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Mode of lymph node metastases in esophageal cancer induced in rabbits with Vx2 carcinoma.

We carried out experimental studies in which Vx2 carcinoma was inoculated submucosally into the esophagi of 57 rabbits. The purpose was to clarify the mode of tumor growth and lymph node metastasis of esophageal cancer. The inoculation was given into five different segments of the esophagus and the cardia in six different groups of rabbits: the cervical (Ce), the cervicothoracic junction (Ce = Iu), the upper thoracic (Iu), the middle and lower thoracic (ImEi) and the abdominal (Ea) segments and the cardia (C). The lymph node metastatic pattern of the Vx2 carcinoma was then observed. The Ce and Ce = Iu located carcinomas metastasized to the cervical and upper thoracic areas; the Iu located carcinomas metastasized mainly above the tracheal bifurcation; the ImEi located carcinomas metastasized equally above and below the tracheal bifurcation. In cases of the Ea and C located carcinomas, the lymph node metastasis was restricted to the abdomen when serosal invasion was excluded but it spread widely from the abdomen to the neck when serosal invasion was positive. Thus, in experimentally-induced carcinoma, tracheal lymph node metastasis occurred with a high frequency. As intraoperative assessment is closely related to anatomical factors and operative risk, care should be taken that such assessments are thoroughly carried out.

Abdomen↗

A detailed histological study on occult metastasis of the lymph nodes.

One representative microsection from each lymph node was carefully surveyed for metastasis in a routine examination. To scrutinize the existence of occult metastasis, three additional sections were then made from half of the remaining lymph node. A total of 1,698 lymph nodes taken from 55 patients with carcinoma of the esophagus, stomach, colon, thyroid or breast were thus reexamined histologically. The initial examination was not able to prove any metastasis in these lymph nodes. Upon reexamination, however, involvement by cancer cells was detected in 10 nodes of 7 patients. The maximum diameter of the metastatic foci varied from 0.2 mm to 1.3 mm and was less than 0.5 mm in more than half of the nodes. The metastatic patterns in the nodes were classified into three types, i.e., marginal sinus type, medullary sinus type and mixed type. The marginal sinus type was the most frequent, with the mixed type being next and the medullary sinus type being found in only one node. Accordingly, surgeons should keep the possibility of occult metastasis in mind and the marginal sinus of the lymph node should be carefully examined in order to detect any small foci of metastasis.

Humans↗

Biomechanical interactions of cancer cells with the microvasculature during metastasis.

Metastasis is a major, life-threatening complication of cancer. The bloodstream is the most important disseminative route for cancer cells liberated from their parent tumors. Single circulating cancer cells are arrested in the microvasculature, where the vast majority are killed by rapid or slow processes, and the relatively few survivors grow into micrometastases. We review the underlying causes of one type of rapid cancer cell death in the microcirculation, namely, that caused by biomechanical interactions of cancer cells with microvessel walls, which may result in cell surface membrane expansion and lethal rupture. These lethal interactions appear to be important rate-regulators in hematogenous metastasis, and to dictate some aspects of metastatic patterns. Although these are not the only interactions involving cancer cells, in contrast to others involving cellular and humoral defense mechanisms, they have received comparatively little attention.

Animals↗

[Rare seminoma metastasis to the corpus spongiosum and urethra].

Anaplastic seminomas account for 5-10% of all seminomas. Their metastatic pattern is similar to the classic form of seminoma. We report on an oligophrenic patient with seminoma pT1 who developed a metastasis to the corpus spongiosum and penile urethra, which was successfully treated by local external radiotherapy resulting in long-term tumor remission over a 4-year follow-up period.

Adult↗

Real-world outcomes of ipilimumab plus nivolumab in esophageal squamous cell carcinoma: a multi-institutional large cohort study.

BACKGROUND: Combination immune checkpoint inhibition with ipilimumab plus nivolumab (NIVO + IPI) has shown promising efficacy in advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate648 trial. However, real-world evidence regarding its safety, efficacy as first-line therapy, and host-related biomarkers relevant to immunotherapy remains limited. METHODS: This multicenter retrospective study evaluated a large cohort of 111 patients with unresectable advanced or recurrent ESCC who received first-line NIVO + IPI therapy. Treatment response, treatment-related adverse events, and prognostic factors were analyzed. RESULTS: The objective response and disease control rates in cases with target lesions were 44.0% and 70.7%, respectively. Treatment-related adverse events ≥ Grade 2 occurred in 58 (52.3%) patients, including one Grade 4 event (type 1 diabetes) and two Grade 5 events (biliary infection and myocarditis). The median overall survival (OS) and progression-free survival were 22 months (95% confidence interval [CI]: 13-not reached) and 5 months (95% CI 3-8), respectively. OS was significantly affected by lymph node metastasis in unresectable advanced disease and by liver metastasis in recurrent disease. Multivariate analysis of OS identified the C-reactive protein-to-albumin ratio (CAR), a marker of host immune-inflammatory status, as the only independent prognostic parameter (hazard ratio = 2.99, 95% CI 1.35-6.63, P = 0.0071). CONCLUSIONS: In this large real-world cohort, first-line NIVO + IPI therapy demonstrated meaningful clinical activity and an acceptable safety profile in advanced ESCC. Treatment outcomes varied according to metastatic patterns, suggesting an influence of organ-specific immune microenvironments, and CAR emerged as a simple and robust prognostic biomarker. These findings support the real-world applicability of dual immune checkpoint blockade and highlight the importance of host immune context in patient selection.

Humans↗

Clinical breast cancer, new developments in selection and endocrine treatment of patients.

Breast cancer is the most common malignant tumor among women, comprising an estimated 24% of all cancer cases and 18% of all cancer deaths. At least half of the patients with primary breast cancer will ultimately die by metastatic disease. The tumor characteristics, the natural course of the disease and the response to therapy vary strongly. A number of recently detected cell biological parameters such as oncogenes/suppressor genes, growth factors and secretory proteins are more or less important prognostic factors, because they influence the characteristics and behavior of a tumor with respect to metastatic pattern, extent of cellular differentiation, growth rate and response to treatment. However, there is no clear consensus how best to identify patients at high or low risk. In our experience c-myc amplification and pS2 protein are strong prognosticators for relapse rate, while in advanced disease (apart from a negative estrogen/progesterone receptor/pS2 status) amplification of HER2/neu is a good prognosticator for failure to endocrine therapy. In the diagnosis of breast cancer, in vivo imaging of tumors by labeled hormones or other factors also forms a new development which might have implications for treatment too. With respect to treatment both endocrine and chemotherapy can cure a minority of patients with micrometastases, but in patients with advanced disease only a prolongation of (progression-free) survival can be reached. Response rates decrease with increasing tumor load. In the past decade a number of interesting new endocrine agents has been developed such as new (pure) (anti)steroidal agents, vitamins, aromatase inhibitors, analogs of peptide hormones, prolactin inhibitors and growth factor antagonists. However, less is known on the (potential) interaction between hormones, chemotherapeutic agents, retinoids, cytokins, growth factor antagonists and irradiation. Rapid detection of new powerful combination therapies are needed to improve treatment results during the nineties.

Breast Neoplasms↗

Skip mediastinal lymph node metastasis and lung cancer: a particular N2 subgroup with a better prognosis.

BACKGROUND: Lymph node (LN) metastases from lung cancer may skip the intrapulmonary nodes directly to the mediastinum ([N1-]N2 vs [N1+]N2). This phenomenon is frequent. Patients with such a metastatic pattern appear to have a better prognosis following surgery. Our purpose was to further study the clinical significance and prognostic value of this particular group of (N1-)N2 patients. METHODS: We retrospectively analyzed the data of 731 patients with a pN2 stage who underwent resection for non-small cell lung cancer. Patients with (N1-)N2 metastases (n = 209) were compared to patients with intrapulmonary (N1+)N2 (n = 522). RESULTS: In the (N1-)N2 group, lobectomies were more frequent (54% vs 33%, p = 0.00), metastases more frequently involved a single LN station (79.4% vs 56.3%, p < 0.000001), and primary tumor was more often located in the upper lobes (67.4% vs 55.6%, p = 0.0066). (N1-)N2 was a factor of better prognosis (5 year survival rates 34.4% vs 18.5%, p = 0.00006), which proved also significant when only a single station was involved (38.4% vs 24%, p = 0.0005). These results were confirmed by multivariate analysis. CONCLUSIONS: (N1-)N2 skip metastasis is a unique subgroup of pN2 disease. Lung lymph drainage anatomy may explain the occurrence of these metastases. They form an independent prognostic factor of survival suggesting the need for further study, the results of which may lead to better knowledge of lung cancer, improved classification, and adapted adjuvant therapy.

Adenocarcinoma↗

CXCR4 and CXCL12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and MMP-9 activation.

Colorectal cancer (CRC) is characterized by a distinct metastatic pattern resembling chemokine-induced leukocyte trafficking. This prompted us to investigate expression, signal transduction and specific functions of the chemokine receptor CXCR4 in CRC cells and metastases. Using RT-PCR analysis and Western blotting, we demonstrated CXCR4 and CXCL12 expression in CRC and CRC metastases. Cell differentiation increases CXCL12 mRNA levels. Moreover, CXCR4 and its ligand are inversely expressed in CRC cell lines with high CXCR4 and low or not detectable CXCL12 expression. CXCL12 activates ERK-1/2, SAPK/JNK kinases, Akt and matrix metalloproteinase-9. These CXCL12-induced signals mediate reorganization of the actin cytoskeleton resulting in increased cancer cell migration and invasion. Moreover, CXCL12 increases vascular endothelial growth factor (VEGF) expression and cell proliferation but has no effect on CRC apoptosis. Therefore, the CXCL12/CXCR4 system is an important mediator of invasion and metastasis of CXCR4 expressing CRC cells.

Apoptosis↗

Unexpected metastatic lobular carcinoma of the breast with intraabdominal spread and subsequent port-site metastasis after diagnostic laparoscopy for exclusion of ovarian cancer.

INTRODUCTION: Although lobular carcinomas metastasize primarily to lymph nodes, bone, lung and liver, they can also spread to the gastrointestinal tract, peritoneum and gynecologic organs. CASE REPORT: We report a case of intraperitoneal carcinomatosis of a lobular breast carcinoma that metastasized primarily to the peritoneum, with a subsequent abdominal wall invasion at the trocar site following laparoscopic surgery for the exclusion of an ovarian carcinoma. DISCUSSION: Port-site metastases (PSM) have occurred after laparoscopic surgery for endometrial, fallopian tube, ovarian, and cervical cancers. This is the first report of PSM of a lobular breast carcinoma primarily metastasized to the abdominal cavity. Every surgeon should be aware of the metastatic pattern of breast cancer, especially in relation to its histological subtypes. This case report emphasizes that PSM can occur in various kinds of gynecologic tumors, including breast cancer.

Aged↗

A case-control study of late recurrence of malignant melanoma.

Late recurrence of malignant melanoma is uncommon but appears to be a growing problem. It is unclear whether late recurrence has a better prognosis than early recurrence. Since the answer may influence treatment, we compared recurrence sites and subsequent survival in 35 patients with disease-free intervals of 72 to 240 months (median: 127 months) with 35 case-controls who had relapse at 4 to 56 months (median: 26.7 months). The distribution of recurrence sites in early relapse was 66% in regional nodes or soft tissue and 34% in distant soft tissue or viscera. In late relapse, this distribution was 49% in regional nodes or soft tissue and 51% in distant soft tissue or viscera (no significant differences). Median survival for patients with early and late recurrences in regional nodes or soft tissue was 26 and 44 months, respectively (no significant differences); 5-year survival was 27% and 33%, respectively (no significant differences). Median survival was similar for early or late relapse in distant soft tissue or viscera (8 and 10 months, respectively), as was 5-year survival (0% and 6%, respectively). These results suggest that the metastatic pattern and survival after recurrence are similar for patients with early and late recurring melanoma.

Case-Control Studies↗

Ciliary body melanoma: a special challenge.

Although there is little doubt that the delayed recognition of ciliary body melanoma has a bearing on patient management and ultimate survival, the most compelling issues that face the clinician treating this neoplasm relate to the metastatic patterns and mechanisms of the disease. Several aspects of diagnosis and management of this tumour provide a unique challenge to the clinician. Ciliary body melanoma can remain clinically inapparent to the patient as well as to the clinician during its formative period. In management, tumour characteristics, including anterior and posterior margins, are more readily visualized with ultrasound biomicroscopy (UBM) than with other imaging techniques. UBM can provide valuable information when considering intervention, including biopsy, resection or plaque radiotherapy. Management depends on tumour size, intraocular involvement, patient preference and the presence or absence of systemic manifestations.

Ciliary Body↗

Lobe-specific extent of systematic lymph node dissection for non-small cell lung carcinomas according to a retrospective study of metastasis and prognosis.

BACKGROUND: Complete lymphadenectomy of the mediastinum is advised for patients with lung cancer to provide prognostic information and possible survival benefit. The proper extent of dissection should be further defined. METHOD: The lymphatic metastatic patterns according to the primary site and prognoses were retrospectively analyzed in 166 patients with non-small cell carcinoma who underwent at least lobectomy with hilar and mediastinal lymphadenectomy. All patients had histologically proven mediastinal metastasis (pN2). RESULTS: Among 54 right upper lobe tumors the most common site of metastasis was the lower pretracheal station (74%), whereas metastases to the subcarinal station were seen only in 13%. Among 8 patients with right middle lobe tumors and 41 patients with right lower lobe tumors, both superior mediastinal and subcarinal stations were involved. The 34 left upper segment tumors metastasized to the aorticopulmonary window most commonly (71%) and to the subcarina only in 12% of cases. Inversely, the 10 left lingular tumors metastasized to the subcarina most commonly (50%) and to the aorticopulmonary window only in 20% of cases. Among 44 left lower lobe tumors the subcarinal station was most common for metastasis (58%), with infrequent metastases to the aorticopulmonary window. The 5-year survival for all 166 patients was 35%. Patients with single-station and single-node metastases had a significantly better prognosis than those with more extensive metastases. Right lower lobe tumors with superior mediastinal metastasis carried a particularly poor 5-year survival of only 4.1%. COMMENT: Subcarinal lymphadenectomy is not always necessary for tumors of the right upper lobe and left upper segment. For tumors of other lobes both superior mediastinal dissection and subcarinal dissection are advised. However, superior mediastinal metastasis should be recognized as an indicator of poor prognosis in tumors of both lower lobes.

Adult↗

Stability of sublines in the R3327-H rat prostatic tumor.

Over several years of in vivo maintenance passage the R3327-H rat prostatic tumor has given rise to nine unique sublines in our laboratory. Some have emerged under selective treatment pressure while others apparently represent spontaneous or random modulation. Each new subline embodied an altered histology, growth rate, metastatic pattern or treatment sensitivity in comparison to its parent subline. However, each has been subsequently passaged enough times to provide evidence of considerable phenotypic stability, a notable point in view of the R3327 tumor's well known potential for modulation.

Animals↗

Small cell carcinoma of the prostate gland with inappropriate antidiuretic hormone secretion: morphological, immunohistochemical and clinical expressions.

Small cell carcinomas of the prostate gland are rare, and their histogenesis and clinical behavior remain poorly defined. We report a case with antidiuretic hormone secretion, which demonstrates direct transformation of the adenocarcinoma into the small cell component. The adenocarcinoma reacted positively for prostatic antigen, and negatively for carcinoembryonic antigen and neuron specific enolase, whereas the small cell component was negative for prostatic antigen, and positive for carcinoembryonic antigen and neuron specific enolase. At biopsy this was interpreted as denoting 2 separate tumors: one of prostatic and the other of nonprostatic origin. The clinical course was rapidly fatal but otherwise manifested the metastatic pattern of prostatic carcinoma. We caution that immunohistochemical reactions may be misleading if not interpreted in the context of other findings in the case. This case is labeled as a small cell carcinoma rather than a poorly differentiated adenocarcinoma of the ordinary type because the tumor exhibited morphological, immunohistochemical and biological features typical for that neoplasm.

Adenocarcinoma↗

[Multifocal osteosarcoma. A case report].

UNLABELLED: Multifocal osteosarcoma is an uncommon and aggressive presentation of osteosarcoma. CASE REPORT: We report a case of multifocal osteosarcoma in a 12-year-old boy who was admitted for a tumor of the skull, associated with pleural and pulmonary nodules. A computed tomography scan of the head showed a calcified lesion with intra- and extracranial extent. A biopsy of the skull tumor showed an osteoblastic osteosarcoma. Three weeks later, the patient developed two other tumors of the skull, a tumor of the left shoulder and a pelvic pain. Radiographic studies confirmed the presence of further lytic lesions at these sites. The patient was unresponsive to chemotherapy (high dose methotrexate and doxorubicin) and died nine months later. COMMENTS: Multifocal osteosarcoma, or osteosarcomatosis, is a highly aggressive form of osteosarcoma. The multiple lesions can all arise synchronously as primary tumors, or appear to be one dominant site with early and rapid appearance of secondary lesions. The incidence is reported to be between 1 and 10% of osteosarcoma. The histology shows an osteosarcoma of osteoblastic type in most cases. CONCLUSION: Despite intensive chemotherapy, the prognosis remains poor. The debate remains as to whether or not this clinical presentation represents true multifocality of the disease or a relatively unusual metastatic pattern of osteosarcoma.

Bone Neoplasms↗

Dissimilar invasive and metastatic behavior of vincristine and doxorubicin-resistant cell lines derived from a murine T cell lymphoid leukemia.

Multidrug resistance (MDR) lines from a murine T-cell lymphoid leukemia were selected in increasing vincristine (VCR) or doxorubicin (DOX) concentrations. Surface markers were determined by flow cytometry in both resistant (LBR-V 160 and LBR-D 160) and sensitive (LBR-) cell lines. Results obtained revealed similar expression of CD25, CD24, CD8, CD4, C18 and CD44, while differences in binding to hyaluronic acid (HA) were found. LBR- and LBR-D 160 bound to HA only after phorbol ester (PMA) activation, while LBR-V160 failed to bind HA even after PMA treatment. Histopathological analysis disclosed that LBR-V160 was less invasive than LBR- and LBR-D160 cell lines. In vitro growth of cell lines analyzed by sulforhodamine-B uptake showed that doubling time for the three lines was 10.24 h (LBR-), 16.75 h (LBR-V160) and 16.29 h (LBR-D160). Mortality rate was determined after i.p. injection of 10(4) cells. Mice inoculated with LBR- died at 23 2.11) days, while those inoculated with LBR-V160 or LBR-D160 died at 41 (+/- 9.53) or 41 (+/- 4.96) days, respectively. Our results demonstrated that leukemic murine T cells cultured in the long-term presence of VCR or DOX not only presented changes in the resistance phenotype but also variations in their growth and metastatic pattern.

Animals↗

Murine melanoma: a model for intracranial metastasis.

A variant subline (B16-F10-B2) selected from the B16-F10 melanoma cell line, shows greater metastatic capacity and preferential growth in the brain after i.v. injection into C57BL/6 mice. Several biological properties of these two cell lines have been compared, in an effort to determine the mechanisms responsible for this non-random metastatic pattern. No differences in cell morphology, in vitro growth rates or exposed cell-surface proteins were detected. Quantitative analysis of tumour-cell arrest and distribution using 125IUdR-labelled cells indicated that, although initial arrest patterns of the cell lines were very similar, B16-F10-B2 cells survived in the lungs to a greater cell line had a higher mean number of chromosomes than the parent line, whereas the variance of chromosome distribution was less. We suggest that the selection of a brain-colonizing variant represents the emergence of a pre-existing subpopulation of cells, and provides a useful model for studying mechanisms of intracranial metastasis.

Animals↗

Histological grade and steroid receptor content of primary breast cancer--impact on prognosis and possible modes of action.

The clinical course of breast cancer was related to degree of anaplasia (DA) and steroid receptor (SR) content of primary tumours in 743 patients (pts) with clinical recurrence, initially enrolled in the DBCG-77 protocols. The oestrogen receptor (ER) and the progesterone receptor (PgR) content was known in 110 and 67 pts. The recurrence-free interval, survival after recurrence, and the overall survival were all prolonged in patients with well differentiated tumours or with high SR content. The tumour growth rates were estimated as clinical rates of progression (i.e., the time elapsed from a single distant metastasis until dissemination). The progression rate was prolonged in relatively well differentiated as well as in receptor rich tumours. The extent of dissemination, as indicated by the number of metastatic sites, was not associated with either DA or SR content. However, the anatomical distribution of metastases varied with both DA and SR content: signs of poor prognosis (high DA or low SR content) were associated with occurrence of visceral metastases. In contrast, SR rich tumours had a propensity for recurrence in bone. The results suggest that the impact on prognosis of the features examined here includes both variations in growth rate and metastatic pattern.

Breast Neoplasms↗