Search

Combining bevacizumab with atezolizumab enhances the antitumor effects of the treatment by activating an immune response. This combination is approved for the treatment of unresectable hepatocellular carcinoma (HCC). An abscopal effect is associated with an immune response triggered by radiation-induced immunogenic cell death, based on experimental models. Thus, combining radiotherapy and immunotherapy is expected to induce an abscopal effect. However, the clinical significance of immunotherapy in the abscopal effect remains unknown due to the rarity of clinical cases. Herein, we report a case of advanced HCC with lung and adrenal metastases. The antitumor efficacy of atezolizumab and bevacizumab (atezo/bev) was enhanced following stereotactic body radiotherapy (SBRT), although atezo/bev did not yield a sufficient therapeutic response pre-SBRT. Furthermore, an abscopal effect following SBRT was not observed during atezolizumab alone but was evoked after resuming bevacizumab in combination with atezolizumab, culminating in the patient achieving a complete response status. These findings suggest that immune activation following radiotherapy may be related to the induction of an abscopal effect in clinical practice as well as in experimental settings, and combining immunotherapy with bevacizumab post-radiotherapy could evoke an abscopal effect in a case of HCC, even though immune checkpoint inhibitor use alone may be insufficient., (© 2024. Japanese Society of Gastroenterology.)

Aim: Atezolizumab and bevacizumab (Atezo/Bev) combination immunotherapy regimens and direct oral anticoagulants (DOACs) are both associated with bleeding. Therefore, combining Atezo/Bev regimens with DOACs may exacerbate the bleeding risk. This study investigated the feasibility of the Atezo/Bev regimen in patients taking DOACs., Methods: This retrospective study included 141 patients with unresectable hepatocellular carcinoma (HCC) or advanced lung cancer (LC) treated with Atezo/Bev regimens. Patients who used antithrombotic agents other than DOACs were excluded. Bleeding events during the Atezo/Bev regimen were analyzed., Results: The incidence rates of bleeding of any grade in the DOAC (n = 11) and no antithrombotic agent (NAA) (n = 130) groups were 9.1% and 10.8%, respectively, with no significant differences. Moreover, no significant difference was found in the frequency of bleeding of grade ≥3 between the DOAC and NAA groups. No patients in the DOAC group discontinued the Atezo/Bev regimen because of severe bleeding. Although serum albumin levels, with a hazard ratio (HR) of 0.298 (95% confidence interval [CI]: 0.105-0.847), independently contributed to bleeding events (p = 0.023), DOAC administration did not (HR: 1.357; 95% CI: 0.157-10.54; p = 0.770). Among only patients with HCC (n = 59), none of the five patients taking DOACs experienced bleeding events. A high albumin-bilirubin score (HR: 9.083, 95% CI: 1.118-73.76) was associated with bleeding events (p = 0.039)., Conclusions: DOACs did not have a considerable effect on bleeding events in the Atezo/Bev regimens for HCC or LC. Under careful surveillance for bleeding, Atezo/Bev regimens may be feasible in patients receiving DOACs., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

A 56-year-old man with advanced lung adenocarcinoma presented to the emergency department with a 6-day history of diarrhea. He was treated for lung cancer with nivolumab 3 mg/kg (144 mg/body) every 2 weeks (Q2W), followed by an increase to 240 mg Q2W for 147 weeks, for a total of 69 administrations. His dose was then increased to 480 mg/body every four weeks (Q4W) 12 days before his presentation. Clostridioides difficile toxin, cytomegalovirus antigenemia, and stool bacterial cultures were negative. Colonoscopy revealed diffusely edematous granular mucosa with mucosal redness, exudates, loss of vascular pattern, and aphtha throughout the colon but no ulcers. We diagnosed the patient with immune checkpoint inhibitor-induced colitis. We started prednisolone at a dose of 60 mg/day. His symptoms gradually improved, and he recovered without diarrhea on day ten after hospitalization. After prednisolone tapering, his symptoms did not worsen. Colonoscopy showed significant improvement on day 29, and the diffuse redness disappeared. The patient did not experience subsequent recurrence of diarrhea. He had no progression of lung cancer despite the termination of nivolumab for seven months. Here, we report a case of lung cancer in which nivolumab dose escalation after prolonged stable use triggered immune checkpoint inhibitor-induced colitis., (© 2021. Japanese Society of Gastroenterology.)

A 42-year-old man was diagnosed with cStage IIIb malignant melanoma and underwent resection. After interferon-beta therapy, 18-fluorodeoxyglucose-positron emission tomography/computed tomography ( 18 F-FDG PET/CT) showed multiple lung metastases, and he received nivolumab (2 mg/kg) every 3 weeks, resulting in a total of 17 cycles. After treatment, 18 F-FDG PET/CT showed a significant decrease in the size of the metastases, but he had a Grade 4 alanine aminotransferase (ALT) elevation. Liver histology revealed drug-induced liver damage. Therefore, we performed steroid half-pulse therapy followed by oral methylprednisolone, but his ALT level did not completely recover to the normal range even after five months. We herein report a case with specific, sustained liver injury induced by nivolumab as an immune-related adverse events.

We report a case of a 60-year-old woman with poor performance status (PS). She suffered from advanced right breast cancer with multiple lung metastases, which was controlled by chemotherapy with trastuzumab as the key drug. The patient presented with a 4 cm-sized large right breast mass. Her PS was poor due to progressive spinocerebellar degeneration. The biopsy specimen of the breast mass showed scirrhous type of the invasive ductal carcinoma (ER+, HER2 2+). Multiple lung metastases were also detected by computed tomography. Considering her poor PS, the patient was treated with mild systemic therapy using trastuzumab as the key drug. A different drug response was achieved between the breast mass and lung metastatic lesions, and the tumors were maintained as stable disease (SD) during first 18 months. However, she finally passed away due to respiratory failure resulting from lung metastasis, 33 months after starting treatment. The autopsy findings showed a difference of HER2 expression between the breast tumor and lung metastatic lesions. It must be recognized that differences of HER2 expression between the primary tumor and metastatic lesions are sometimes demonstrated in patients with breast cancer, and that trastuzumab can be used as a key drug in some patients as in the current case.

Patients with large cell neuroendocrine carcinoma (LCNEC) of the lung are considered to have poor prognosis. However, the benefit of adjuvant chemotherapy for these patients has not been established. In this study, we retrospectively evaluated the efficacy of perioperative chemotherapy for patients with completely resected LCNEC in a single-center setting. From 1999 through 2007, 45 patients with surgically resected LCNEC or mixed LCNEC containing at least one portion of the neuroendocrine differentiation or morphology in non-small cell lung carcinoma were enrolled as participants of this study. Survival rates were calculated by the Kaplan-Meier method. Differences between survival curves were computed with the log-rank test. For multivariate analysis, the Cox's proportional hazards regression model was used to evaluate variables that were significant predictors of survival. Of 1397 patients undergoing surgical resection for primary lung cancer from 1999 to 2007, 45 (3.2%) were classified as LCNEC. Thirty-six (80%) patients were men, and nine (20%) were women. Twenty-four (92%) of 26 patients were present or past smokers. Twenty-three (41%) of 45 patients received perioperative chemotherapy, including seven induction chemotherapies and 16 adjuvant chemotherapies. Survival of patients who underwent perioperative adjuvant chemotherapy was significantly higher than that of those who received surgery alone (P = 0.04). The 5-year survival rate of patients who underwent perioperative adjuvant chemotherapy was 87.5%, whereas that of patients who underwent surgery alone was 58.5%. Even in stage I cases, perioperative adjuvant chemotherapy still favors survival compared with surgery alone. In the Cox proportional hazard multivariate analysis, surgery with or without chemotherapy showed an independent prognostic influence on overall survival (P = 0.0457). Patients who received surgery alone were 9.5 times more likely to die than patients who underwent surgery plus chemotherapy. In conclusion, perioperative chemotherapy will be needed to improve survival in patients with LCNEC. As the population of LCNEC is small, it has been difficult to conduct randomized controlled trials to show the survival benefit of adjuvant chemotherapy. This should be, therefore, evaluated further in prospective multi-institutional phase II trials.

Although postoperative adjuvant chemotherapy (PAC) with uracil-tegafur significantly improves the prognosis of patients with stage I lung adenocarcinoma, subset analysis has revealed that only 11.5% of patients with stage IB derive actual benefit from such therapy. Therefore, it is extremely important to identify patients for whom adjuvant chemotherapy will be beneficial. We performed comprehensive protein analysis of 24 surgically resected specimens of stage I adenocarcinoma using liquid chromatography-tandem mass spectrometry (LC-MS/MS), followed by bioinformatical investigations to identify protein molecules. Furthermore, we carried out immunohistochemical studies of 90 adenocarcinoma specimens to validate the results of LC-MS/MS. We detected two kinds of protein molecules (myosin IIA and vimentin) by LC-MS/MS. We confirmed their immunohistochemical expression and distribution, and evaluated the relationship between the expression of these proteins and prognosis after adjuvant chemotherapy. Patients with no expression of either myosin IIA or vimentin showed a significantly better outcome regardless of PAC using uracil-tegafur. However, we were unable to select responders to uracil-tegafur using these proteins. Cases of adenocarcinoma lacking expression of either myosin IIA or vimentin show a good outcome without PAC, and therefore do not require such treatment.

Purpose: Highly invasive and metastatic cancer cells, such as adenocarcinoma of the lung cells, form irregular protrusions by assembling a branched network of actin filaments. In mammalian cells, the actin-related protein 2 and 3 (Arp2/3) complex initiates actin assembly to form lamellipodial protrusions by binding to Wiskott-Aldrich syndrome (WASP)/WASP family verproline-homologous protein 2 (WAVE2). In this study, colocalization of Arp2 and WAVE2 in adenocarcinoma of the lung was investigated to elucidate its prognostic value., Experimental Design: Immunohistochemical staining of Arp2 and WAVE2 was done on mirror sections of 115 adenocarcinomas of the lung from pathologic stage IA to IIIA classes. Kaplan-Meier disease-free survival and overall survival curves were analyzed to determine the prognostic significance of the coexpression of Arp2 and WAVE2., Results: Immunoreactivity for both Arp2 and WAVE2 was detected in the same cancer cells in 78 (67.8%) of the 115 lung cancer specimens. The proportion of cancer cells expressing both Arp2 and WAVE2 was significantly higher in cases with lymph-node metastasis (P = 0.0046), and significantly lower in bronchioloalveolar carcinomas (P < 0.0001). The patients whose cancer cells coexpressed them had a shorter disease-free survival time (P < 0.0001) and overall survival time (P < 0.0001). Multivariate Cox regression analysis revealed that coexpression of Arp2 and WAVE2 is an independent risk factor for tumor recurrence., Conclusions: Coexpression of Arp2 and WAVE2 is correlated with poorer patient outcome, and may be involved in the mechanism of cancer metastasis.

Beta-catenin is involved in cell motility in the extracellular matrix, and is expressed in normal and neoplastic mesenchymal cells. In order to clarify whether beta-catenin expression in the cytoplasm and/or nucleus is associated with a propensity for pulmonary metastasis in osteosarcoma, the LM8 murine osteosarcoma cell line with a high metastatic potential to the lung was compared with original Dunn cells in terms of the beta-catenin expression level. Both osteosarcoma cell lines lost membrane localization of beta-catenin. However, beta-catenin gene had no mutation in exon 3 by direct sequence analysis. A large number of LM8 cells showed diffuse cytoplasmic and/or nuclear staining of beta-catenin (30.8 per high power field (HPF)), while a much smaller number of Dunn cells showed expression of beta-catenin (7.7 per HPF). Cells with positive staining of beta-catenin were frequently seen at the invasive front and in intravenous tumor deposits within the metastatic lesions to the lung. Thus, LM8 cells express a larger amount of the beta-catenin protein than Dunn cells, as judged by immunoblot analysis. In five resected cases of pulmonary metastasis, translocation of beta-catenin to the cytoplasm and/or nucleus of osteosarcoma cells was detected, although seven primary osteosarcomas cells that did not metastasize for more than five years did not show beta-catenin expression. These data indicate that the cytoplasmic and/or nuclear staining of beta-catenin is a biological marker of metastatic potential of osteosarcoma to the lung.

Successful simultaneous operation for cardiac and lung disease was performed in a 71-year-old man with lung carcinoma and ischemic heart disease. Chest CT scan revealed a mass in the right lower lobe and absence of mediastinal lymphadenopathy. Coronary angiography revealed significant stenosis of the left anterior descending artery, circumflex artery and right coronary artery. We performed concomitant video-assisted right lower lobectomy with mediastinal lymph node dissection as a form of less invasive surgery and triple coronary artery bypass grafting under cardiopulmonary bypass. Curative surgery for lung carcinoma and complete revascularization for ischemic heart disease were completed. The postoperative course was uneventful.

Although chromium has been the most extensively investigated metal with respect to mutagenicity and carcinogenicity, its genetic effects in humans are only partly understood. Our previous study demonstrated that lung cancer from chromate-exposed workers infrequently (20%) displayed p53 gene mutations as well as a particular mutation pattern. In the present study, we examined the replication error (RER) and loss of heterozygosity (LOH) in 38 lung cancers from 28 chromate-exposed workers (chromate lung cancer group) and in 26 lung cancer patients without chromate exposure (non-chromate lung cancer group), using six microsatellite markers containing CA repeats: D3S647 (3p23), D3S966 (3p21.3), D3S1289 (3p21.1), D5S346 (5q21-q22), D9S161 (9p21), and TP53 (17p13.1). The RER phenotype was defined as the presence of microsatellite instability (MSI) at two or more loci. Thirty (78.9%) of 38 tumors in the chromate lung cancer group exhibited RER. In contrast, only four (15.4%) of 26 tumors in the non-chromate lung cancer group exhibited RER. The frequency of RER in the chromate lung cancer group was significantly higher than that in the non-chromate lung cancer group (P < 0.0001). By contrast, the frequency of LOH at 3p, 5q, 9p, and 17p loci in tumors with chromate exposure was not significantly different from that in tumors without chromate exposure. In the chromate lung cancer group, the period of chromate exposure in workers with RER (24.5 +/- 6.7 yr) was significantly longer than that in workers without RER (17.0 +/- 3.5 yr) (P = 0.0046). In addition, a longer period of chromate exposure was associated with a tendency toward a higher frequency of MSI. This finding suggests that MSI may play a role in chromium-induced carcinogenesis. In addition to our previous study of p53 mutations, the present findings suggest that the carcinogenic mechanism of chromate lung cancer may differ from that of non-chromate lung cancer., (Copyright 2002 Wiley-Liss, Inc.)

To evaluate the correlation between the degree of basement membrane (BM) preservation and clinicopathological characteristics in the replacement-growth type (lepidic growth type) of small peripheral adenocarcinomas of the lung, the BM components of 72 surgically resected replacement-growth type adenocarcinomas of the lung, 2 cm or less in diameter, were evaluated immunohistochemically by using a monoclonal antibody to Type IV collagen and polyclonal antibodies to 7S collagen and laminin. The tumors were classified into the following three distinctive histological types according to the condition of the elastic framework: Type I, bronchioloalveolar carcinoma without fibrotic foci; Type II, sclerosing bronchioloalveolar carcinoma without elastic framework destruction; and Type III, sclerosing bronchioloalveolar carcinoma with elastic framework destruction. The BM was well preserved in the area of bronchioloalveolar spread along fully expanded alveoli in all tumor types; however, BM preservation was significantly lost in the areas of collapsed alveoli in Type III tumors. There were no BM component staining reactions in the scarred regions of Type III tumors. In addition, lymph node metastasis was significantly greater in Type III tumors and BM-destroyed tumors. We concluded that the BM was largely destroyed by tumor cell invasion in the scarred region of Type III adenocarcinomas. Type III tumors had discontinuous BMs in the area of collapsed alveoli, indicating that this BM-destructive pattern must be the first step in tumor invasion. Type I and II tumors were concluded to be noninvasive adenocarcinomas, because their BM components were well preserved and they had a good outcome.

Background: Chromium carcinogenicity and mutagenicity are no longer disputed. However, although chromium has various genetic effects that induce cancer, its mechanism of inducing lung cancer in humans is still not fully understood. p53, a tumor suppressor gene, was found to be infrequently mutated in samples of lung cancer in workers with long occupational exposure to chromium, suggesting other cancer-related genes to be targeted in such tumors., Methods: To assess the contribution of the ras oncogenes in the pathogenesis of chromate-related lung cancer, we studied point mutations at the critical positions of codons 12, 13, and 61 of the Ha-ras and Ki-ras oncogenes in 38 lung cancer samples derived from Japanese patients who worked in the chromate industry for long periods. We used both radioactive isotope and non-radioisotope PCR-SSCP techniques., Results: The results of this study demonstrated that activation of ras genes due to point mutations in chromate-related lung cancer is a rare event., Conclusions: Ras oncogenes activated by point mutations do not have a major role in the process of tumorigenesis of chromate-related lung cancer., (Copyright 2001 Wiley-Liss, Inc.)

Adenosquamous carcinoma of the lung is a subset of pulmonary carcinomas, and comprises less than 4% of lung carcinomas. Its histogenesis remains unclear. The clonality of adenosquamous carcinoma from four female patients was analyzed to determine whether the clonality between the squamous cell and adenocarcinomatous components coincides. Each lesion was precisely microdissected from methanol-fixed sections. Adjacent normal lung tissue was collected as a normal control. DNA was extracted for clonal analysis based on an X-chromosome-linked polymorphic marker, the human androgen receptor gene (HUMARA). HUMARA was found to be amplified with or without previous digestion by the methylation-sensitive restriction endonuclease HpaII. All four cases were informative. Squamous cell and adenocarcinomatous components showed identical monoclonal patterns in all four patients. In one case, only the squamous cell carcinomatous component showed loss of heterozygosity of the HUMARA locus. The results suggest that the squamous cell and adenocarcinomatous components originate from the same cell.

A new cytometric device, a laser scanning cytometer was developed to overcome the limitations of flow cytometry (FCM) and image analyses. The purpose of this study was to develop a method that allows laser scanning cytometry (LSC) to be used for measuring the cellular DNA content of paraffin-embedded tissues. Paraffin-embedded lung cancer tissue from 30 patients was analyzed by both FCM (p-FCM) and LSC (p-LSC). In addition, touch preparations from fresh frozen tissues were prepared to provide material for LSC (f-LSC). The limits of agreement for the DNA indices (DI) measured by p-LSC and p-FCM were -0.07 to 0.07, indicating that for a given case, these methods would be expected to differ by no more than 0.07. The limits of agreement for comparisons between the other materials and methods were wider and depended upon the size of the measurements. Agreement between f-LSC and p-FCM was good for small DI values, but poor for large values. Agreement between f-LSC and p-LSC was poor for small and large DI values, but good for moderately sized values. Discordancies in DNA ploidy status between different materials and methods may have been caused by either the heterogeneity within tumors, sampling errors or differences in the interpretation of histograms. This method allows a comparison of the results of DNA analysis with histologic findings from hematoxylineosin-stained sections and the prognosis of the patients.

We report a case of unique double primary lung cancers with neuroendocrine features in a 63-year-old male smoker. The mass in the left lower lobe (LLL) was a small cell/large cell carcinoma with spindle cell sarcomatous areas and organoid structure. The mass in the left upper lobe (LUL) was a tubular adenocarcinoma with neuroendocrine features including organoid nests showing occasional rosette formation, nuclear palisading in the periphery of the nests and positive immunoreaction for CD56, chromogranin A and synaptophysin. The difference in histological structures between the two masses led us to diagnose double primary lung cancer. The combination of small cell lung carcinoma and spindle cell carcinoma is very uncommon. The relationship between LLL and LUL tumors remains unclear. Multiple lung cancers with neuroendocrine features have only rarely been reported in the literature. The patient in our case died of widespread cancer 2 years and 4 months after the surgery without adjuvant chemotherapy, a longer postoperative survival time than in cases of ordinary extensive small cell lung cancer. Multiple lung cancers with neuroendocrine features are extremely rare and similar cases have not been reported in the literature. Neuroendocrine differentiation has attracted widespread attention and, therefore, examining neuroendocrine features in lung cancers is important.

The histogenesis of meningothelial-like nodule or so-called minute pulmonary chemodectoma remains unclear, with various immunohistochemical analyses giving inconsistent results. We performed an immunohistochemical and clonal analysis of minute pulmonary meningothelial-like nodules. Thirty-one histologically defined meningothelial-like nodules in 14 cases were stained immunohistochemically. One case had multiple lesions with brown pigment granules, which were positively stained with Berlin blue method, indicating the presence of hemosiderin. All meningothelial-like nodules were positive for vimentin and epithelial membrane antigen (EMA), but not for S-100 protein, chromogranin A, or synaptophysin. Five of 13 cases (13 of 28 lesions) were positive for CD68 by KP-1. Ten cases (24 lesions) stained for CD68 by PG-M1 were weakly positive. All lesions were negative for lysozyme, myosin, actin, keratin, and melanoma-associated antigen. Alveolar macrophages were intensely positive for CD68 and lysozyme in all examined cases. We analyzed the clonality of 11 minute pulmonary meningothelial-like nodule lesions in two female cases based on an X-chromosome-linked polymorphic marker, the human androgen receptor gene (HUMARA). The HUMARA was found to be amplified with or without prior digestion by the methylation-sensitive restriction endonuclease HpaII. Six of 11 lesions showed monoclonal expansion. Five lesions in a multiple case showed different patterns of monoclonality. Our findings showed that minute pulmonary meningothelial-like nodules have meningothelial-like and phagocytic characteristics but no muscular phenotype. Furthermore, some minute pulmonary meningothelial-like nodules may show monoclonal expansion, whereas others are polyclonal. Our data indicate that minute pulmonary meningothelial-like nodules are reactive rather than neoplastic.

To investigate the potential allelic loss of tumor suppressor gene loci in the tuberous sclerosis complex (TSC)-associated regions located on the long arm of chromosome 9 (9q) and on the short arm of chromosome 16 (16p) in human lung carcinoma, we analyzed 21 paired normal and tumor DNAs with 11 polymorphic markers on the chromosomes. All tumors were adenocarcinoma of the lung, which included 9 adenocarcinomas with associated multiple atypical adenomatous hyperplasia (AAH). A precise microdissection technique followed by polymerase chain reaction (PCR) amplification to prevent under-evaluation of loss of heterozygosity (LOH) was used. Twelve of the 21 (57%) adenocarcinomas displayed LOH on 9q. Five of the 21 adenocarcinomas (24%) showed LOH at all informative loci on 9q, whereas 7 (33%) demonstrated partial LOH on 9q34. Among these 21, 5 (24%) showed partial LOH between D9S149 and D9S150, where TSC1 is located. The incidence of associated AAH was significantly higher in adenocarcinoma harboring a partial LOH in the TSC1-associated region (p = 0.0048). Twelve of the 21 (57%) adenocarcinomas displayed LOH on 16p. No significant differences in the clinico-pathological characteristics could be discerned between adenocarcinomas with and without LOH on 16p. When combining these data, a partial LOH at TSC1- and/or TSC2-associated loci was observed more frequently in cases with well-differentiated adenocarcinoma (p = 0.086) and associated AAH (p = 0.081). In conclusion, our results suggest that the TSC-associated regions are new candidate loci for tumor suppressor genes in lung adenocarcinoma, especially when it is accompanied by multiple AAH.

There is accumulating evidence of an increased risk of familial clustering of cancer in the first-degree relatives of lung cancer probands. However, no explanation has been proposed for these epidemiological data. We reviewed 379 female non-small-cell lung cancer (NSCLC) patients to obtain their family histories of malignancy. Among them, nine female NSCLC patients with three or more relatives diagnosed with malignancy and 28 control patients without a family history of malignancy were selected to be analysed for instability at six different microsatellite loci. We observed microsatellite instability (MSI) more frequently in the patients with three or more family histories of malignancy (six out of nine, 67%) than the control patients (5 out of 28, 18%). The incidence of MSI in the former was significantly higher than that in the control (P=0.011: Fisher's exact test). We detected no significant difference in clinicopathological characteristics between the cases with MSI and those without MSI, except for their family histories of cancer. Our results show that a significantly higher rate of MSI is associated with familial clustering of malignancy. MSI could be one of the underlying mechanisms for familial clustering of malignancy in female NSCLC patients.

A malignant phyllodes tumour with a noninvasive ductal carcinoma component is reported. The patient was an 80-year-old Japanese woman with a breast tumour detected by routine physical examination. A simple mastectomy was performed. The excised tumour was 10.5 x 9.4 x 5.4 cm in size and bulged into the skin with ulceration. The macroscopic appearance was that of a phyllodes tumour. Histologically the tumour consisted mainly of stromal components with a leaf-like structure lined by atypical ductal epithelium. The epithelial component showed gradual evolution to intraductal papillary carcinoma in a few areas. The stromal component was composed mainly of fibrosarcoma with areas of osteosarcoma and rhabdomyosarcoma. Neither stromal invasion of intraductal carcinoma nor transition between the stromal and epithelial elements was seen. Three months after the operation, death occurred, with multiple pulmonary and subcutaneous metastases. This case probably represents malignant change in both the stromal and the epithelial components of a phyllodes tumour. Since the two elements were independent, the possibility that a phyllodes tumour may be one of the origins of true carcinosarcoma is raised.

Lung cancer in the young, which has the characteristics of a higher incidence of adenocarcinoma, lower male-to-female ratio of the patients, and less frequent smoking history in the patients, may possibly be associated with genetic predisposition to cancers. We studied six microsatellite loci (D2S123, D3S659, D3S966, D5S346, WT1, and TP53) in 18 surgically treated lung cancer patients aged 25-40 years and nine control patients aged 62-74 to determine the presence of microsatellite instability (MSI) and to correlate its occurrence with clinicopathological characteristics. Of the 18 patients, 11 were female and seven were non-smokers. There were 15 adenocarcinomas and three squamous cell carcinomas, 15 (83%) of which had vascular invasion. MSI was positive in seven (39%) of 18 young patients and one (11%) of nine control patients. Moreover, MSIs in a half or more of six loci examined were demonstrated in five (28%) young patients, whereas no control patients showed such a high frequency of MSI. We observed no significant differences in clinical or pathologic parameters between cases with and without MSI. This result suggests that genetic factors play an important role in the development of lung cancer in young adults.

Atypical adenomatous hyperplasia (AAH) of the lung has been regarded as a precancerous lesion of lung adenocarcinoma, but the biologic significance of this lesion is still not well understood. In this study, DNA histogram patterns and nuclear size were examined, using an image cytometer. We studied 14 cases of Type II pneumocyte hyperplasia (HP), 7 cases of adenomatous hyperplasia with slight or no nuclear atypia (AH), 21 cases of AAH, and 26 cases of adenocarcinoma. The difference in mean nuclear sizes between the HP (32.08 microns2) and the AH (32.86 microns2) was not significant but between the AH, the AAH (38.52 microns2), and the well-differentiated adenocarcinomas with mild nuclear atypia (51.12 microns2), statistically significant differences were observed (P < 0.05). Seven (33%) of the 21 cases of AAH and 22 (85%) of the 26 cases of adenocarcinoma showed aneuploid histogram patterns. The difference in the incidence of aneuploid pattern between AAH and adenocarcinomas was statistically significant (P < 0.01). All of the cases of HP and AH were diploid. Two of the seven aneuploid cases of AAH showed hyperdiploid DNA histogram patterns, and the remaining five showed polyploid histogram patterns with diploid and hyperdiploid stemlines. In these five cases, the small-sized nuclei showed a diploid stemline and the large-sized nuclei showed a hyperdiploid stemline. Our data indicated that AAH can be distinguished from HP, AH, or adenocarcinoma by morphometric analysis and that some cases of AAH that display aneuploid histogram patterns are precancerous lesions that may lead to adenocarcinoma.

Metastases to the larynx from distant primaries are very rare. The present article reports a case of metastatic papillary adenocarcinoma of the larynx of lung origin. The patient was a 59-year-old female non-smoker, who had a history of adenocarcinoma of the right lung. For the laryngeal tumor, we performed a partial laryngectomy following biopsy. The tumor of the larynx was a papillary adenocarcinoma resembling the lung tumor, both demonstrating positive immunohistochemical staining for pulmonary surfactant apoprotein. The findings emphatically indicated the laryngeal tumor to be metastasis from the primary papillary adenocarcinoma of the lung. The present case report presents the clinical findings, course of disease and histopathological findings with brief reviews of the literature.

CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy camptothecin, is a well-known DNA topoisomerase I inhibitor. SN-38 is a metabolite of this compound. Both emit fluorescence when activated by a laser beam. With a confocal laser scanning microscope (CLSM), we determined the intracellular distribution of CPT-11 and SN-38 and the chronological changes in drug-treated PC-7, a cell line of human non-small cell lung cancer, and its CPT-11 resistant variant, PC-7/CPT cells. There were many more granules in the cytoplasm in PC-7/CPT than in the parent cell line (PC-7). The granule formation of the resistant cell could indicate a different drug metabolism in the cytoplasm from that of the parent cell. This technique would provide a new way of investigating the mechanism of resistance of cancer cells to anticancer drugs.

Relationships among cytological features, doubling time, S-phase percentage, expression of myc-family oncogenes, DNA ploidy and biochemical properties were studied in thirteen small cell lung cancer cell lines. Six cell lines that grew slowly (average doubling time 99 h) and had lower S-phase percentages (average 32%) showed inconspicuous nucleoli (average area of 1.5 microns 2), and the remaining seven cell lines that grew quickly (average doubling time 45 h) and had higher S-phase percentages (average 44%) showed large and prominent nucleoli (average area of 6.1 microns 2). DNA index value obtained from flow cytometric DNA histograms showed that all cell lines except for H-69 cell line displayed aneuploidy. Ribbon-like cell arrangements were observed in the 7 cell lines that grew quickly, and in 1 cell line that grew slowly. Biochemically, six slow-growing cell lines and four fast-growing cell lines showed high levels of aromatic L-amino acid decarboxylase activity, while in the remaining three fast-growing cell lines its level was low. A high level of c-myc or N-myc oncogene expression was observed in all 7 cell lines that grew quickly, but not in any of the 6 cell lines that grew slowly. It appears that small cell lung cancer cell lines that grow quickly can be expected to have large nucleoli and ribbon-like cell arrangements and to express high levels of myc-family oncogenes, and that nucleolar size is a good indicator for growth characteristics.

Immunohistochemical reactivity with OKT9 (antitransferrin receptor) monoclonal antibody was studied in 58 surgically resected adenocarcinomas of the lung. The cell surface and cytoplasm of the tumor cells were stained in 44 cases (76 percent). The expression of the transferrin receptor (TrfR) in tumor cells was compared with histopathologic prognostic factors, such as TNM factors, degree of histologic differentiation, degree of nuclear atypia, and frequency of mitotic figures. The expression of TrfR showed significant correlation with the degree of histopathologic differentiation (p less than 0.025), degree of nuclear atypia (p less than 0.025), and frequency of mitotic figures (p less than 0.001). However, there was no definite correlation with TNM factors. These results indicate that the expression of the TrfR in pulmonary adenocarcinoma corresponds to the elevated proliferative activity of the tumor cells, and that immunohistochemical reactivity with OKT9 can be used as one of the histopathologic indicators of prognosis of pulmonary adenocarcinoma.

Lymphocyte subsets in pulmonary venous blood (PVB) smears from 42 patients with lung cancer were immunocytochemically determined. In four patients, pulmonary arterial blood (PAB) smears were also studied for comparison with PVB. Seven healthy donor peripheral blood (PB) smears were used as controls. The percentage of T cells, helper/inducer T (Th) cells and B cells were significantly lower (P less than 0.01) than in normal controls but those of suppressor/cytotoxic T (Ts) cells, natural killer (NK) cells (P less than 0.01) and S100+ small lymphoid cells (P less than 0.05) were higher. This resulted in a decrease in the Th:Ts value in cancer patients (1.46 vs. 2.28 for normal controls; P less than 0.01). The Th and Ts value of PVB from patients in pathological Stages III and IV was lower than from those in Stages I and II because of the increase in Ts cells in the former (P less than 0.05). S100+ small lymphoid cells were increased in cancer patients, especially in those with adenocarcinoma. The present study demonstrates immunoregulation abnormalities in cancer bearing hosts, the results correlating well with the stage of the cancer. Determining lymphocyte subset alterations in PVB did not, however, enable us to detect the changes associated with local immune responses against cancer.

We report the history, laboratory findings, and studies performed on a 27-yr-old patient with a metastatic parasellar adenoma of the pituitary and Cushing's syndrome. She developed intense hyperpigmentation and extraordinarily high ACTH levels after bilateral adrenalectomy in 1974. With the exception of marked hyperpigmentation, she did well on glucocorticoid replacement therapy until August 1979, when multiple hepatic nodules were observed during a cholecystectomy. Histological studies and immunoperoxidase staining indicated that these lesions were pituitary tumor metastases. What were presumed to be metastatic lesions also developed in lungs and bone. This combination of liver, bone, and lung metastases from primary pituitary tumors has not previously been reported. Immunoreactive plasma ACTH concentrations were as high as 230,000 pg/ml. Similarly, high levels of plasma immunoreactive beta MSH and immunoreactive beta-endorphin were found. High doses of glucocorticoids reduced the concentration of ACTH to one seventh to one tenth the basal level. The sensitivity of plasma ACTH to exogenous steroid administration strongly suggests that an intact intracellular mechanism for negative feedback control of ACTH secretion persisted within the tumor cells. The rapid rise in ACTH and related peptides and the development of metastases after adrenalectomy suggest that both the secretory capacity and the oncogenic potential of the parasellar tumor were chronically inhibited by glucocorticoid hormones.

The nuclear DNA content of tumor cells in imprint smears prepared from 72 surgically resected adenocarcinomas of the lung was determined prospectively by means of cytofluorometry, and its relationship to pathologic stage, degree of histologic differentiation, and nuclear atypia represented by the mean nuclear area (MNA) and standard deviation of the nuclear area (SDNA) was studied. The mean nuclear DNA content (MNDC) of poorly differentiated adenocarcinomas was significantly larger than that of well-differentiated adenocarcinomas both in Stages I + II and III + IV (P less than 0.001, each), and the MNDC of Stages III + IV was significantly larger than that of I + II in poorly differentiated adenocarcinomas (P less than 0.01). There was a tendency for histogram Patterns III and IV, in which more aneuploid cells were present than in I and II, to be more common and for the incidence of the aneuploid stem cell line to be higher in less differentiated and more advanced adenocarcinomas, although the differences were not significant statistically. Furthermore, there were significant positive correlations between MNDC and MNA (P less than 0.01) and between MNDC and SDNA (P less than 0.05). The averages of the MNA according to the histogram pattern increased significantly in the increasing order of Patterns I to IV. These results indicate that the nuclear DNA content increases in less differentiated and more advanced adenocarcinomas, and that the nuclear atypia is reflected in abnormal nuclear DNA content (DNA aneuploidy).

A case of extramedullary plasmacytoma of the lung associated with nodular immunoglobulin deposits is presented. The main tumor was located in the posterior basal segment of the lower lobe of the left lung and showed intrabronchial polypoid growth. Multiple metastatic tumors were observed in regional lymph nodes and the visceral and parietal pleura. Histologically, the tumor was composed of sheets of plasma cells with mild atypia. A large amount of amorphous material resembling amyloid was observed in the tumors, and was more marked in the metastatic lesions. Immunohistochemically, the tumor cells were shown to contain monoclonal IgG-kappa immunoglobulin. The amorphous deposits were not identical to amyloid since congo red stain was negative and amyloid fibrils were not observed ultrastructurally. By Western blotting, immunoglobulin (IgG, kappa) was identified as the major component in an extract from the nodular deposits. In the preoperative serum from the patient, M-protein (IgG-kappa) was detected by immunoelectrophoresis. Bone marrow examination revealed no abnormality.

Forty-six cases of adenocarcinoma of the lung, categorized as stage I (T1N0M0, T2N0M0) pathologically, were studied in terms of nuclear DNA content (NDC) determined by cytofluorometry. They comprised 23 cases each with and without tumor recurrence within five years postoperatively, and the NDC was compared in 23 pairs in which the tumor size and the degree of histologic differentiation were completely matched. The NDC was larger in the recurrent group than in the nonrecurrent group in terms of mean nuclear DNA content (MNDC), DNA histogram pattern, and occurrence of the aneuploid stem cell line, of which the difference in MNDC was statistically significant (p less than 0.05). When the comparison of NDC was made between the nonrecurrent and recurrent groups in the well differentiated (W/D), moderately to poorly differentiated (M.P/D), T1, and T2 subgroups, the NDC of the recurrent group was significantly larger than that of the nonrecurrent group in the W/D (MNDC, p less than 0.01 and DNA histogram pattern, p less than 0.005) and T1 subgroups (MNDC, p less than 0.05), but not in the M.P/D and T2 subgroups. The results indicate that the NDC is a good predictor of prognosis in stage I adenocarcinoma of the lung and its prognostic importance increases in more differentiated and smaller tumors, compared to less differentiated and larger tumors.

A case of early esophageal cancer, 2.5 cm in length, located just above the esophagogastric junction is presented. This cancer seemed to originate from the fundic gland of the esophagus, because it consisted of the submucosal invasion of well-differentiated adenocarcinoma which was almost completely covered with the squamous cell mucosa of the esophagus. This patient was referred to our clinic because of lower to be a small-cell carcinoma of the lung extending to the mediastinum. He died of the lung cancer one year after operation.