Background: Opioid therapy provides essential pain relief for cancer patients. We used the population-based Surveillance Epidemiology and End Results (SEER) linked with Medicare database to identify the patterns of opioid use and associated factors in pancreatic adenocarcinoma cancer patients 66 years or older.

Patients and methods: We assessed opioid types, dispensed days, opioid uptake rates, and factors associated with opioid use after pancreatic adenocarcinoma cancer diagnosis in Medicare beneficiaries between 2007 and 2015 from the SEER-Medicare data. Multivariable regression analysis was used to adjust for a variety of patient-related factors.

Results: We identified a cohort of 10,745 pancreatic cancer patients with a median age of 76 years old and median survival of 7 months; 75% of patients-initiated opioids after cancer diagnosis. African Americans had the lowest rate of opioid use of 69.1% compared with all other race/ethnicity groups at around 75%. No significant yearly trend of prescribing opioids was detected. Hydrocodone was the most frequently prescribed opioid type. Regression analysis revealed that age ≤80 years, residing in Southern or Western SEER registries, residing in urban/less urban versus big metro areas, having stage IV cancer at diagnosis, longer survival time, and undertaking cancer-directed treatment or using palliative care were positively associated with opioid initiation, more prescribed opioid types, and higher opioid doses.

Discussion: While a range of sociodemographic variables were associated with opioid use in unadjusted analysis, the associations between race/ethnicity, gender, and socioeconomic status with opioid initiation disappeared when sociodemographic factors, tumor characteristics, and cancer treatment were adjusted.

Conclusion: Health care professionals' opioid prescription pattern for pancreatic cancer patients does not parallel the U.S. opioid epidemic. Racial/ethnic disparities in opioid treatment were not identified.

Keywords: SEER-Medicare; cancer disparities; opioid use; pancreatic cancer.

Introduction: Although several studies have investigated the prognostic significance of the radiographic appearance of stage IA lung adenocarcinoma, the prognostic impact of solid component size or consolidation-to-tumor ratio (CTR) of part-solid nodules (PSNs) still remains controversial. This study aimed to clarify the combined prognostic impact of the mentioned radiographic features of PSNs and compare it with that of pure solid nodules in the current TNM classification.

Methods: We retrospectively investigated 1014 patients with clinical stage IA (TNM eighth edition) adenocarcinoma who underwent curative resection. Overall survival (OS) and pathologic characteristics of pure solid nodules, solid-dominant PSNs (CTR > 0.5), and ground-glass opacity (GGO)-dominant PSNs (CTR ≤ 0.5) were compared according to T category.

Results: Patients with pure solid nodules (297 cases) had significantly shorter OS compared with those with PSNs (717 cases) (p < 0.001) but a marginal difference compared with those with solid-dominant PSNs (286 cases) (p = 0.051). No significant difference in OS was found according to T category in those with GGO-dominant PSNs (431 cases). Patients with cT1b and T1c solid-dominant PSNs had significantly worse prognosis compared with those with other PSNs and had comparable prognosis with those with cT1b pure solid nodules (p = 0.892). Higher frequency of nodal and lymphovascular involvement and pathologic upstaging was observed with T category progression in solid-dominant PSNs.

Conclusions: An hierarchy of prognosis and pathologic malignant characteristics was observed according to T category in patients with solid-dominant PSNs but not in those with GGO-dominant PSNs, suggesting the importance of classifying PSNs on the basis of solid component size and CTR for accurate prognostic comparison with pure solid nodules.

Keywords: Ground-glass opacity; High-resolution computed tomography; Lung adenocarcinoma; Part-solid nodule; Prognosis.

Motivation: RNA sequencing and other high-throughput technologies are essential in understanding complex diseases, such as cancers, but are susceptible to technical factors manifesting as patterns in the measurements. These batch patterns hinder the discovery of biologically relevant patterns. Unbiased batch effect correction in heterogeneous populations currently requires special experimental designs or phenotypic labels, which are not readily available for patient samples in existing datasets.

Results: We present POIBM, an RNA-seq batch correction method, which learns virtual reference samples directly from the data. We use a breast cancer cell line dataset to show that POIBM exceeds or matches the performance of previous methods, while being blind to the phenotypes. Further, we analyze The Cancer Genome Atlas RNA-seq data to show that batch effects plague many cancer types; POIBM effectively discovers the true replicates in stomach adenocarcinoma; and integrating the corrected data in endometrial carcinoma improves cancer subtyping.

Availability: https://bitbucket.org/anthakki/poibm/ (archived at https://doi.org/10.5281/zenodo.6122436).

Isoform-specific functions of Numb in the development of cancers, especially in the initiation of epithelial-to-mesenchymal transition (EMT) remains controversial. We study the specific function of Numb-PRRL isoform in activated EMT of pancreatic ductal adenocarcinoma (PC), which is distinguished from our previous studies that only focused on the total Numb protein. Numb-PRRL isoform was specifically overexpressed and silenced in PC cells combining with TGF-β1 and EGF stimulus. We systematically explored the potential effect of Numb-PRRL in the activated EMT of PC in vitro and in vivo. The total Numb protein was overexpressed in the normal pancreatic duct and well-differentiated PC by IHC. However, Numb-PRRS isoform but not Numb-PRRL showed dominant expression in PC tissues. Numb-PRRL overexpression promoted TGF-β1-induced EMT in PANC-1 and Miapaca-2 cells. TGF-β1-induced EMT-like cell morphology, cell invasion, and migration were enhanced in Numb-PRRL overexpressing groups following the increase of N-cadherin, Vimentin, Smad2/3, Snail1, Snail2, and cleaved-Notch1 and the decrease of E-cadherin. Numb-PRRL overexpression activated TGFβ1-Smad2/3-Snail1 signaling was significantly reversed by the Notch1 inhibitor RO4929097. Conversely, Numb-PRRL silencing inhibited EGF-induced EMT in AsPC-1 and BxPC-3 cells following the activation of EGFR-ERK/MAPK signaling via phosphorylating EGFR at tyrosine 1045. In vivo, Numb-PRRL overexpression or silencing promoted or inhibited subcutaneous tumor size and distant liver metastases via regulating EMT and Snail signaling, respectively. Numb-PRRL promotes TGF-β1- and EGF-induced EMT in PC by regulating TGF-β1-Smad2/3-Snail and EGF-induced EGFR-ERK/MAPK signaling.

We analyzed an EGFR-mutated lung cancer with a pathologic diagnosis of combined large cell neuroendocrine carcinoma with mixed adenocarcinoma subtypes. Targeted next-generation sequencing of each component suggested that mutations in RB1, TP53, and SMAD4 and apparent loss of heterozygosity of TP53 and SMAD4 accompanied the transition of different adenocarcinoma subtypes. Additional gene mutations including PTEN, MST1R, and PIK3CA were noted during transdifferentiation from acinar adenocarcinoma to large cell neuroendocrine carcinoma. Combined DNA and RNA analysis using Todai OncoPanel revealed that transdifferentiation to different pathologic subtypes occurred in a single tumor through the accumulation of gene mutations.

Keywords: Case report; Clonal analysis; EGFR; Gene mutations; NSCLC; Pathologic subtypes.

The association of ovarian malignancy with pregnancy is rare; accounting for 3-6% of ovarian masses of which malignant germ cell tumors represent the type most frequently associated with pregnancy, whereas the incidence of epithelial ovarian cancer is only 1/12,000 to 1/50,000 of pregnancies. The diagnosis and management of ovarian cancer in pregnancy remain poorly codified because of the rarity of cases and the limited data available on this pathology. We report here the case of a 45-year-old woman with a large ovarian mucinous adenocarcinoma diagnosed during pregnancy, identified by ultrasound and magnetic resonance imaging. The patient was treated by surgical resection followed by adjuvant chemotherapy with carboplatin and paclitaxel with a follow-up of 36 months, she is in complete remission.

Keywords: Adenocarcinoma; Chemotherapy; Childbirth; Ovary; Pregnancy.

Here, we report a rare case of lung adenocarcinoma with intrapulmonary metastases that have "spread through air spaces" (STAS) by means of the alveoli and bronchioles. The peripheral intrapulmonary metastases were exhibiting pure ground-glass nodules along the bronchioles on computed tomography. The primary pathologic diagnosis was micropapillary adenocarcinoma with prominent tumor STAS. Histopathologic examination revealed that the cancer cells in the bronchioles around the primary tumor revealed micropapillary clusters on the mucosal surface or in the air spaces and reached peripheral intrapulmonary metastatic nodules. Notably, no vascular and stromal invasion was observed. The pathologic findings suggest that cancer cells are viable in the airspace of the bronchioles and alveoli and may support the significance of STAS as a pattern of airborne metastasis.

Keywords: Case report; Lung adenocarcinoma; Micropapillary adenocarcinoma; Tumor-spread through air spaces (STAS).

Evasion from drug-induced apoptosis is a crucial mechanism of cancer treatment resistance. The proapoptotic protein NOXA marks an aggressive pancreatic ductal adenocarcinoma (PDAC) subtype. To identify drugs that unleash the death-inducing potential of NOXA, we performed an unbiased drug screening experiment. In NOXA-deficient isogenic cellular models, we identified an inhibitor of the transcription factor heterodimer CBFβ/RUNX1. By genetic gain and loss of function experiments, we validated that the mode of action depends on RUNX1 and NOXA. Of note is that RUNX1 expression is significantly higher in PDACs compared to normal pancreas. We show that pharmacological RUNX1 inhibition significantly blocks tumor growth in vivo and in primary patient-derived PDAC organoids. Through genome-wide analysis, we detected that RUNX1-loss reshapes the epigenetic landscape, which gains H3K27ac enrichment at the NOXA promoter. Our study demonstrates a previously unknown mechanism of NOXA-dependent cell death, which can be triggered pharmaceutically. Therefore, our data show a way to target a therapy-resistant PDAC, an unmet clinical need.

Keywords: NOXA; PDAC; RUNX1; apoptosis; pancreatic cancer.

Background: Colorectal cancer (CRC) consists of several histological subtypes that greatly affect prognosis. Venous invasion (VI) has been implicated in the postoperative recurrence of CRC, but the relationship between the VI grade and postoperative recurrence in each histological subtype has not been clarified thus far.

Methods: A total of 323 CRCs without distant metastasis at surgery (pathologic stage III or lower), including 152 well-to-moderately differentiated adenocarcinomas (WMDAs), 98 poorly differentiated adenocarcinomas (PDAs), and 64 mucinous adenocarcinomas (MUAs), were analyzed. They were routinely processed pathologically, and VI was graded as follows irrespective of location by elastica van Gieson staining: v0 (none), no venous invasion; v1 (mild), 1-3 invasions per glass slide; v2 (moderate), 4-6 invasions per glass slide; and v3 (severe), ≥ 7 invasions per glass slide. Filling-type invasion in veins with a minor axis of ≥ 1 mm increased the grade by 1. The association of VI grade with prognosis was statistically analyzed.

Results: All recurrences occurred as distant metastases. Recurrence increased with VI grade in WMDA (v0 11.8%, v1 15.8%, v2 73.9%, v3 75.0%) and MUA (v0 15.2%, v1 30.8%, v2 40.0%). The recurrence rate was relatively high in PDA even with v0 and increased with VI grade (v0 27.8%, v1 32.7%, v2 33.3%, v3 60.0%). VI grade was a significant predictor of recurrence in WMDA but not in PDA and MUA by multivariate analysis. In node-negative (stage II or lower) CRC, the recurrence-free survival (RFS) rate exceeded 90% in v0 and v1 WMDA until postoperative day (POD) 2100 and v0 MUA until POD 1600 but fell below 80% in the other settings by POD 1000. In node-positive (stage III) CRC, the RFS rate fell below 80% in all histological subtypes by POD 1000.

Conclusions: VI grade v1 had a similar recurrence rate and RFS as grade v0 and may not warrant adjuvant chemotherapy in node-negative (stage II or lower) WMDA. In addition to node-positive (stage III) CRC, adjuvant chemotherapy may be indicated for node-negative (stage II or lower) CRC when it is WMDA with VI grade v2 or v3, MUA with VI, or PDA.

Keywords: Adjuvant chemotherapy; Colorectal cancer; EVG staining; Histological subtype; Metastasis; Recurrence; Stage II; Stage III; Venous invasion.

Background: Heterotopic tumor is a rare disease. Thus far, no cases of heterotopic cholangiocarcinoma have been reported in the world. Cholangiocarcinoma mainly metastasizes by direct invasion, and it can lead to liver metastasis in its advanced stage. There were few clinical cases of gastric metastasis in advanced tumors, mainly seen in breast cancer, lung cancer, liver cancer, malignant melanoma, choriocarcinoma, and hematological tumors. Metastases of cholangiocarcinoma to the stomach also are exceptionally rare.

Case presentation: A 58-year-old man was admitted to the hospital because of difficulty swallowing for one year. Upon gastroscopy, we found the tumor at the region of the cardia and gastric fundus. Macroscopical appearance of the tumor suggested its malignant nature. Computed tomography (CT) findings showed that the wall of the cardia, fundus, and stomach body were thickened, suggesting a tumor. Because the patient had obvious difficulty swallowing, we invited cardiothoracic surgeons for consultation. They considered that the patient had definite mechanical obstruction in the lower esophagus; hence, they performed an operation. Immunohistochemical staining revealed low-to-medium differentiated adenocarcinoma (containing mucinous adenocarcinoma components) of biliary origin.

Conclusions: We highlight the importance of the endoscopic biopsy of gastric tumor. However, when its results are inconsistent with the clinician's judgment, further examination is required. Endoscopic ultrasonography and enhanced CT may be a good choice. If necessary, on the premise of patient acceptance, the diagnosis could be confirmed after surgical excision. Here we report a case of a patient with heterotopic cholangiocarcinoma in the gastric fundus. The most common tissue ectopias in the digestive tract include esophagogastric gastric mucosal ectopia, duodenal gastric mucosal ectopia, and gastric mucosal small intestinal ectopia. Thus far, there have been no reports of ectopic cholangiocarcinoma and associated cancer in the stomach. In addition, metastases of cholangiocarcinoma to the stomach are also exceptionally rare, and most of them are due to a direct invasion. The discovery of the primary lesion is an important clue for the reliable diagnosis in such cases.

Keywords: Cardia; Cholangiocarcinoma; Gastric fundus.