Thyroid transcription factor-1 (TTF-1) expression and the efficacy of combination therapy with immune checkpoint inhibitors and cytotoxic chemotherapy in non-squamous non-small cell lung cancer.

Background: Thyroid transcription factor-1 (TTF-1) is expressed in approximately 70% of lung adenocarcinomas and is one of the most reliable makers to distinguish primary lung adenocarcinoma from metastatic disease. TTF-1-negative status is a poor prognostic factor, and TTF-1-negative lung adenocarcinoma is associated with poor efficacy of immune checkpoint inhibitor (ICI) monotherapy. However, the relationship between TTF-1 expression and the efficacy of ICI plus chemotherapy is still unclear. Methods: We performed a retrospective analysis of 129 consecutive patients with advanced non-squamous non-small cell lung cancer (NS-NSCLC) treated with ICI monotherapy or ICI plus chemotherapy between January 2016 and December 2021. The expression of programmed death ligand-1 (PD-L1) and TTF-1 was also determined in cases for which no previous data were available. We then evaluated the association between TTF-1 expression status and treatment efficacy. Results: Of the 129 cases, 33 were TTF-1-negative and 96 were positive. In the ICI monotherapy group (N=70), progression-free survival (PFS) was not significantly different between TTF-1-positive and negative patients (median 3.6 vs. 3.8 months, P=0.27); however, in patients with wild-type epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), a trend for worse PFS was observed in TTF-1-negative cases compared with those that were TTF-1-positive (median 3.8 vs. 4.5 months, P=0.088). Moreover, long-term efficacy of ICI monotherapy (>2 years) was not observed in the TTF-1-negative group. TTF-1-negative patients tended to have worse overall survival (OS) than TTF-1-positive patients (median 15.6 vs. 19.5 months, P=0.13). In the ICI plus chemotherapy group (N=59), TTF-1-negative patients tended to have better PFS and similar OS compared with TTF-1-positive patients (median 9.9 vs. 9.6 months, P=0.14; median 32.3 vs. 18.9 months, P=0.78). Long-term efficacy was generally observed in TTF-1-negative patients treated with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) (median PFS 22.5 months, median OS not reached). Conclusions: ICI monotherapy is generally less efficacious in TTF-1-negative NS-NSCLC patients, and clinicians should consider ICI plus chemotherapy in these cases. Our study suggests that ABCP is an optimal regimen for TTF-1-negative NS-NSCLC.

A remarkable response to combination chemotherapy with nivolumab and ipilimumab in a patient with primary pulmonary choriocarcinoma: a case report.

Background: Primary pulmonary choriocarcinoma (PPC) is a rare malignancy, and only 41 PPC cases have been reported in males up to 2021. Due to its rarity, no standardized treatments for PPC have been established. Cytotoxic chemotherapy has limited efficacy, and the prognosis of advanced PPC is notably poor. Immune checkpoint inhibitors (ICIs) are expected to provide long-term survival for PPC patients, but only a few cases have been reported. The optimal treatment for PPC has not been determined. Case Description: Here, we report a 72-year-old male with post-surgery relapsed PPC, presenting with multiple pulmonary nodules and an intracardiac mass. The OncomineTM Dx target test showed no mutation of cancer-relevant genes, and programmed death-ligand 1 (PD-L1) expression was negative (0%) in the 22C3 assay. He received a combination of carboplatin, paclitaxel, nivolumab, and ipilimumab which is widely used as a first-line treatment for advanced non-small-cell lung cancer (NSCLC). Two months after treatment began, computed tomography (CT) showed multiple lung nodules and an intracardiac mass reduction, which has been sustained for 12 months. Grade 3 febrile neutropenia and grade 2 rash were observed, however, these adverse events were manageable. Conclusions: This is the first case of postoperative relapse PPC that has been successfully treated with the combination of chemotherapy, nivolumab, and ipilimumab. This therapy may be a promising option for advanced PPC.

Extranodular background liver parenchyma of focal nodular hyperplasia: histopathological characteristics.

Focal nodular hyperplasia (FNH) of the liver is considered to develop as a hyperplastic response to a preexisting vascular abnormality. From the pathogenic point of view, we studied histological alterations in the extranodular background liver tissue of FNH (FNH-bg-liver). We compared ten FNH-bg-livers with ten non-FNH cases (non-FNH-liver) and found small uniform nodule formations with ring-like siderosis in the FNH-bg-livers (4/7, 57%) but not in the non-FNH-livers. Abnormal small arteries not accompanied by portal tracts were observed in six of six FNH-bg-livers for which immunohistochemical study was available, while this was observed in only three of the ten non-FNH-livers. CD34-positive sinusoids around the portal tracts were observed in only the FNH-bg-livers (3/6, 50%). Further, two of ten FNH-bg-livers had ectopic pancreatic tissue. Ring-like siderosis, abnormal small arteries, CD34-positive sinusoids, and ectopic pancreatic tissue were characteristic in the extranodular background liver tissue in cases of FNH.

Mucin expression profile in pancreatic cancer and the precursor lesions.

In this review article, we demonstrate the mucin expression profile in normal tissue, invasive ductal carcinoma (IDC), two subtypes of intraductal papillary-mucinous neoplasm (IPMN dark cell type and IPMN clear cell type), pancreatic intraepithelial neoplasia (PanIN), and mucinous cystic neoplasm (MCN) of the pancreas. In MUC1, there are various glycoforms, such as poorly glycosylated MUC1, sialylated MUC1, and fully glycosylated MUC1. IDCs showed high expression of all the glycoforms of MUC1. IPMNs dark cell type showed no expression or low expression of all the glycoforms of MUC1. IPMNs clear cell type showed low expression of poorly glycosylated MUC1, but expression of sialylated MUC1 and fully glycosylated MUC1. Expression of MUC2 was negative in IDCs, high in IPMNs dark cell type and low in IPMNs clear cell type. MUC5AC was highly expressed in IDCs, IPMNs dark cell type, and IPMNs clear cell type. MUC6 expression was higher in IPMNs clear cell type than in IDCs and IPMNs dark cell type. Our recent study demonstrated that high expression of MUC4 in IDCs is correlated with a poor outcome for patients. In PanINs, expression of both MUC5AC and MUC6 are an early event, whereas up-regulation of MUC1 is a late event. MCNs do not look as if they will show a specific mucin expression profile according to the literature review.

Successful treatment of an endodermal sinus tumor of the vagina by chemotherapy alone: a rare case of an infant diagnosed by pathological examination of discharged tumor fragment.

A 7-month-old infant was noted to have vaginal bleeding that was accompanied by a discharged tumor fragment. The histological diagnosis was endodermal sinus tumor. Her serum alpha-fetoprotein (AFP) was increased to 358.7 ng/mL, and magnetic resonance imaging showed a 1.8 x 1.0 cm tumor in the vagina. She received combination chemotherapy with cyclophosphamide, pirarubicin, carboplatin, and etoposide. The tumor in the images disappeared and the serum level of AFP returned to the normal range after 2 cycles. Treatment was complete without surgical or radiological therapy. More than 45 months after the completion of chemotherapy, she is alive without signs of recurrence.

[A case of malignant peritoneal mesothelioma successfully treated with carboplatin and paclitaxel].

A 71-year-old woman was seen at our hospital because of abdominal fullness and dyspnea. Examinations revealed a tumor in the pelvis with fluid collection and dissemination was seen in the abdomen and chest. Moreover, hyaluronate in ascites rose to 20,000 mg/dl. Finally, by cytology of ascites using immunohistochemistry, the patient was diagnosed as malignant peritoneal mesothelioma with disseminations in the abdomen and chest. After intraperitoneal administration of 25 mg of cisplatin (CDDP), we started carboplatin (CBDCA) plus paclitaxel (PTX) combination chemotherapy (each treatment course consisted of 100 mg of PTX and 400 mg of CBDCA on day 1 and PTX 100 mg on day 8 and day 15 by intravenous administration followed by 2 drug-free weeks). After the sixth course, a complete remission was observed. Malignant mesothelioma is known to have a poor prognosis. However, we successfully treated malignant peritoneal mesothelioma with CBDCA and PTX combined chemotherapy. Our case suggests that we could improve the prognosis of malignant mesothelioma by aggressive chemotherapy.

New classification of pancreatic intraductal papillary-mucinous tumour by mucin expression: its relationship with potential for malignancy.

In previous studies of the expression of MUC1 (membrane-bound type mucin) and MUC2 (intestinal type secretory mucin) in pancreatic tumours, invasive ductal carcinoma (IDC) usually showed MUC1+ and MUC2- expression, whereas intraductal papillary-mucinous tumour (IPMT) showed MUC1- and MUC2+ expression. Recently, however, many IPMTs have been collected, a considerable number of which have shown MUC1- and MUC2- expression. In the present study, the clinicopathological features were examined of 18 IPMTs with MUC2+ and 32 IPMTs with MUC2-, and their potential for malignancy was compared. Most of the IPMTs with MUC2+ were composed of dark columnar cells, whereas most of the IPMTs with MUC2- were composed of clear columnar cells. The incidence of carcinomatous change and invasive proliferation of the carcinoma in the MUC2+ tumours was significantly higher than in the MUC2- tumours. The clinical outcome for the patients with IPMT showing the MUC2+ pattern tended to be worse than for those with IPMT showing the MUC2- pattern, although the overall outcome for the two types of IPMT was significantly better than for those with IDC. Because of the differences in mucin expression pattern, morphological appearance and potential for malignancy between the two types of IPMT, we believe that they belong to different neoplastic lineages and that it may be reasonable to classify them as different entities, although the WHO classification contains a single clinicopathological entity of IPMT forming an adenoma-carcinoma sequence. In conclusion, our classification of IPMTs by MUC2 expression pattern may be of value in the better assessment of the biological behaviour of IPMTs and their potential for malignancy.