A case of acinar cell carcinoma originating from the accessory papilla of the duodenum.

CASE PRESENTATION: A 61-year-old female was referred to our hospital with a neoplastic lesion in the duodenum. Computed tomography with contrast enhancement revealed a 10-mm tumor in the duodenum. Upper gastrointestinal endoscopy revealed a submucosal tumor-like lesion in the descending part of the duodenum. Endoscopic ultrasound revealed a well-defined hypoechoic tumor. Biopsy and immunohistochemical findings including negative Synaptophysin and Chromogranin A staining and positive Trypsin and BCL10 staining suggested a carcinoma with acinar cell differentiation. Pancreatoduodenectomy was performed, and the resected specimen had a 15-mm solid nodule in the submucosal layer of the duodenum. Pancreatogram of the resected specimen revealed a tumor localized in the accessory papilla region. In histopathological examination, the tumor was found in the submucosa of the duodenum with pancreatic tissue present nearby, and these were separated from the pancreatic parenchyma by the duodenal muscle layer. These findings led to a diagnosis of acinar cell carcinoma originating from the accessory papilla of the duodenum. CONCLUSION: Acinar cell carcinoma originating from the accessory papilla of the duodenum is exceptionally rare, with no reported cases to date. The origin was considered to be pancreatic tissue located in the accessory papilla region.

EBV+ nodal T/NK-cell lymphoma associated with clonal hematopoiesis and structural variations of the viral genome.

ABSTRACT: Epstein-Barr virus (EBV)-positive (EBV+) nodal T- and natural killer (NK)-cell lymphoma is a peripheral T-cell lymphoma (EBV+ nPTCL) that presents as a primary nodal disease with T-cell phenotype and EBV-harboring tumor cells. To date, the genetic aspect of EBV+ nPTCL has not been fully investigated. In this study, whole-exome and/or whole-genome sequencing was performed on 22 cases of EBV+ nPTCL. TET2 (68%) and DNMT3A (32%) were observed to be the most frequently mutated genes whose presence was associated with poor overall survival (P = .004). The RHOA p.Gly17Val mutation was identified in 2 patients who had TET2 and/or DNMT3A mutations. In 4 patients with TET2/DNMT3A alterations, blood cell-rich tissues (the bone marrow [BM] or spleen) were available as paired normal samples. Of 4 cases, 3 had at least 1 identical TET2/DNMT3A mutation in the BM or spleen. Additionally, the whole part of the EBV genome was sequenced and structural variations (SVs) were found frequent among the EBV genomes (63%). The most frequently identified type of SV was deletion. In 1 patient, 4 pieces of human chromosome 9, including programmed death-ligand 1 gene (PD-L1) were identified to be tandemly incorporated into the EBV genome. The 3' untranslated region of PD-L1 was truncated, causing a high-level of PD-L1 protein expression. Overall, the frequent TET2 and DNMT3A mutations in EBV+ nPTCL seem to be closely associated with clonal hematopoiesis and, together with the EBV genome deletions, may contribute to the pathogenesis of this intractable lymphoma.

Japanese Society of Medical Oncology clinical guidelines: Molecular testing for colorectal cancer treatment, 5th edition.

Molecular testing to determine optimal therapies is essential for managing patients with colorectal cancer (CRC). In October 2022, the Japanese Society of Medical Oncology published the 5th edition of the Molecular Testing Guideline for Colorectal Cancer Treatment. In this guideline, in patients with unresectable CRC, RAS/BRAF V600E mutational and mismatch repair tests are strongly recommended prior to first-line chemotherapy to select optimal first- and second-line therapies. In addition, HER2 testing is strongly recommended because the pertuzumab plus trastuzumab combination is insured after fluoropyrimidine, oxaliplatin, and irinotecan in Japan. Circulating tumor DNA (ctDNA)-based RAS testing is also strongly recommended to assess the indications for the readministration of anti-EGFR antibodies. Both tissue- and ctDNA-based comprehensive genomic profiling tests are strongly recommended to assess the indications for targeted molecular drugs, although they are currently insured in patients with disease progression after receiving standard chemotherapy (or in whom disease progression is expected in the near future). Mutational and mismatch repair testing is strongly recommended for patients with resectable CRC, and RAS/BRAF V600E mutation testing is recommended to estimate the risk of recurrence. Mutational and mismatch repair and BRAF testing are also strongly recommended for screening for Lynch syndrome. Circulating tumor DNA-based minimal residual disease (MRD) testing is strongly recommended for estimating the risk of recurrence based on clinical evidence, although MRD testing was not approved in Japan at the time of the publication of this guideline.

Brain metastasis and intracranial leptomeningeal metastasis from malignant peripheral nerve sheath tumors: illustrative cases.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft-tissue tumors. Intracranial metastasis from MPNSTs is quite rare. OBSERVATIONS: The authors report on a 73-year-old male whose MPNST metastasized to the brain and a 32-year-old male with leptomeningeal metastasis from MPNST and review 41 cases of MPNST that developed intracranial metastasis, as reported in the literature. LESSONS: Brain metastasis and leptomeningeal metastasis of MPNSTs show different clinical courses and require pathology-specific treatment.

Diagnostic utility of DNA integrity number as an indicator of sufficient DNA quality in next-generation sequencing-based genomic profiling.

OBJECTIVES: DNA integrity number (DIN) is a metric for assessing DNA degradation, calculated based on electrophoresis using the Agilent TapeStation System. The utility of DIN as a diagnostic indicator of sufficient DNA quality in clinical next-generation sequencing (NGS) has not been well described. METHODS: We evaluated the DINs of 166 tumor formalin-fixed, paraffin-embedded (FFPE) tissue samples submitted for 124-gene panel sequencing. We also investigated a new metric on the electropherogram that could improve the predictive accuracy of the DIN. RESULTS: A DIN cutoff of 2.5 discriminated samples with successful analysis (n = 143) from samples with failed analysis (n = 23), with a sensitivity of 0.84 and a specificity of 0.78 (area under the curve [AUC] = 0.88). The DIN was positively correlated with the mean coverage (r = 0.72, P < .0001) but could not discriminate success from failure when the DIN was below 2.5 (negative predictive value, 0.44). We introduced a new metric, the peak/base ratio, that distinguished success from failure with higher accuracy than the DIN (cutoff = 1.6; sensitivity = 0.98, specificity = 0.83, and AUC =0.96). CONCLUSIONS: To predict successful NGS, the DNA quality of FFPE tissue can be easily and reliably assessed using the DIN and peak/base ratio.

Brentuximab vedotin plus AVD followed by involved-node radiotherapy in a patient with classic Hodgkin lymphoma following gray zone lymphoma after autologous stem-cell transplantation failure.

BACKGROUND: No consensus has been reached yet concerning treatment strategies for a sequential classic Hodgkin lymphoma (CHL) following gray zone lymphoma (GZL). Prognosis of GZL after a failed autologous hematopoietic stem-cell transplantation (auto-HCT) is poor and treatment strategy is very limited. As yet there are limited data showing clinical outcomes of brentuximab vedotin (BV) for GZL, especially for sequential CHL after GZL. CASE PRESENTATION: We report a case of CHL following primary refractory GZL after a failed auto-HCT and showed favorable response to first-line CHL-directed chemoradiotherapy consisting of BV plus doxorubicin, vinblastine, and dacarbazin (AVD) followed by irradiation. The sequential cases with an early evolution, whose diagnosis of second lymphoma was made within a year, have been recently reported very poor survival shorter than a year. Whether a sequential CHL following GZL should be treated as a primary or relapsed disease has not been clearly elucidated. Our patient showed favorable response to first-line CHL-directed chemoradiotherapy without allogenic hematopoietic stem-cell transplantation and has in continuous remission for 2 years. CONCLUSIONS: The management of our case could help for physicians to make better treatment decisions and provide insights for further exploration in future studies.

Clinical outcomes of patients diagnosed with cancer of unknown primary or malignancy of undefined primary origin who were referred to a regional cancer center.

BACKGROUND: A regional cancer hospital has been identified to be crucial in the management of malignancies of undefined primary origin (MUO) and cancer of unknown primary (CUP). This hospital primarily consists of oncologists with expertise in CUP, pathologists, and interventional radiologists. Early consultation or referral of MUO and CUP to a cancer hospital is deemed important. METHODS: This study retrospectively collected and analyzed the clinical, pathological, and outcome data of all patients (n = 407) referred to the Aichi Cancer Center Hospital (ACCH) in Japan over an 8-year period. RESULTS: In total, 30% of patients were referred for a second opinion. Among 285 patients, 13% had non-neoplastic disease or confirmed primary site and 76% had confirmed CUP (cCUP), with 29% of cCUP being identified as favorable risk. In 155 patients with unfavorable-risk CUP, 73% had primary sites predicted by immunohistochemistry (IHC) and distribution of metastatic sites, whereas 66% of them received site-specific therapies based on the predicted primary sites. The median overall survival (OS) was found to be poor in patients with MUO (1 month) and provisional CUP (6 months). In addition, the median OS of 206 patients with cCUP treated at the ACCH was 16 months (favorable risk, 27 months; unfavorable risk, 12 months). No significant difference was noted in OS between patients with non-predictable and predictable primary-sites (13 vs 12 months, p = 0.411). CONCLUSION: The outcome of patients with unfavorable-risk CUP remains to be poor. Site-specific therapy based on IHC is not recommended for all patients with unfavorable-risk CUP.

CD83 expression characterizes precursor exhausted T cell population.

T cell exhaustion is a main obstacle against effective cancer immunotherapy. Exhausted T cells include a subpopulation that maintains proliferative capacity, referred to as precursor exhausted T cells (TPEX). While functionally distinct and important for antitumor immunity, TPEX possess some overlapping phenotypic features with the other T-cell subsets within the heterogeneous tumor-infiltrating T-lymphocytes (TIL). Here we explore surface marker profiles unique to TPEX using the tumor models treated by chimeric antigen receptor (CAR)-engineered T cells. We find that CD83 is predominantly expressed in the CCR7+PD1+ intratumoral CAR-T cells compared with the CCR7-PD1+ (terminally differentiated) and CAR-negative (bystander) T cells. The CD83+CCR7+ CAR-T cells exhibit superior antigen-induced proliferation and IL-2 production compared with the CD83- T cells. Moreover, we confirm selective expression of CD83 in the CCR7+PD1+ T-cell population in primary TIL samples. Our findings identify CD83 as a marker to discriminate TPEX from terminally exhausted and bystander TIL.

The Absence of Cancer in the Location of a Breast Tissue Marker After Neoadjuvant Chemotherapy may Predict Pathological Complete Response with High Accuracy: Results from a Phase II Trial.

BACKGROUND: It is difficult to determine pathological complete response (pCR) before surgery in clinical complete response (cCR) cases by imaging alone. We designed a prospective study to evaluate whether a breast tissue marker placed in a tumor before neoadjuvant chemotherapy (NAC) can predict a pCR, possibly removing the need for surgery. METHODS: We recruited patients with primary invasive breast cancer assigned to undergo curative surgery and possible NAC. A breast marker (UltraClip®) was placed in the primary tumor before standard NAC. We evaluated the probability of no cancer in the marker but cancer in removed specimens from a cCR group. RESULTS: A total of 102 patients were enrolled. Patients were categorized by cancer stage and subtypes. Seventy-two patients (70.6%) received standard NAC; 23 (34.3%) attained cCR, of whom pCR was obtained in 12 (52.2%). The probability of no cancer in the marker's location but cancer in the removed specimens was 4.3% (95% confidence interval, 0.1-21.9). The false-negative rate was 9.1% (1/11), and the negative predictive value was 92.3% (12/13). In only one case, no cancer was found in the marker's location, but cancer cells were present in the removed specimen. CONCLUSIONS: The absence of cancer in the location of a breast tissue marker after NAC predicted pCR with high accuracy. Therefore, the rebiopsy of a marker's location might mean surgery is unnecessary.

The impact of combined PD-L1 positive score on clinical response to nivolumab in patients with advanced esophageal squamous cell carcinoma.

BACKGROUND: Nivolumab is recommended for patients with advanced esophageal squamous cell carcinoma (aESCC) refractory or intolerant to fluoropyrimidine- and platinum-based chemotherapy regardless of the tumor proportion score (TPS). However, the role of combined positive score (CPS) in predicting nivolumab efficacy remains unclear. We aimed to study whether TPS or CPS is a more suitable biomarker for predicting nivolumab efficacy in these patients. METHODS: We retrospectively collected data from patients with aESCC treated with fluoropyrimidines and platinum and subsequently received nivolumab monotherapy between January 1, 2014 and September 15, 2020. Next, we evaluated the efficiencies of TPS and CPS in predicting the clinical response to nivolumab using PD-L1 IHC 22C3 pharmDx assay. RESULTS: This study included 50 patients (CPS groups: ≥ 10/1-10/ < 1, n = 24/18/8, respectively; TPS groups, ≥ 10%/1%-10%/ < 1%, n = 17/8/25, respectively). The median progression-free survival was 3.2, 2.5, and 1.5 months in the ≥ 10, 1-10 [hazard ratio (HR) vs. CPS of ≥ 10 group, 1.01; p = 0.98; adjusted HR, 1.33; p = 0.56], and < 1 CPS groups (HR vs. CPS of ≥ 10 group, 3.44; p = 0.006; adjusted HR, 1.67; p = 0.41), respectively. For the patients with CPS of ≥ 10/1-10/ < 1 and TPS of ≥ 10%/1%-10%/ < 1%, the objective response rate was 30%/25%/0% and 36%/0%/19% and the disease control rate was 60%/50%/12% (p = 0.06) and 65%/40%/38% (p = 0.30), respectively. CONCLUSIONS: This study suggests that a CPS of < 1 is not a strong predictor of efficacy but can predict the absence of response to nivolumab in patients with aESCC.

A rare case of a superficial squamous cell carcinoma (so-called cloacogenic carcinoma) of the rectum.

A rare case of a squamous cell carcinoma (so-called cloacogenic carcinoma) showing extensive superficial spread to the rectum is presented. A 69-year-old woman had undergone colonoscopy for annual check-up, and a whitish, flat lesion with a central depressed area, 20 mm in size, was identified in the lower rectum. Narrow-band imaging with magnifying observation showed abnormal microvessels without the intrapapillary capillary loop patterns. Endoscopically, the margin of the lesion was unclear. Biopsy was performed, and a histological diagnosis of transitional cell carcinoma was made. Computed tomography showed no evidence of involvement of adjacent organs, lymph nodes or distant sites. Cystoscopy found no abnormality in the bladder mucosa. Owing to difficulty diagnosing this tumor accurately, local excision with transanal endoscopic microsurgery was performed. Cloacogenic carcinoma with submucosal invasion was diagnosed. A human papilloma virus (HPV) polymerase chain reaction test was positive. Judging from the histological findings and the positive HPV test, we hypothesis that the tumor was likely arising from the anal transitional zone with marked superficial spread to the rectum. Clinicians should keep in mind that this variant of squamous cell carcinoma may occur in the rectum, even if no endoscopic findings are seen in the anal transitional zone.

The cAMP/PKA/CREB and TGFß/SMAD4 Pathways Regulate Stemness and Metastatic Potential in Colorectal Cancer Cells.

SIGNIFICANCE: This study identifies signaling pathways essential for maintaining the stemness and metastatic potential of colorectal cancer cells and proposes CREB as a therapeutic target in metastatic colorectal cancer.

Endoscopic Management of Adenomas in the Ileal Pouch and the Rectal Remnant after Surgical Treatment in Familial Adenomatous Polyposis.

In patients with familial adenomatous polyposis (FAP), adenomas and even carcinomas may develop in the rectal remnant and the ileal pouch after surgical treatment. The aim of this study was to evaluate the outcome of endoscopic management in patients with FAP. The main outcome measurements were the appearance of secondary cancer, complications, and the need for additional surgery. Thirty-four FAP patients with Kock's continent ileostomy (Kock) (n = 3), ileorectal anastomosis (IRA) (n = 12), and ileal pouch-anal anastomosis (IPAA) (n = 19) were identified. The median follow-up period of endoscopic surveillance was 11.5 years for pouch patients (Kock + IPAA) and 21.7 years for IRA. Metachronous adenomas appeared in 32 patients (94.1%). In pouch patients, a total of 120 treatments were given to 20 patients, and 12 sessions of delayed bleeding (10%) occurred, which was significantly higher compared to IRA patients, with 0 sessions (p < 0.001). In IRA patients, a total of 169 treatments were given to 11 patients, with one case of perforation. No adenocarcinoma has developed since the start of endoscopic surveillance. Regular endoscopic surveillance and treatment are feasible and safe. However, in pouch patients, one must be cautious about delayed bleeding in the treatment of adenomas.

Prognostic Significance of Intraoperative Peritoneal Lavage Cytology in Patients with Pancreatic Ductal Adenocarcinoma: A Single-Center Experience and Systematic Review of the Literature.

BACKGROUND: The prognostic significance of peritoneal lavage cytology (PLC) in patients with pancreatic ductal adenocarcinoma (PDAC) remains controversial. The purpose of this study was to evaluate the prognostic impact of PLC status in PDAC patients. METHODS: Patients intending to undergo resection for PDAC between 2007 and 2020 were included. Survival was compared among patients who underwent resection with negative or positive PLC status and those who did not undergo resection. Univariable and multivariable analyses were conducted to evaluate the prognostic impact of positive PLC status. A systematic literature review was performed to evaluate the correlation between prognosis and the positive PLC rate. RESULTS: A total of 480 patients formed the study cohort and were divided as follows: 438 in the negative PLC group, 18 in the positive PLC group, and 24 in the no resection group. Although the median survival time significantly differed between the negative and positive PLC groups (35.7 vs. 13.6 months, P < 0.001), it did not significantly differ between the positive PLC and no resection groups (13.6 vs. 12.2 months, P = 0.605). Multivariable analyses demonstrated that positive PLC status (hazard ratio = 3.54, 95% confidence interval = 1.97-6.38, P < 0.001) was the strongest poor prognostic factor. Based on statistical analyses for the systematic review, the prognostic impact of positive PLC status weakened significantly as the institutional positive PLC rate increased (P = 0.044). CONCLUSIONS: Resection did not improve the prognosis of patients with positive PLC status in our cohort. The institutional positive PLC rate may be a good reference for surgical indication in these patients.

Successful IMRT and concurrent chemotherapy for a patient with intrathoracic extensive-stage small cell lung cancer.

Treatment of extensive-stage (ES) small cell lung cancer (SCLC) is a challenge with poor local control and dismal overall survival. Although single extrathoracic metastasis was defined as M1b according to the eighth edition of the tumour-node-metastasis (TNM) classification of lung cancer, M1b includes involvement of a single intrathoracic nonregional lymph node (LN) such as pericardial, internal mammary or paravertebral LNs. Here, we report a successful treated case of a 50-year-old female with ES-SCLC with right pericardial LN involvement, cT1cN3M1b (LYM). She initially received two cycles of induction chemotherapy consisting of cis-Diamminedichloroplatinum/cisplatin (CDDP) and etoposide and achieved a very good partial response. She then received curative chemoradiotherapy with intensity-modulated techniques (45 Gy in 30 fractions BID), followed by an additional cycle of chemotherapy. She is free of recurrence for more than 2.5 years.

PCR-based quantitative detection of intraperitoneal free cancer cells for predicting locoregional recurrence after rectal cancer resection.

INTRODUCTION: Locoregional recurrence after curative resection remains an important issue in the treatment of colorectal cancer (CRC). The aim of the present study was to investigate the clinical significance of quantitative detection of intraperitoneal free cancer cells by a PCR-based method for predicting locoregional recurrence after CRC resection. METHOD: A total of 114 patients with CRC were enrolled between March 2017 and December 2018, and 95 patients with Stage I-III CRC were analyzed. Peritoneal lavage fluid was collected before and after tumour resection and subjected to cytology and quantitative reverse transcription-PCR (qRT-PCR) with carcinoembryonic antigen (CEA) as a genetic marker. RESULTS: 2.1% of patients had positive cytology after resection, whereas 9.5% had positive CEA qRT-PCR (PCR+) after resection. Eight of nine PCR+ patients after resection had tumours in the rectum. Fifteen (15.8%) patients developed recurrence during the follow-up period, including three with locoregional recurrence. One of 86 (1.2%) PCR- patients and 2 of 9 (22.2%) PCR+ patients after resection developed locoregional recurrence. Overall and in rectal cancer patients, the 3-year cumulative risk of locoregional recurrence was 25.0% and 28.6% for PCR+ patients, which is significantly higher than PCR- patients (1.3% and 0%, P < 0.001 and P = 0.001, respectively). CONCLUSION: Intraperitoneal free cancer cells can serve as a sensitive predictor of locoregional recurrence after rectal cancer resection. qRT-PCR for CEA can be a suitable method for detecting intraperitoneal free cancer cells in peritoneal lavage fluid.

SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1-Negative Lung Adenocarcinomas.

BACKGROUND: Approximately 20% of lung adenocarcinoma (LUAD) is negative for the lineage-specific oncogene Thyroid transcription factor 1 (TTF-1) and exhibits worse clinical outcome with a low frequency of actionable genomic alterations. To identify molecular features associated with TTF-1-negative LUAD, we compared the transcriptomic and proteomic profiles of LUAD cell lines. SRGN , a chondroitin sulfate proteoglycan Serglycin, was identified as a markedly overexpressed gene in TTF-1-negative LUAD. We therefore investigated the roles and regulation of SRGN in TTF-1-negative LUAD. METHODS: Proteomic and metabolomic analyses of 41 LUAD cell lines were done using mass spectrometry. The function of SRGN was investigated in 3 TTF-1-negative and 4 TTF-1-positive LUAD cell lines and in a syngeneic mouse model (n = 5 to 8 mice per group). Expression of SRGN was evaluated in 94 and 105 surgically resected LUAD tumor specimens using immunohistochemistry. All statistical tests were 2-sided. RESULTS: SRGN was markedly overexpressed at mRNA and protein levels in TTF-1-negative LUAD cell lines (P < .001 for both mRNA and protein levels). Expression of SRGN in LUAD tumor tissue was associated with poor outcome (hazard ratio = 4.22, 95% confidence interval = 1.12 to 15.86, likelihood ratio test, P = .03), and with higher expression of Programmed cell death 1 ligand 1 (PD-L1) in tumor cells and higher infiltration of Programmed cell death protein 1-positive lymphocytes. SRGN regulated expression of PD-L1 as well as proinflammatory cytokines, including Interleukin-6, Interleukin-8, and C-X-C motif chemokine 1 in LUAD cell lines; increased migratory and invasive properties of LUAD cells and fibroblasts; and enhanced angiogenesis. SRGN was induced by DNA demethylation resulting from Nicotinamide N-methyltransferase-mediated impairment of methionine metabolism. CONCLUSIONS: Our findings suggest that SRGN plays a pivotal role in tumor-stromal interaction and reprogramming into an aggressive and immunosuppressive tumor microenvironment in TTF-1-negative LUAD.