outcome of this study was overall survival (length of time from the date of first diagnosis until the date of death from any cause, or the last follow-up). Kaplan-Meier analysis, propensity score matching, and Cox-regression analyses were used to assess treatment outcomes and risk factors. 1288 participants were included in the study; 610 in the SEER cohort and 678 in the Chinese cohort. Both univariable and multivariable Cox regression analysis (SEER hazard ratio [HR] 0·65 [95% CI 0·48–0·88], p=0·0058; China HR 0·53 [0·37–0·76], p=0·0005) showed that surgery was associated with a better prognosis. In subgroup analyses, surgery remained a protective factor for patients with locally advanced disease in both cohorts (SEER HR 0·61 [95% CI 0·39–0·94], p=0·024; China HR 0·59 [0·37–0·95]; p=0·029). Furthermore, the protective effect of surgery was observed among patients with locally advanced disease after propensity score matching in the SEER cohort (HR 0·52 [95% CI 0·32–0·84]; p=0·0077). In the China registry, surgery was associated with better outcomes in patients with stage IB3-IIA2 cancer (HR 0·17 [95% CI 0·05–0·50]; p=0·0015). This study provides evidence that surgery improves outcomes of patients with small cell carcinoma of the cervix. Although guidelines recommend non-surgical methods as first-line treatment, patients with locally advanced disease or stage IB3-IIA2 cancer might benefit from surgery. The National Key R&D Program of China and the National Natural Science Foundation of China. [ABSTRACT FROM AUTHOR]

Olfactory neuroblastoma (ONB) is often difficult to pathologically distinguish from other small round cell tumors (SRCTs) arising in the nasal cavities. Although there are several diagnostic markers used for differential diagnosis of ONB, these molecules are also expressed in various neuronal derived tumors. Here, we examined the expression of NeuroD, GAP43, and olfactory marker protein (OMP) in ONB and non-ONB SRCT to determine their utility in the differential diagnosis of ONB. Twenty-six patients diagnosed with and treated for ONB at Kobe University Hospital between 1997 and 2017 with formalin-fixed, paraffin-embedded biopsy or surgical resection specimens were included. The expressions of NeuroD, GAP43, and OMP were immunohistochemically examined in these 26 ONB specimens and specimens from 13 SRCTs arising in the nasal cavities for reference. Among the 26 ONB samples, focal, patchy, and marked staining for NeuroD was observed in 4, 3, and 9 samples, respectively. Focal, patchy, and marked GAP43 staining was observed in 5, 3, and 11 samples, respectively. Consequently, marked positive staining for either NeuroD or GAP43 was observed in 54% (14/26) of ONBs. Among the 13 SRCTs, marked staining for NeuroD was observed in two small cell carcinomas, one undifferentiated carcinoma, and one neuroendocrine carcinoma, whereas marked positive staining for GAP43 was observed only in one undifferentiated carcinoma. No specimen in this study exhibited OMP staining. Our results suggest possible roles of GAP43 immunostaining in the differential diagnosis of ONB. [ABSTRACT FROM AUTHOR]

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare neoplasm that occurs mostly in women younger than 40 years of age. The unknown histogenesis makes the diagnosis of SCCOHT difficult. SCCOHT was recently shown to be associated with SMARCA4 gene mutation. Serum calcium levels can be used as a marker of treatment response and relapse in SCCOHT. Here we report on a 16-year-old girl who presented with pelvic mass and hypercalcemia. SCCOHT was diagnosed histopathologically. However, loss of neither BRG1 nor INI1 expression was detected. The diagnosis of SCCOHT should be among the differential diagnoses in adolescents presenting with pelvic mass and hypercalcemia. We would like to share our experience with this rare case, discuss recent management, and emphasize the importance of a multidisciplinary approach. Although it is known that almost all cases have a loss of BRG1 expression and a small group exhibit loss of INI1 , our patient indicates that there could be exceptional cases with hitherto undescribed genetic abnormalities. [ABSTRACT FROM AUTHOR]

Undifferentiated small round cell sarcomas (URCSs) represent a diagnostic challenge, and their optimal treatment is unknown. We aimed to define the clinical characteristics, treatment, and outcome of URCS patients. URCS patients treated from 1983 to 2019 at 21 worldwide sarcoma reference centres were retrospectively identified. Based on molecular assessment, cases were classified as follows: (1) CIC -rearranged round cell sarcomas, (2) BCOR::CCNB3 -rearranged round cell sarcomas, (3) unclassified URCSs. Treatment, prognostic factors and outcome were reviewed. In total, 148 patients were identified [88/148 (60%) CIC -rearranged sarcoma (median age 32 years, range 7–78), 33/148 (22%) BCOR::CCNB3 -rearranged (median age 17 years, range 5–91), and 27/148 (18%) unclassified URCSs (median age 37 years, range 4–70)]. One hundred-one (68.2%) cases presented with localised disease; 47 (31.8%) had metastases at diagnosis. Male prevalence, younger age, bone primary site, and a low rate of synchronous metastases were observed in BCOR::CCNB3- rearranged cases. Local treatment was surgery in 67/148 (45%) patients, and surgery + radiotherapy in 52/148 (35%). Chemotherapy was given to 122/148 (82%) patients. At a 42.7-month median follow-up, the 3-year overall survival (OS) was 92.2% (95% CI 71.5–98.0) in BCOR::CCNB3 patients, 39.6% (95% CI 27.7–51.3) in CIC -rearranged sarcomas, and 78.7% in unclassified URCSs (95% CI 56.1–90.6; p < 0.0001). This study is the largest conducted in URCS and confirms major differences in outcomes between URCS subtypes. A full molecular assessment should be undertaken when a diagnosis of URCS is suspected. Prospective studies are needed to better define the optimal treatment strategy in each URCS subtype. • Undifferentiated small round cell sarcomas (URCS) represent a therapeutic challenge. • Pathological, clinical and molecular data of these ultra-rare sarcomas are provided. • CIC-rearranged tumours have poor survival compared to BCOR:CCNB3/unclassified URCS. • Translational research and RNA-seq findings are discussed. [ABSTRACT FROM AUTHOR]

We evaluated the performance of ultrasound image-based deep features and radiomics for differentiating small fat-poor angiomyolipoma (sfp-AML) from small renal cell carcinoma (SRCC). This retrospective study included 194 patients with pathologically proven small renal masses (diameter ≤4 cm; 67 in the sfp-AML group and 127 in the SRCC group). We obtained 206 and 364 images from the sfp-AML and SRCC groups with experienced radiologist identification, respectively. We extracted 4024 deep features from the autoencoder neural network and 1497 radiomics features from the Pyradiomics toolbox; the latter included first-order, shape, high-order, Laplacian of Gaussian and Wavelet features. All subjects were allocated to the training and testing sets with a ratio of 3:1 using stratified sampling. The least absolute shrinkage and selection operator (LASSO) regression model was applied to select the most diagnostic features. Support vector machine (SVM) was adopted as the discriminative classifier. An optimal feature subset including 45 deep and 7 radiomics features was screened by the LASSO model. The SVM classifier achieved good performance in discriminating between sfp-AMLs and SRCCs, with areas under the curve (AUCs) of 0.96 and 0.85 in the training and testing sets, respectively. The classifier built using deep and radiomics features can accurately differentiate sfp-AMLs from SRCCs on ultrasound imaging. [ABSTRACT FROM AUTHOR]

Thymic epithelial tumours include the subcategory of thymic neuroendocrine neoplasms, which comprise a spectrum of entities that mirrors their counterparts in the lung, i.e. typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma. These tumours are classified according to the current WHO classification for lung tumours, and their relevant histomorphological and immunohistochemical criteria will be discussed in this brief review. Thymic neuroendocrine neoplasms do, however, also have clinical and molecular characteristics which set them apart from their pulmonary relatives, and recent research has provided valuable insights into possible molecularly-informed classification systems, which broadly align with classical categories, but also show some discrepancies. The most salient recent studies in that respect will also be discussed, as will the avenues for locally ablative therapy and possibilities for systemic treatment. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. Chemotherapy, immunotherapy and radiotherapy all play important roles in the management of SCLC. The aim of this study was to provide a comprehensive overview of the role and evidence of radiotherapy in the cure and palliation of SCLC. The search strategy included a search of the PubMed database, hand searches, reference lists of relevant review articles and relevant published abstracts. ClinicalTrials.gov was also queried for relevant trials. Thoracic radiotherapy improves overall survival in limited stage SCLC, but the timing and dose remain controversial. The role of thoracic radiotherapy in extensive stage SCLC with immunotherapy is the subject of several ongoing trials. Current evidence supports the use of prophylactic cranial irradiation (PCI) for limited stage SCLC but the evidence is equivocal in extensive stage SCLC. Whole brain radiotherapy is well established for the treatment of brain metastases but evidence is rapidly accumulating for the use of stereotactic radiosurgery. Further studies will define the role of PCI, whole brain radiotherapy and hippocampal avoidant PCI in the immunotherapy era. Radiotherapy is an essential component in the multimodality management of SCLC. Technological advances have allowed safer delivery of radiotherapy with reduced toxicities. Discussion at multidisciplinary team meetings is important to ensure radiotherapy is considered and offered in appropriate patients. • Radiotherapy has an important role in both the cure and palliation of SCLC. • Technological advances allow safer delivery of thoracic radiotherapy with reduced toxicities. • Role of thoracic radiotherapy in the immunotherapy era is uncertain and is a subject of ongoing trials. • Hippocampal avoidance PCI in LS-SCLC may reduce neurotoxicity without compromising outcomes. • Shared decision making on PCI versus MRI surveillance in ES-SCLC is essential. [ABSTRACT FROM AUTHOR]

We evaluated long-term outcomes of small cell carcinoma of the bladder (SCCB), a rare, aggressive disease. Among 199 patients with SCCB treated from 1990 to 2015, those with nonmetastatic disease had excellent longterm survival following neoadjuvant chemotherapy with 5-year disease-free survival rate of 50%. Patients with metastases had poor survival, with median overall survival of 10.3 months. Pathologic downstaging following neoadjuvant chemotherapy was associated with superior survival and ERCC2 mutations conferred increased likelihood of pathologic response. Introduction: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC). Patients and Methods: Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed. Results: One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (< pT2pN0) and pathologic complete response (pT0pN0) rates of 48% and 38%, respectively, with median follow-up of 7.2 years, and median DFS and OS of 5.6 and 14.5 years, respectively. NAC responders (< ypT2N0) had superior median DFS (14.5 vs. 0.6 years, hazard ratio [HR] 0.24, P < .001) and OS (14.5 vs. 2.5 years, HR 0.31, P = .002). DFS rates for responders and nonresponders were 76% and 27% at 5 years, and 71% and 23% at 10 years, respectively. Local and central nervous system recurrences were infrequent. Median progression-free survival (PFS) and OS for M1 disease were 6.9 and 10.3 months, respectively. Genomic profiling was performed on 47 NAC patients. Loss of ERCC2 function was significantly enriched among those with pathologic complete response to NAC (mutations present in 50% of pathologic complete responders vs. 15% nonresponders, P = .045). Conclusion: M0 SCCB is chemosensitive and patients have excellent long-term survival following response to NAC. Patients with M1 disease have poor survival despite systemic therapy. Loss-of-function mutations of ERCC2 were associated with pathologic complete response to NAC. [ABSTRACT FROM AUTHOR]

To investigate the causal relationship between human papillomavirus (HPV) and lung cancer, we conducted a study using the two-sample Mendelian randomization (TSMR). Data from genome-wide association studies (GWAS) were analyzed with HPV E7 Type 16 and HPV E7 Type 18 as exposure factors. The outcome variables included lung cancer, small cell lung cancer, adenocarcinoma and squamous cell lung cancer. Causality was estimated using inverse variance weighted (IVW), MR-Egger and weighted median methods. Heterogeneity testing, sensitivity analysis, and multiple validity analysis were also performed.. The results showed that HPV E7 Type 16 infection was associated with a higher risk of squamous cell lung cancer (OR = 7.69; 95% CI:1.98–29.85; p = 0.0149). HPV E7 Type 18 infection significantly increased the risk of lung adenocarcinoma (OR = 0.71; 95% CI: 0.38–1.31; p = 0.0079) and lung cancer (OR = 7.69; 95% CI:1.98–29.85; p = 0.0292). No significant causal relationship was found between HPV E7 Type 16 and lung adenocarcinoma, lung cancer, or small cell lung carcinoma, and between HPV E7 Type 18 and squamous cell lung cancer or small cell lung carcinoma. This study has revealed a causal relationship between HPV and lung cancers. Our findings provide valuable insights for further mechanistic and clinical studies on HPV-mediated cancer. • We aim to investigate the causal relationship between HPV lung cancer. • Positive correlation between HPV16 E7 and HPV18 E7 and the risk of overall LC and SCLC. • Provide valuable insights for further mechanistic and clinical studies on HPV-mediated cancer. [ABSTRACT FROM AUTHOR]

Lurbinectedin is a promising new drug being investigated in pre-treated patients with small cell lung cancer (SCLC) or malignant pleural mesothelioma (MPM). Its clinical activity in the real-world setting has not been investigated yet. Clinical data of patients with SCLC and MPM who were treated with lurbinectedin were prospectively collected. Comprehensive immune cell profiling by flow cytometry was performed on screening and treating peripheral blood samples. A total of 95 patients (43 SCLC and 52 MPM) were treated, mostly as ≥3-line of therapy. In the SCLC cohort, a median progression-free survival (mPFS) was 1.5 months (95% CI: 1.4–3.0), and median overall survival was 7.0 months (95% CI: 4.7–not reached). Objective radiological response and disease control rate after 12 weeks were 16% and 28%, respectively. In the MPM cohort, median progression-free survival was 2.8 months (95% CI: 1.4–4.2), and median overall survival was 7.2 months (95% CI: 5.9–not reached). Disease control rate after 12 weeks was 29%, whereas no partial responses were registered. No new safety signals were observed. Lurbinectedin treatment was significantly associated with the depletion of circulating classical monocytes, which correlated with a better PFS in patients with SCLC. Lurbinectedin increased the proliferation of CD4+ and CD8+ T cells (SCLC) and natural killer and natural killer T cells (SCLC and MPM) and altered co-stimulatory and co-inhibitory receptor expression on circulating lymphocytes. Lurbinectedin has a manageable safety profile and shows clinical activity in pre-treated patients with SCLC and MPM. Its immune-modulatory functions make lurbinectedin a potential platform for immunotherapy combinations. • Lurbinectedin was effective in heavily pre-treated patients with small cell lung cancer with objective response rate 16%. • In patients with pre-treated malignant mesothelioma (MM), the disease control rate of lurbinectedin after 12 weeks was 29%. • No new safety signals of lurbinectedin were observed in the real-world setting. • Lurbinectedin displays specific immune-modulatory effects. • Lurbinectedin seems to be a potential platform for immunotherapy combinations. [ABSTRACT FROM AUTHOR]

Gallbladder (GB) Small Cell Carcinoma (SCC) is an uncommon entity with very poor prognosis. There is a paucity of literature regarding its natural history and management, with only 73 prior cases reported in the world literature. In this case report, we present three cases of SCC of the GB with varied presentations, clinical course, management, and outcomes along with a brief review of the available literature on this subject. [ABSTRACT FROM AUTHOR]

The current standard treatment for limited-stage small-cell lung cancer (LS-SCLC) is chemotherapy with concurrent chemoradiotherapy (CCRT). In this single-arm phase II study, patients with LS-SCLC received four cycles of etoposide, cisplatin, and durvalumab every 3 weeks. Thoracic radiotherapy of 52.5 Gy in 25 once-daily fractions was started with the third cycle of chemoimmunotherapy. After CCRT plus durvalumab, patients received durvalumab consolidation therapy every 4 weeks for a maximum of 2 years after study enrolment. Prophylactic cranial irradiation (PCI) was recommended. Fifty-one patients were enrolled, and 50 were included in the full analysis set. With the median follow-up duration of 26.6 months, the median PFS was 14.4 months (95% confidence interval: 10.3–NA), and the 24-month PFS rate was 42.0%. The median overall survival was not reached with a 24-month overall survival rate of 67.8%. The positive PD-L1 group (n = 22) was not associated with longer PFS (hazard ratio, 0.70; 0.31–1.58) and overall survival (0.64; 0.22–1.84) compared with the negative PD-L1 group (n = 20). Among the 43 patients who were candidates for PCI treatment, the PCI group (n = 22) had significantly fewer events of brain metastasis as the first failure sites compared to the no PCI group (n = 21) (13.6% vs. 42.9%, P = 0.033). There were several grade 3 or 4 adverse events which were well managed with appropriate supportive care. Durvalumab with CCRT for LS-SCLC exhibited promising clinical efficacy with a tolerable safety profile, prompting its validation in a randomized study. NCT03585998. • Durvalumab with chemoradiotherapy demonstrates the promising efficacy in LS-SCLC. • Durvalumab administered concurrently with radiotherapy was tolerable. • Prophylactic cranial irradiation demonstrated lower brain metastases rate. • The predictive role value of PD-L1 expression was insufficient. [ABSTRACT FROM AUTHOR]

[Display omitted] • p53 and Rb alterations are confirmed as predisposing to SCLC transformation in EGFR- LUAD. • Paired EGFR-LUAD/SCLC samples showed diverse clonal evolution patterns. • TERT amplification is an acquired event during EGFR-LUAD to SCLC transformation. Among the different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) reported in EGFR -mutated lung adenocarcinoma (EGFR -LUAD) patients, histological transformation into small cell carcinoma (SCLC) occurs in 3–14% of resistant cases, regardless of the generation of EGFR-TKI. In recent studies, bi-allelic inactivation of TP53 and RB1 has been identified in a vast majority of transformed SCLCs. However, the molecular mechanisms driving this histologic transformation remain largely unknown, mainly due to the rarity of samples. Out of an initial cohort of 64 patients, tumor tissues of adequate quality and quantity for whole exome sequencing (WES) analysis were available for nine tumors for six patients: paired pre- and post-SCLC transformation samples for three Patients and post-SCLC transformation samples for three other patients. Mutational analyses showed concurrent TP53 mutations and Rb pathway alterations in five of the six patients analyzed, confirming their suggested role as predisposing genetic alterations to SCLC transformation. In addition, TERT amplification was detected in four of the six patients and found to be an event acquired during SCLC transformation. Clonal history evolution analyses from the paired LUAD/SCLC samples showed different evolution patterns. In two patients, a large proportion of mutations were present in the most recent common ancestor cell of the initial LUAD and the transformed SCLC clones, whereas in the third patient, few clonal mutations were common between the LUAD and SCLC samples and the ancestor clone that lead to SCLC was present at low frequency in the initial LUAD. Despite varied clinical presentations and clonal history evolution patterns, in addition to p53 and Rb pathways alterations, TERT amplification emerged as another common genetic mechanism of EGFR- LUAD to SCLC transformation in our cohort, and could represent a candidate therapeutic target in this subset of SCLC tumors. [ABSTRACT FROM AUTHOR]

• Lung cancer survival improved in all Nordic countries 1990–2017. • Similar patterns of improval across age and in both women and men. • Previously observed survival disadvantage in Denmark no longer present. • Improvements seen in adenocarcinoma, squamous cell and small-cell carcinoma. • Three of four patients still die from lung cancer within five years of diagnosis. The aim of this study was to evaluate if the previously reported improvements in lung cancer survival were consistent across age at diagnosis and by lung cancer subtypes. Data on lung cancers diagnosed between 1990 and 2016 in Denmark, Finland, Iceland, Norway and Sweden were obtained from the NORDCAN database. Flexible parametric models were used to estimate age-standardized and age-specific relative survival by sex, as well as reference-adjusted crude probabilities of death and life-years lost. Age-standardised survival was also estimated by the three major subtypes; adenocarcincoma, squamous cell and small-cell carcinoma. Both 1- and 5-year relative survival improved continuously in all countries. The pattern of improvement was similar across age groups and by subtype. The largest improvements in survival were seen in Denmark, while improvements were comparatively smaller in Finland. In the most recent period, age-standardised estimates of 5-year relative survival ranged from 13% to 26% and the 5-year crude probability of death due to lung cancer ranged from 73% to 85%. Across all Nordic countries, survival decreased with age, and was lower in men and for small-cell carcinoma. Lung cancer survival has improved substantially since 1990, in both women and men and across age. The improvements were seen in all major subtypes. However, lung cancer survival remains poor, with three out of four patients dying from their lung cancer within five years of diagnosis. [ABSTRACT FROM AUTHOR]

POU class 2 homeobox 3 (POU2F3)-positive small cell bladder carcinoma (SCBC) is an extremely rare entity, and its clinicopathologic features have not been fully described. Here, we investigated the clinicopathologic features of 4 cases of POU2F3-positive small cell bladder carcinoma (SCBC) and reviewed the literature. We collected 12 cases of SCBC from our departmental archives and detected the expression of POU2F3 by immunohistochemical (IHC) staining. Selected cases with or without POU2F3 expression were subjected to gene expression analysis between two different groups using DESeq2 software. We identified 4 POU2F3-positive SCBC patients, 2 males and 2 females, with a mean age of 77 years. Three patients had hematuria, and 1 patient had dysuria. Radiologic findings showed a bladder mass. Pathologic diagnosis showed that 3 cases were pure SCBC and 1 was mixed urothelial cancer (UC). Histopathologically, four POU2F3-positive SCBC tumors were composed of small round cells with sparse cytoplasm, the nuclei were salt-and-pepper-like or finely granular. Tumor cells showed characteristic cytoplasmic staining with punctate positive signals for cytokeratin. Syn and CD56 were diffusely positive in all the 4 patients. CgA was positive in only one patient. POU2F3-positive SCBC showed higher expression levels of POU2F3, HMGA2 and PLCG2 genes by RNA-Seq. Our data showed the specific clinicopathologic features of 4 rare POU2F3-positive SCBC cases, and the distinct molecular feature was observed between POU2F3-positive and negative SCBC in the limited number of cases. • We found that POU2F3-positive SCBC in our study may express at least one of the classic neuroendocrine markers. • Our results also suggest that POU2F3-positive and negative SCBC have distinct molecular characteristics in the limited number of cases. • POU2F3-positive SCBC showed higher expression levels of POU2F3 , HMGA2 , and PLCG2 genes by RNA-Seq. [ABSTRACT FROM AUTHOR]

Pulmonary large-cell neuroendocrine carcinoma (LCNEC), a disease with poor prognosis, is classified as pulmonary high-grade neuroendocrine carcinoma, along with small-cell lung cancer. However, given its infrequent occurrence, only a limited number of preclinical models have been established. Here, we established three LCNEC tumoroids for long-term culture. Whole-exome sequencing revealed that these tumoroids inherited genetic mutations from their parental tumors; two were classified as small-cell carcinoma (S-LCNEC) and one as non-small cell carcinoma (N-LCNEC). Xenografts from these tumoroids in immunodeficient mice mimicked the pathology of the parent LCNEC, and one reproduced the mixed-tissue types of combined LCNEC with a component of adenocarcinoma. Drug sensitivity tests using these LCNEC tumoroids enabled the evaluation of therapeutic agent efficacy. Based on translational research, we found that a CDK4/6 inhibitor might be effective for N-LCNEC and that Aurora A kinase inhibitors might be suitable for S-LCNEC or LCNEC with MYC amplification. These results highlight the value of preclinical tumoroid models in understanding the pathogenesis of rare cancers and developing treatments. LCNEC showed a high success rate in tumoroid establishment, indicating its potential application in personalized medicine. • LCNEC showed a high success rate in tumoroid establishment. • They were classified as small-cell carcinoma type (S-LCNEC) and non-small cell carcinoma type (N-LCNEC). • The tumoroids enabled the evaluation of therapeutic agent efficacy. • Tumoroids can be used to study LCNEC pathogenesis and develop new treatments. [ABSTRACT FROM AUTHOR]

• Acquired nephrotoxicity is a concern with prolonged pemetrexed use. • Reversible factors have not been identified in prior studies. • Two reversible risk factors were identified in our study. • Evacuation of third-space fluid may prevent pemetrexed-induced nephrotoxicity. • Avoiding cisplatin use during induction may mitigate risk of pemetrexed-induced nephrotoxicity. Nephrotoxicity is one of the concerns of prolonged maintenance therapy with pemetrexed. No reversible risk factors for pemetrexed-induced nephrotoxicity have been identified in previous studies. Identification of such factors would be clinically meaningful to maximize the chemotherapeutic benefits by avoiding premature termination of maintenance therapy which might otherwise result from the development of renal impairment. This was a retrospective single-center cohort study conducted in Queen Mary Hospital in Hong Kong. The study included 134 patients with advanced stage non-squamous NSCLC that received first line pemetrexed-platinum doublets followed by maintenance pemetrexed. The primary endpoint was the occurrence of nephrotoxicity. The risk factors of nephrotoxicity were identified. Presence of non-evacuated third-space fluid during treatment course (OR 4.185, 95% CI = 1.150–15.191, p-value 0.030), the use of cisplatin (instead of carboplatin) during the induction phase (OR 8.761, 95% CI = 1.684–45.577, p-value 0.010) and receiving more than 15 cycles of maintenance pemetrexed (OR 3.839, 95% CI = 1.022–14.413, p-value 0.046) were identified as independent risk factors to the development of nephrotoxicity associated with maintenance pemetrexed use. In order to reduce the risk of development of nephrotoxicity in NSCLC patient receiving first-line pemetrexed-platinum doublets, third-space fluid should be evacuated and carboplatin should be chosen over cisplatin whenever possible. [ABSTRACT FROM AUTHOR]

The purpose was to compare the treatment outcomes of radical chemoradiotherapy versus radical surgery plus adjuvant chemotherapy or chemoradiotherapy in locally advanced primary small cell carcinoma of the esophagus (LA-PSCCE). The hypothesis was that radical chemoradiotherapy had better overall survival (OS) than radical surgery plus adjuvant chemotherapy or chemoradiotherapy. This large-scale multicenter retrospective study in China enrolled patients with newly diagnosed LA-PSCCE (T3-4N0M0 or TanyN+M0, AJCC 8th edition) from 2008 to 2021. According to different curative treatment approaches, patients were divided into two groups: radical chemoradiotherapy (group: CRT), and radical surgery following adjuvant chemotherapy or chemoradiotherapy (group: S + CT/CRT). The propensity score match (PSM) was applied to reduce the effect of confounding biases in clinicopathological characteristics (age, gender, KPS, tumor location, tumor length, and cTNM stage). Univariate Cox-regression analysis and Kaplan-Meier curve were calculated for OS. Statistical results were summarized as hazard ratio (HR), 95% confidence interval (CI) and P value. A two-sided P < 0.05 was regarded to be statistically significant. A total of 291 patients with a median follow-up of 4.3 years were retrospectively enrolled. After PSM analysis, 94 and 94 patients were eventually included in group CRT and S + CT/CRT, respectively. Group CRT demonstrated a significantly superior survival than group S + CT/CRT (HR, 0.63; 95% CI, 0.43-0.91; P = 0.01), with a 3-year OS of 49.5% and 27.8% (P = 0.02), respectively. In secondary analysis, patients treated with radical chemoradiotherapy consistently showed significant survival benefit than those with radical surgery plus adjuvant chemoradiotherapy (HR, 0.4; 95% CI, 0.21-0.79; P = 0.008). For patients with newly diagnosed LA-PSCCE, radical chemoradiotherapy should be a preferred recommendation in real-world clinical practice. [ABSTRACT FROM AUTHOR]

Primary small cell carcinoma of esophageal (PSCCE) is a rare malignancy with aggressive behavior associated with a perceived poor prognosis. Due to its rarity, the clinical characteristics and the optimal clinical management have not yet been defined, therefore, we designed a multicenter retrospective study to analyze the prognostic factors and the impact of treatment on the prognosis of PSCCE patients. We retrospectively evaluated 704 consecutive patients with PSCCE from five participating centers between April 2008 and July 2021. The PSCCE was diagnosed based on the World Health Organization classification. Treatment strategies included surgery, radiotherapy (RT), or chemotherapy only, and combination of 2-3 treatment modalities (surgery, RT and chemotherapy). The estimated hazard rates provide the trajectory of progression and death overtime. Univariate survival analysis was conducted by using Kaplan-Meier plots, and the log-rank test was used to compare survival differences. Cox regression analysis was used to determine the independent prognostic factors in multivariate analysis. Overall, 69.0% (486/704) of the patients were male, with a median age of 63 years (range 38-96). Most of the patients were regional lymph node positive (N+, 64.0%), and nearly half with advanced stage (M+, 47.2%). With a median follow-up time of 16 months, 472 patients (67.0%) exhibited disease progression and 429 patients (60.9%) died. Following initial treatment, 85.1% (402/472) of progression/death and 80.1% (344/429) of mortalities occurred within 24 months. Consistently, the maximum annual death and progression/death hazards are highest in the 15.6 months and 9.6 months. The overall survival (OS) rates at 1, 3 and 5 years for all patients were 65.1%, 26.5% and 18.3%, respectively. Univariate survival analysis showed that ECOG score, alcohol abuse, TNM stage, N stage, and M stage were correlated with OS (P <0.05). Multivariate analysis showed that the N stage (HR: 1.378, P = 0.018) and M stage (HR: 1.945, P <0.001) carried independent prognostic factors for OS. In the term of treatment, the OS rates for M- patients treated with combined modality therapy (CMT, surgery±radiotherapy/chemotherapy) were better than those treated with surgery alone or radiotherapy/chemotherapy (3-year OS: 36.7% VS 25.6% VS 32.2%; P = 0.045). The OS rates for M+ patients treated with chemotherapy alone, radiotherapy alone, or radiotherapy combined with chemotherapy were no significant differences (3-year OS: 12.2% VS 19.4% VS 11.1%; P = 0.400). PSCCE is characterized by a high degree of malignancy with high risks of lymphatic and distant metastasis, N and M stages are the most important prognostic factor. In terms of treatment, comprehensive treatment is most likely to benefit patients without distant metastasis. [ABSTRACT FROM AUTHOR]

We studied comparative outcomes of efficacy of radiotherapy (RT) versus surgery for small-cell carcinoma of the prostate (SCCP). The National Cancer Database (NCDB) was queried for patients with nonmetastatic disease diagnosed from 2004 to 2015. Overall survival for patients who received RT or surgery was similar among patients with either pure or mixed small-cell histology. Both RT and surgery yield comparable outcomes when provided as local therapy. Background: Small-cell carcinoma of the prostate (SCCP) is a rare but aggressive prostate cancer histology. We studied the reported comparative outcomes of the efficacy of radiotherapy (RT) versus surgery for nonmetastatic SCCP. Methods: The National Cancer Database (NCDB) was queried for nonmetastatic disease diagnosed from 2004 to 2015 as SCCP (defined as having a component of SCCP) receiving a single definitive local control modality (RT or surgery). Results: A total of 243 patients were included (177 RT and 66 surgery). A total of 142 patients received chemotherapy (CHT). Mean age was 68 years. One hundred forty patients had adenocarcinoma concurrently with the SCCP while 103 patients had pure histology. For pure histology, multivariable analysis (MVA) showed nonacademic facility, stage 4 disease, and poorly differentiated grade were associated with worse survival. On MVA, receipt of CHT (hazard ratio [HR] = 0.84, P = .644) or receipt of androgen deprivation therapy (HR = 0.88, P = .715) did not affect overall survival. Receipt of RT was nonsignificant compared to surgery (HR = 0.75, P = .475). For mixed histology, MVA showed receipt of CHT and prostate-specific antigen > 20 ng/mL were associated with worse survival. Receipt of androgen deprivation therapy (HR = 1.35, P = .414) did not affect overall survival. Receipt of RT was also nonsignificant compared to surgery (HR = 1.42, P = .344). Conclusion: RT and surgery for nonmetastatic SCCP yield comparable options as local therapies. [ABSTRACT FROM AUTHOR]

To retrospectively analyse the impact of prophylactic cranial irradiation (PCI) on survival and intracranial progression in patients with limited stage small cell lung cancer (LS-SCLC) in the modern era of widespread magnetic resonance imaging brain screening. Patients with LS-SCLC treated within our network between 2009 and 2020 who responded to initial therapy were stratified by receipt of PCI and stage of disease. A propensity score match analysis was carried out for stage II–III patients. Overall and neurological survival were defined as time to death and presumed death due to uncontrolled intracranial disease, respectively. Brain metastasis-free survival and symptomatic brain metastasis-free survival were defined as freedom from intracranial progression and symptomatic intracranial progression, respectively. The effect of PCI on these outcomes was assessed using Kaplan–Meier and Cox proportional hazards models. In total, 243 (69.6%) of 349 patients received PCI. On multivariate analysis in the propensity matched stage II–III cohort, PCI was a significant predictor of improved neurological survival (hazard ratio 0.23, 95% confidence interval 0.08–0.65; P = 0.01), brain metastasis-free survival (hazard ratio 0.25, 95% confidence interval 0.12–0.51; P < 0.01) and symptomatic brain metastasis-free survival (hazard ratio 0.21, 95% confidence interval 0.08–0.55; P < 0.01), but not improved overall survival. Two-year neurological survival estimates within the propensity matched cohort were 96.8% (95% confidence interval 87.6–99.2%) with PCI and 77.2% (95% confidence interval 63.0–86.4%) without PCI and 1- and 2-year estimates of incidence of brain metastases were 3.9% (95% confidence interval 1.3–11.7%) and 11.7% (95% confidence interval 5.6–23.5%) in the PCI group and 31.6% (95% confidence interval 22.1–43.9%) and 40.4% (95% confidence interval 29.2–54.0%) in the no PCI group, respectively. In the modern era of magnetic resonance imaging screening, PCI was associated with reduced incidence of intracranial progression in patients with stage II–III LS-SCLC who respond to initial therapy. This, importantly, translated to a decreased risk of neurological death within our propensity matched cohort, without significant improvement in overall survival. • Benefit of PCI in LS-SCLC remains unclear due to lack of modern prospective data. • PCI improved neurological survival but not overall survival in stage II–III score matched cohort. • Significant decline in incidence of brain metastases was seen with addition of PCI. • Large prospective studies are needed to elucidate overall survival benefit of PCI in modern era. [ABSTRACT FROM AUTHOR]

Purpose: Small cell carcinoma of the bladder (SCCB) is rare, accounting for less than 1% of all bladder carcinomas. It is aggressive, and outcomes are poor as a result of its early metastatic spread. Owing to its rarity, there are limitations on data to propose standardized management pathways.Methods and Materials: We conducted a retrospective analysis of patients presenting with pure or predominant-histology SCCB to 26 institutions in the United Kingdom between 2006 and 2016. The data cutoff date was February 1, 2018. We report patient characteristics, treatment received, and subsequent clinical outcomes.Results: A total of 409 eligible patients were included. Among these, 306 (74.8%) were male, the median age was 71 years (range, 35-96 years), and 189 patients (46.2%) had pure-histology SCCB. At data cutoff, 301 patients (73.6%) had died. The median overall survival (OS) was 15.9 months (95% CI, 13.2-18.7 months). Two hundred patients (48.9%) were confirmed to have bladder-confined disease (N0, M0), with a median OS of 28.3 months (95% CI, 20.9-35.8 months), versus a median OS of 12.7 months (95% CI, 10.9-14.6 months) for the 172 patients (42.1%) with confirmed N1-3 and/or M1 disease (hazard ratio [HR], 2.03; 95% CI, 1.58-2.60; P < .001). A total of 247 patients (61.5%) received primary chemotherapy, with a median OS of 21.6 months (95% CI, 15.5-27.6 months), versus a median OS of 9.1 months (95% CI, 5.4-12.8 months) in patients who did not receive primary chemotherapy (HR, 0.46; 95% CI, 0.37-0.59; P < .001). Choice of chemotherapy agent did not alter outcomes. For those with bladder-confined disease, 61 (30.5%) underwent cystectomy, and 104 (52.0%) received radiation therapy. Survival outcomes were similar for both cystectomy and radiation therapy. Only 6 patients (1.5%) were identified as having brain metastases at any time point.Conclusions: To our knowledge, this is the largest retrospective study of all-stage SCCB to date. Patients have a poor prognosis overall, but survival is improved in those able to receive chemotherapy and with organ-confined disease. Brain metastases are rare. [ABSTRACT FROM AUTHOR]

p16 immunostaining is considered as a surrogate marker for human papillomavirus (HPV)-related head and neck squamous cell carcinomas (HNSCC). Herein, the utility of p16 is evaluated in cytology specimens. The electronic data of a large academic institution was searched for cytology cases accompanied by p16 (2014-2018). Cases were categorized based on body sites. P16 staining was quantified (negative [0%], focal/patchy, or diffusely positive [>70%]). HPV testing was correlated where available. A total of 372 cases were included (male:female, 239:133). The largest differences in application of p16 between men and women were in head/neck cases (209 versus 59) and the abdominal cases (1 versus 33), respectively. p16 diffuse staining is seen in most squamous cell carcinomas, small cell carcinomas, and gynecologic serous carcinomas. p16 expression was patchy or negative in most adenocarcinoma, neuroendocrine carcinoma, spindle cell neoplasms, and benign conditions. HPV testing was done on 217 cases including 138 cases with strong p16 (127 HPV+/11 HPV−), 20 cases with focal/patchy P16 staining (6 HPV+/14 HPV−) and 59 cases with negative p16 staining (3 HPV+/56 HPV−). Diffuse p16 staining aids in the diagnosis of HPV-related carcinomas, particularly HPV-related HNSCC, across the body and according to sex. In contrast, focal/patchy p16 staining does not correlate with HPV status across various body sites. In conclusion, intensity of p16 matters and should be correlated with cytomorphology, clinical history, and ancillary studies (eg, p40 immunostaining) for an accurate diagnosis and preventing diagnostic pitfalls. • Squamous cell carcinomas, small cell carcinoma, and serous carcinoma of gynecologic primary express the highest percentage of diffuse p16 positivity regardless of body region. • HPV testing is widely used in head and neck squamous cell carcinomas. • Occasionally, HPV positive HNSCC may exhibit focal or patchy expression of p16 (8.3%) on cytology p16 and cytology material. • Focal expression of p16 is non-specific and can be seen in variety of conditions such as adenocarcinomas. • Cytomorphologic correlation with intensity of p16, history, and other ancillary studies such as p40 immunostaining and HPV testing can improve diagnostic accuracy and prevent diagnostic pitfalls. [ABSTRACT FROM AUTHOR]

• The most common mutations identified were TP53 and RB1 in transformation to SCLC. • The rates of RB1 and TP53 were similar between first and third-generation TKI treatment. • Earlier occurrence of SCLC transformation was associated with poorer prognosis. • Anlotinib may be a good treatment choice in transformation to SCLC population. Transformation to small cell lung cancer (SCLC) is a resistance mechanism to tyrosine kinase inhibitor (TKI) treatment that develops in lung adenocarcinoma. The genomic and treatment outcomes in these populations have not been comprehensively reported in China. We performed a retrospective study analyzing patients with advanced non-SCLC (NSCLC) from eight sites who were diagnosed with SCLC transformation after receiving epidermal growth factor receptor (EGFR)-TKI treatment including first/second- or third-generation EGFR-TKIs. We assessed the genomic features and clinical prognosis in these patients with EGFR-mutated lung cancer. Thirty-two eligible patients with EGFR mutations were identified, 25 of whom had sufficient tumor tissues for detection of genes by next-generation sequencing. The median progression free survival (mPFS) for first/second-generation TKIs was 14.0 months. The most common mutations identified in samples with transformation to SCLC were in TP53 (17/25, 68.0 %), RB1 (9/25, 36.0 %), and PIK3CA (3/25, 12.0 %), and the incidence rates of RB1 and TP53 mutations were similar between patients receiving first/second-generation and third-generation TKI treatment. The estimated median time to SCLC transformation was 17.0 months. After SCLC transformation, platinum-etoposide was the most common treatment regimen, and the mPFS after platinum-etoposide treatment was 3.5 months. Anlotinib showed good efficacy in these patients (overall response rate, 66.7 %; mPFS, 6.2 months). The median overall survival after the initial diagnosis of metastatic lung cancer was 34.5 months, and patients with small cell transformation after third-generation TKI treatment had better prognosis than patients with transformation after first/second-generation treatment (49.4 months vs. 20.0 months, P = 0.013). We observed that TP53 and RB1 mutations were common in Chinese patients with SCLC transformation, regardless of whether first/second-generation or third-generation EGFR-TKI treatments were used. Earlier occurrence of small cell transformation after EGFR-TKI treatment was associated with poorer prognosis of patients. After the standard chemotherapy regimens for the management of primary SCLC, anlotinib may be a therapeutic option. [ABSTRACT FROM AUTHOR]

The clinical scenario of a pulmonary nodule following lung transplantation is one with limited experience and no supporting guidelines for the approach to diagnosis and management. Given the broad differential diagnosis for pulmonary nodules in this setting, most of which are life-threatening without appropriate treatment, aggressive evaluation is required. Here we present a case of a 70-year-old female with the development of a large pulmonary nodule in the native lung four years following a single lung transplant. She underwent bronchoscopy with endobronchial ultrasound to achieve a tissue diagnosis which showed small cell lung carcinoma. The patient was started on chemotherapy and has shown clinical and radiographic improvement at most recent follow up seven months after the initial diagnosis. In this report we discuss the differential diagnosis and corresponding imaging findings for the pulmonary nodule following lung transplantation to aid in guiding clinicians navigate this challenging clinical situation. • Pulmonary nodules following lung transplantation require aggressive evaluation. • There is limited experience and no guidelines for this clinical scenario. • The differential diagnosis is broad and the cause is generally life-threatening. • The most common etiologies are malignancy and infection. [ABSTRACT FROM AUTHOR]

• SOX2, MYC and CD44 gradually enrich in an in vitro SCLC disease progression model. • CSC marker increase correlated with colony formation potential and IR resistance. • CD44 could serve as a biomarker for advanced disease. Cancer stem cells (CSCs) have been implicated in disease progression of aggressive cancers including small cell lung carcinoma (SCLC). Here, we have examined the possible contribution of CSCs to SCLC progression and aggressiveness. GLC-14, GLC-16 and GLC-19 SCLC cell lines derived from one patient, representing increasing progressive stages of disease were used. CSC marker expressions was determined by RT-qPCR and western blotting analyses, and heterogeneity was studied by CSC marker expression by immunofluorescence microscopy and flow cytometry. Colony formation assays were used to assess stem cell properties and therapy sensitivity. Increasing expression of stem cell markers MYC, SOX2 and particularly CD44 were found in association with advancing disease. Single and overlapping expression of these markers indicated the presence of different CSC populations. The accumulation of more homogeneous double- and triple-positive CSC populations evolved with disease progression. Functional characterization of CSC properties affirmed higher proficiency of colony forming ability and increased resistance to γ-irradiation in GLC-16 and GLC-19 compared to GLC-14. GLC-19 colony formation was significantly inhibited by a human anti-CD44 antibody. The progressive increase of MYC, SOX2 and particularly CD44 expression that was accompanied with enhanced colony forming capacity and resistance in the in vitro GLC disease progression model, supports the potential clinical relevance of CSC populations in malignancy and disease relapse of SCLC. [ABSTRACT FROM AUTHOR]

Exosome-mediated epithelial mesenchymal transition (EMT) is key to cancer metastasis. c-Src is involved in the secretion of exosomes and initiation of EMT. Effects of exosomes from metastatic non-small cell lung carcinoma (NSCLC) cells on the EMT process in primary NSCLC cells were assessed. Levels of c-Src in NSCLC tissues were detected and the influence of exosomes from metastatic NSCLC cells on the exosome secretion and EMT process in primary NSCLC cells was assessed. The expression of c-Src was modulated, and the influence on the secretion of exosomes and EMT initiation was evaluated. The level of c-Src was higher in NSCLC specimen and NSCLC cells with promoted EMT process. The suppression of c-Src inhibited secretion of exosomes. Exosomes from metastatic NSCLC cells enhanced migration and invasion abilities of primary NSCLC cells, which had identical effects to c-Src overexpression. The suppression of c-Src inhibited growth and metastasis of solid tumors as well as secretion of exosomes, while the injection of exosomes with c-Src overexpression promoted lung metastasis. TGF-β1 restored the invasion and migration abilities even with c-Src knockdown. The exosomes from metastatic NSCLC cells with high c-Src expression of can increase c-Src level in primary NSCLC cells, contributing to the promoted EMT process through TGF-β1 pathway. [ABSTRACT FROM AUTHOR]

• Evaluation of the immune microenvironment of pulmonary pleomorphic carcinoma. • Comparison of the non-small cell carcinoma component and sarcomatoid component. • Higher expression of Programmed death ligand 1 expression in sarcomatoid component. • Programmed death ligand 1 expression can be a prognostic factor. Pulmonary pleomorphic carcinoma (PC) is a rare non-small cell lung carcinoma (NSCLC) and is characterized by sarcomatoid and NSCLC components. This study aimed to characterize the association between immune microenvironmental factors and clinicopathological characteristics of PC. Eighty consecutive PC patients who had undergone complete surgical resection were enrolled. We calculated the immunohistochemical staining scores for E-cadherin, vimentin, programmed death ligand 1 (PD-L1), and carbonic anhydrase IX in cancer cells and counted the numbers of CD204-positive tumor-associated macrophages (TAMs) and Foxp3-, CD8-, and CD20-positive tumor-infiltrating lymphocytes (TILs). We also examined the association between these scores and the prognostic outcomes. The staining score for PD-L1 in cancer cells and the number of CD204-positive TAMs in the sarcomatoid component were significantly higher than those in the NSCLC component; E-cadherin score in the sarcomatoid component was significantly lower. Patients with high PD-L1 expression in the NSCLC component had significantly longer overall survival (OS) and recurrence-free survival (RFS) than those with low PD-L1 expression in the NSCLC component (OS: p = 0.001, RFS: p = 0.038). Multivariate analysis revealed that high PD-L1 expression in the NSCLC component was an independent favorable prognostic factor for OS (p = 0.018), whereas high PD-L1 expression in the sarcomatoid component was not. The number of CD8-positive TILs was significantly higher in the high PD-L1 expression group than in the low expression group (NSCLC components: p < 0.001). High PD-L1 expression in the NSCLC component may be associated with a favorable prognostic value in pulmonary PC. [ABSTRACT FROM AUTHOR]

Objective: This multi-institutional study aimed to identify the optimal treatment strategy for small cell carcinoma of the cervix.Study Design: We retrospectively collected the medical records of 166 patients diagnosed with small cell carcinoma of the uterine cervix from January 2000 to December 2015 from 13 institutions of the Korean Radiation Oncology Group. After excluding 18 (10.8 %) patients who initially had distant metastasis, the treatment outcomes of 148 patients were analyzed.Results: After a median 46.4 (1.4-231.9) months of follow-up, the 5-year progression-free survival (PFS) and overall survival (OS) rates of all patients were 45.9 % and 63.5 %, respectively. Distant metastasis was the dominant pattern of failure occurring in 67 patients (45.3 %). We stratified the patients according to the primary local treatment: primary surgery (n = 119), primary radiotherapy (RT) (n = 26), and no local treatment group (n = 3). Although the primary RT group had advanced disease (FIGO stage ≧ IIB) more frequently than the primary surgery group (80.8 % vs. 47.9 %), the PFS and OS did not differ between the groups in multivariate analysis.Conclusion: Definitive RT is a reasonable local treatment option for small cell cervical cancer, particularly for advanced cases. Given the high rates of distant relapse, an effective systemic therapy protocol is warranted for small cell cervical cancer patients. [ABSTRACT FROM AUTHOR]

Tumor positive for synaptophysin (c), cytokeratin (d), CD56 (e), and negative for PDL-1 (f) Discussion With less than 100 cases described in the English literature, gallbladder small cell carcinoma is a rare, aggressive malignancy that most commonly presents with cholelithiasis and metastatic disease. PET-MRI demonstrated FDG-avid locally confined disease, with extensive soft tissue thickening centered around the gallbladder involving liver segments 4B and 5 (Fig. Given the poor prognosis, our account emphasizes the importance of surgical resection in managing patients with suspected gallbladder small cell carcinoma. [Extracted from the article]

Small cell carcinoma of ovary, hypercalcemia type (SCCOHT), also known as the malignant rhabdoid tumor of the ovary, is a rare and highly aggressive malignancy affecting younger women. The pathogenesis involves mutations in SWI/SNF-related, matrix-associated, actin-dependent regulator chromatin group A4 (SMARCA 4)/Brahma-related gene 1 (BRG1) and/or SWI/SNF-related, matrix-associated, actin-dependent regulator chromatin group A2 (SMARCA2)/Brahma homolog (BRM). A 10-year-old girl presented with lower abdominal pain and a mass for the past 2 weeks. She underwent ultrasound-guided fine needle aspiration and core needle biopsy from the pelvic mass followed by surgery. On the basis of the characteristic morphologic and immunohistochemical features, a diagnosis of SCCOHT was rendered. Chemotherapy was started, however, she succumbed to the disease. [ABSTRACT FROM AUTHOR]

Although carcinoma metastasis to primary intracranial neoplasms has occasionally been reported, metastasis to a cerebral arteriovenous malformation (AVM) has been exceedingly rare, with only 5 cases reported to date. In the present study, we have reported a case of lung carcinoma that had metastasized to a cerebral AVM. To the best of our knowledge, the present report is the first case in which the pathological examination detected the bleeding mechanism of this rare condition, showing destruction of the feeders by the metastatic tumor. A 61-year-old man who had had a tumor shadow in the right middle lung field identified at a medical examination 5 weeks previously had suddenly experienced a disturbance of consciousness. Head computed tomography and computed tomography angiography revealed a right occipital subcortical hemorrhage with abnormal vessels, suggesting a ruptured AVM. Magnetic resonance imaging with gadolinium-based contrast agents did not show any other lesions. Cerebral angiography revealed a Spetzler-Martin grade III AVM in the right occipital lobe. Endovascular feeder embolization and subsequent removal of the AVM were performed. Histopathological examination of the resected mass showed a small cell carcinoma that had metastasized to the AVM. The tumor cells had infiltrated to the vessel walls of the feeders, which might have elicited the bleeding. Although rare, clinicians should recognize that undifferentiated carcinomas can metastasize to AVMs and cause bleeding. Because the preoperative diagnosis can be difficult, even using the latest imaging modalities, careful examination of the resected specimen is required to reveal such pathological conditions. [ABSTRACT FROM AUTHOR]

To test the performance of free-breathing Dynamic Contrast-Enhanced MRI (DCE-MRI) using a radial volumetric interpolated breath-hold examination (VIBE) sequence combined with diffusion-weighted imaging (DWI) for quantitative solitary pulmonary nodule (SPN) assessment. A total of 67 SPN cases receiving routine MRI routine scans, DWI, and dynamic-enhanced MRI in our hospital from May 2017 to November 2018 were collected. These cases were divided into a malignant group and a benign group according to the characteristics of the SPNs. The quantitative DCE-MRI parameters (Ktrans, K ep , V e) and apparent diffusion coefficient (ADC) values of the nodules were measured. The Ktrans and K ep values in the malignant group were higher than those in the benign group, while the ADC values in the malignant group were lower than those in the benign group. Furthermore, the Ktrans value of adenocarcinoma was higher than that of squamous cell carcinoma and small cell carcinoma (P < 0.05). The V e value was significantly different between non-small cell carcinoma and small cell carcinoma (P < 0.05). With an ADC value of 0.98 × 10−3 mm2/s as the threshold, the specificity and sensitivity to diagnose benign and malignant nodules was 90.6% and 80%, respectively. High-temporal-resolution DCE-MRI using the r-VIBE technique in combination with DWI could contribute to pulmonary nodule analysis and possibly serve as a potential alternative to distinguish malignant from benign nodules as well as differentiate different types of malignancies. [ABSTRACT FROM AUTHOR]

• Carcinoids are characterized by well differentiated morphology and low proliferation. • LCNEC is characterized by poorly differentiated morphology and high proliferation. • We identified 7 pulmonary NEN with high proliferation but preserved differentiation. • pRb expression might be useful in this subgroup as a classifying or prognostic marker. Pulmonary neuroendocrine neoplasms (NENs) are subdivided in carcinoids and neuroendocrine carcinomas (small cell lung carcinoma and large cell neuroendocrine carcinoma (LCNEC)), based on the presence of necrosis and mitotic index (MI). However, it is unclear if tumors with well differentiated morphology but high proliferation rate should be regarded as LCNEC or as high grade carcinoids. In previous case series, a longer overall survival then expected in LCNEC has been suggested. We describe 7 of those cases analyzed for pRb expression and overall survival. Cases with well differentiated morphology, but MI > 10/2mm2 and/or Ki-67 proliferation index >20% were selected based on pathology reports of consecutive NENs in our university medical center (Maastricht UMC+, 2007-2018) and confirmed by pathological review. Immunohistochemistry was performed to assess pRb expression. Seven stage IV cases were included in this study. Median overall survival was 8 months (95% confidence interval 5-11 months). Cases with well differentiated morphology and preserved pRb expression (4/7) had a median overall survival of 45 months. A subgroup of pulmonary NENs with well differentiated morphology but high proliferation rate likely exists. pRb staining might be helpful to predict prognosis, but clinical relevance remains to be studied. [ABSTRACT FROM AUTHOR]

Small cell neuroendocrine carcinoma of the Bartholin gland is an extremely uncommon gynecologic tumor. Brain metastasis from a malignant gynecologic lesion is rarely encountered and the prognosis for this type of metastasis is quite poor. We report a case of a brain metastasis from a small cell neuroendocrine carcinoma of the Bartholin gland that was treated by surgical resection followed by whole-brain radiation therapy and review the literature. Different treatment options, including resection, stereotactic radiosurgery, and whole-brain radiation therapy, as well as chemotherapy, are available and should each be considered on an individual basis. [ABSTRACT FROM AUTHOR]

• LCNEC has radiological characteristics of both SCLC and NSCLC. • LCNEC can be classified in molecular SCLC-like and NSCLC-like subtypes. • Molecular LCNEC subtypes could not be identified based on radiological imaging. • Most LCNEC are molecular SCLC-like, but have a radiological NSCLC-like appearance. • These results highlight LCNEC as a unique tumor entity. Radiological characteristics and radiomics signatures can aid in differentiation between small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). We investigated whether molecular subtypes of large cell neuroendocrine carcinoma (LCNEC), i.e. SCLC-like (with pRb loss) vs. NSCLC-like (with pRb expression), can be distinguished by imaging based on (1) imaging interpretation, (2) semantic features, and/or (3) a radiomics signature, designed to differentiate between SCLC and NSCLC. Pulmonary oncologists and chest radiologists assessed chest CT-scans of 44 LCNEC patients for 'small cell-like' or 'non-small cell-like' appearance. The radiologists also scored semantic features of 50 LCNEC scans. Finally, a radiomics signature was trained on a dataset containing 48 SCLC and 76 NSCLC scans and validated on an external set of 58 SCLC and 40 NSCLC scans. This signature was applied on scans of 28 SCLC-like and 8 NSCLC-like LCNEC patients. Pulmonary oncologists and radiologists were unable to differentiate between molecular subtypes of LCNEC and no significant differences in semantic features were found. The area under the receiver operating characteristics curve of the radiomics signature in the validation set (SCLC vs. NSCLC) was 0.84 (95% confidence interval (CI) 0.77-0.92) and 0.58 (95% CI 0.29-0.86) in the LCNEC dataset (SCLC-like vs. NSCLC-like). LCNEC appears to have radiological characteristics of both SCLC and NSCLC, irrespective of pRb loss, compatible with the SCLC-like subtype. Imaging interpretation, semantic features and our radiomics signature designed to differentiate between SCLC and NSCLC were unable to separate molecular LCNEC subtypes, which underscores that LCNEC is a unique disease. [ABSTRACT FROM AUTHOR]

Airway micro-aspiration might contribute to the proposed associations between gastroesophageal reflux disease (GERD) and some lung diseases, including lung cancer. This study aimed to examine the hypothesis that antireflux surgery decreases the risk of small cell carcinoma, squamous cell carcinoma and adenocarcinoma of the lung differently depending on their location in relation to micro-aspiration. Population-based cohort study including patients having undergone antireflux surgery during 1980–2014 in Denmark, Finland, Iceland, Norway or Sweden. Patients having undergone antireflux surgery were compared with two groups: 1) the corresponding background population, by calculating standardised incidence ratios (SIRs) with 95% confidence intervals (CIs) and 2) non-operated GERD-patients, by calculating hazard ratios (HRs) with 95% CIs using multivariable Cox regression with adjustment for sex, age, calendar period, country, chronic obstructive pulmonary disease and obesity diagnosis or type 2 diabetes. Among all 812,617 GERD-patients, 46,996 (5.8%) had undergone antireflux surgery. The SIRs were statistically significantly decreased for small cell carcinoma (SIR = 0.57, 95% CI 0.41–0.77) and squamous cell carcinoma (SIR = 0.75, 95% CI 0.60–0.92), but not for adenocarcinoma of the lung (SIR = 0.90, 95% CI 0.76–1.06). The HRs were also below unity for small cell carcinoma (HR = 0.63, 95% CI 0.44–0.90) and squamous cell carcinoma (HR = 0.80, 95% CI 0.62–1.03), but not for adenocarcinoma of the lung (HR = 1.03, 95% CI 0.84–1.26). Analyses restricted to patients with objective GERD (reflux oesophagitis or Barrett's oesophagus) showed similar results. This all-Nordic study indicates that patients who undergo antireflux surgery are at decreased risk of small cell carcinoma and squamous cell carcinoma of the lung, but not of adenocarcinoma of the lung. • Among 812,617 patients with gastroesophageal reflux disease from the Nordic countries, 46,996 had undergone antireflux surgery. • Antireflux surgery decreased the risk of lung small cell carcinoma and squamous cell carcinoma. • Antireflux surgery did not decrease the risk of lung adenocarcinoma. • Analyses in patients with reflux oesophagitis or Barrett's oesophagus showed similar results. [ABSTRACT FROM AUTHOR]

Objective: Small cell carcinoma of the cervix uteri (SCCC) is an uncommon cancer associated with unsatisfactory survival outcomes. We aimed to investigate the incidence and prognostic factors of survival in SCCC patients using the Surveillance, Epidemiology, and End Results database.Methods: Eligible patients with histopathologic diagnoses of SCCC were identified between 2004 and 2015. Overall survival (OS) and cause-specific survival (CSS) for the included patients were calculated using the Kaplan-Meier method. Univariate and multivariate analyses of clinical factors were performed using Cox proportional hazard regression models.Results: We identified 272 SCCC patients based on predefined criteria. The average incidence of SCCC was 1.01 % per year between 2004 and 2015. The median OS and CSS were 17.0 and 19.0 months, respectively, accompanying with 5-year OS rate was 26.3 % and 5-year CSS rate was 30.1 %. In the multivariate analysis, advanced age (age ≥ 65 years old), late FIGO stage, surgery at the primary site, radiotherapy (RT) and chemotherapy (CT) were strong prognostic factors for OS. The corresponding variables for CSS were: advanced age, late FIGO stage, RT and CT. In the subgroup analysis for nonsurgical management of SCCC, the combination of RT and CT provided the best survival outcomes when compared with other therapeutic modalities. Again, advanced age was interrelated to worse survival outcomes for both OS and CSS.Conclusions: SCCC is an infrequent disease with aggressive nature, which lead to poor survival outcomes. In addition to other known parameters, advanced age is a strong predictive factor for OS and CSS. The combination of RT and CT was the best therapeutic strategy for patients who received nonsurgical management. [ABSTRACT FROM AUTHOR]

Extensive-stage small-cell lung cancer (ES-SCLC) is an aggressive cancer that remains very hard to treat. The life expectancy of a patient diagnosed with this disease has not changed over the past three decades. Recently, three large clinical studies showed a survival benefit by adding an anti–programmed death (ligand) 1 (PD-(L)1 antibody to the current chemotherapy regimen. Although significant and important, the benefit seems less than what has been achieved in patients with non–small-cell lung cancer treated with chemoimmunotherapy. A number of hypotheses have been explored to explain this discrepancy. Here, we hypothesise that the current chemotherapy backbone in ES-SCLC does not contain the optimal drugs to trigger immunogenic cell death and therefore does not induce a synergy between chemotherapy and immune checkpoint inhibitor therapy. Thereby, we advocate that doxorubicin treatment instead of etoposide should be reconsidered as standard-of-care (SoC) first-line treatment of SCLC. • Chemotherapy + immunotherapy combination yielded survival in extensive-stage small-cell lung cancer (ES-SCLC). • This benefit was modest, compared with what was established in other cancer types. • Immunogenic cell death (ICD) is essential for chemotherapy + immunotherapy clinical responses. • Chemotherapeutic agent etoposide does not induce ICD. • We argue for better informed choices concerning the chemotherapy regimen combined with immunotherapy in ES-SCLC. [ABSTRACT FROM AUTHOR]