Pleurectomy and decortication are associated with better survival for bicavitary cytoreductive surgery for mesothelioma compared with extrapleural pneumonectomy.

OBJECTIVES: Mesothelioma is a nearly uniformly fatal tumor. Multimodality therapy including cytoreductive surgery and chemotherapy is associated with long-term survival in some patients. Cytoreductive surgery for thoracic disease includes a lung-sparing operation called an "extended pleurectomy/decortication" or a lung-sacrificing surgery called an "extrapleural pneumonectomy." The benefit of cytoreductive surgery for bicavitary disease (chest and abdomen) is poorly understood. Our objective was to evaluate the long-term survivals for patients undergoing cytoreductive surgery for bicavitary disease and to determine whether any prognostic factors were associated with outcome. METHODS: We reviewed our Institutional Review Board-approved, institutional, International Association for the Study of Lung Cancer Mesothelioma Staging Project database. Inclusion criteria were all patients who underwent cytoreductive surgery for bicavitary disease. Overall survival was calculated by Kaplan-Meier methodology. All International Association for the Study of Lung Cancer database elements were evaluated by univariable analysis. RESULTS: From February 2014 to August 2021, 440 patients with mesothelioma were evaluated. Fourteen patients (3%) underwent cytoreductive surgery of both chest and abdomen as a planned 2-stage operation. Most patients (13/14; 93%) underwent chest surgery before abdomen surgery. For the entire cohort, the median overall survival was 33.6 months with a 5-year survival of 20%. Extended pleurectomy/decortication was associated with a better outcome compared with extrapleural pneumonectomy, with median overall survivals of 58.2 versus 13.5 months, respectively. CONCLUSIONS: For a highly selected group of patients with bicavitary mesothelioma, long-term survival can be achieved with an aggressive, staged surgical approach. The patients who undergo extended pleurectomy/decortication with preservation of the lung appear to have more favorable outcomes compared with patients undergoing extrapleural pneumonectomy.

A Gigantic Uterine Leiomyoma and Big Bilateral Adrenal Myelolipomas as a Result of Untreated Congenital Adrenal Hyperplasia.

INTRODUCTION: Patients with congenital adrenal hyperplasia (CAH) can present early with salt wasting, adrenal insufficiency, and hyperandrogenism. Late consequences as a result of untreated CAH are now rarely seen. We present a patient with a massive uterine leiomyoma and bilateral adrenal myelolipomas due to longstanding treatment noncompliance. CASE REPORT: A female patient with CAH was treated with glucocorticoids until the age of 29 years when they stopped with the intention of identifying as a male. The patient then presented with abdominal pain and distension. Computed tomography images of the abdomen and pelvis revealed a 31 × 35 × 31-cm abdominal mass, a 5.9× 2.4-cm right adrenal mass, and an 11.8 × 8.8-cm left adrenal mass. The patient underwent total hysterectomy and bilateral adrenalectomy. Pathology of the abdominal mass was consistent with uterine leiomyoma, and bilateral adrenal masses were consistent with adrenal myelolipomas. DISCUSSION: The goal of CAH therapy is to provide adequate replacement while reducing adrenocorticotropic hormone and adrenal androgens levels. Due to the conversion of androgens to estrogens, untreated females with CAH have elevated androgen and estrogen levels. High levels of these hormones can stimulate the growth of estrogen-dependent organs as exemplified by our patient. Chronic adrenocorticotropic hormone stimulation can not only cause adrenal hyperplasia but has also been associated with the development of adrenal myelolipomas. CONCLUSION: This case demonstrates the significance of CAH treatment compliance as there are several serious sequela outside of the expected adrenal insufficiency and virilization. Even when the desired effect is virilization, other means of hormonal therapy should be considered.

Diagnostic Laparoscopy Improves Staging of Malignant Pleural Mesothelioma With Routine Positron Emission Tomography Imaging.

BACKGROUND: With a multimodal treatment strategy, cytoreductive surgery extends survival in malignant pleural mesothelioma. Improving the accuracy of staging can refine patient selection. Our objective was to determine whether diagnostic laparoscopy (DL) improves staging for patients with malignant pleural mesothelioma with the routine use of positron emission tomography (PET). METHODS: We performed a retrospective review of our prospectively maintained database from February 2014 to May 2019. Inclusion criteria were patients who had disease in the chest that was deemed potentially resectable by radiographic criteria and who underwent DL as part of the staging evaluation before surgery. RESULTS: Of 187 patients (71% men, 80% epithelial) who underwent DL during staging, 76% proceeded to surgery; 22% were unresectable at exploratory thoracotomy and 78% underwent resection (pleurectomy and decortication, 68%; extrapleural pneumonectomy, 32%). Also, 89% had a PET computed tomography (CT), and 11% had a preoperative CT without PET. DL revealed peritoneal disease in 17%. Among patients with pathologically proven disease at DL, 77% had negative PET-CT imaging. Based on the pathologic findings at DL the sensitivity, specificity, positive predictive value, and negative predictive value of PET-CT were 23%, 78%, 17%, and 83%, respectively. The accuracy of PET-CT was 68%. CONCLUSIONS: PET-CT has low sensitivity and diagnostic accuracy to identify peritoneal disease in malignant pleural mesothelioma. DL as part of the preoperative staging defines an important subset of patients with bicavitary disease. We recommend DL as a component of staging before surgery.

Nutritional and Metabolic Derangements in Pancreatic Cancer and Pancreatic Resection.

Pancreatic cancer is an aggressive malignancy with a poor prognosis. The disease and its treatment can cause significant nutritional impairments that often adversely impact patient quality of life (QOL). The pancreas has both exocrine and endocrine functions and, in the setting of cancer, both systems may be affected. Pancreatic exocrine insufficiency (PEI) manifests as weight loss and steatorrhea, while endocrine insufficiency may result in diabetes mellitus. Surgical resection, a central component of pancreatic cancer treatment, may induce or exacerbate these dysfunctions. Nutritional and metabolic dysfunctions in patients with pancreatic cancer lack characterization, and few guidelines exist for nutritional support in patients after surgical resection. We reviewed publications from the past two decades (1995-2016) addressing the nutritional and metabolic status of patients with pancreatic cancer, grouping them into status at the time of diagnosis, status at the time of resection, and status of nutritional support throughout the diagnosis and treatment of pancreatic cancer. Here, we summarize the results of these investigations and evaluate the effectiveness of various types of nutritional support in patients after pancreatectomy for pancreatic adenocarcinoma (PDAC). We outline the following conservative perioperative strategies to optimize patient outcomes and guide the care of these patients: (1) patients with albumin < 2.5 mg/dL or weight loss > 10% should postpone surgery and begin aggressive nutrition supplementation; (2) patients with albumin < 3 mg/dL or weight loss between 5% and 10% should have nutrition supplementation prior to surgery; (3) enteral nutrition (EN) should be preferred as a nutritional intervention over total parenteral nutrition (TPN) postoperatively; and, (4) a multidisciplinary approach should be used to allow for early detection of symptoms of endocrine and exocrine pancreatic insufficiency alongside implementation of appropriate treatment to improve the patient's quality of life.

Treatment sequencing strategy for hepatic epithelioid haemangioendothelioma.

BACKGROUND: The biology of hepatic epithelial haemangioendothelioma (HEHE) is variable, lying intermediate to haemangioma and angiosarcoma. Treatments vary owing to the rarity of the disease and frequent misdiagnosis. METHODS: Between 1989 and 2013, patients retrospectively identified with HEHE from a single academic cancer centre were analysed to evaluate clinicopathological factors and initial treatment regimens associated with survival. RESULTS: Fifty patients with confirmed HEHE had a median follow-up of 51 months (range 1-322). There was no difference in 5-year survival between patients presenting with unilateral compared with bilateral hepatic disease (51.4% versus 80.7%, respectively; P = 0.1), localized compared with metastatic disease (69% versus 78.3%, respectively; P = 0.7) or an initial treatment regimen of Surgery, Chemotherapy/Embolization or Observation alone (83.3% versus 71.3% versus 72.4%, respectively; P = 0.9). However, 5-year survival for patients treated with chemotherapy at any point during their disease course was decreased compared with those who did not receive any chemotherapy (43.6% versus 82.9%, respectively; P = 0.02) and was predictive of a decreased overall survival on univariate analysis [HR 3.1 (CI 0.9-10.7), P = 0.02]. CONCLUSIONS: HEHE frequently follows an indolent course, suggesting that immediate treatment may not be the optimal strategy. Initial observation to assess disease behaviour may better stratify treatment options, reserving surgery for those who remain resectable/transplantable. Prospective cooperative trials or registries may confirm this strategy.

A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle.

Protein kinase Calpha (PKCalpha) has been implicated in cancer, but the mechanism is largely unknown. Here, we show that PKCalpha promotes head and neck squamous cell carcinoma (SCCHN) by a feed-forward network leading to cell cycle deregulation. PKCalpha inhibitors decrease proliferation in SCCHN cell lines and xenografted tumors. PKCalpha inhibition or depletion in tumor cells decreases DNA synthesis by suppressing extracellular signal-regulated kinase phosphorylation and cyclin E synthesis. Additionally, PKCalpha down-regulates miR-15a, a microRNA that directly inhibits protein synthesis of cyclin E, as well as other cell cycle regulators. Furthermore, both PKCalpha and cyclin E protein expression are increased in primary tumors, and PKCalpha inversely correlates with miR-15a expression in primary tumors. Finally, PKCalpha is associated with poor prognosis in SCCHN. These results identify PKCalpha as a key regulator of SCCHN tumor cell growth by a mechanism involving activation of mitogen-activated protein kinase, an initiator of the cell cycle, and suppression of miR-15a, an inhibitor of DNA synthesis. Although the specific components may be different, this type of feed-forward loop network, consisting of a stimulus that activates a positive signal and removes a negative brake, is likely to be a general one that enables induction of DNA synthesis by a variety of growth or oncogenic stimuli.

Patient selection and outcome of hepatectomy for noncolorectal non-neuroendocrine liver metastases.

Improved patient selection, introduction of more effective systemic treatments including targeted biologic and combined therapies, and the low morbidity and mortality rates of hepatobiliary surgery in centers of excellence are likely to provide continued improvements in outcomes for patients with noncolorectal non-neuroendocrine liver metastases. Further advances in treatment may emerge from better understanding of the underlying tumor biology for each cancer type and application of individualized care to each patient.

Surgical resection in metastatic gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract. Traditionally, surgery has been the primary treatment modality for these tumors, with only modest results. The recent development of kinase inhibitors (most notably, imatinib mesylate) has provided a new paradigm for the treatment of this disease. Response rates approaching 60% have been seen in studies in patients with advanced disease. Previously, chemotherapy played little role in the treatment of this disease. Now, however, treatment with kinase inhibitors can increase the number of patients who may potentially benefit from surgical intervention. Many questions regarding the use of kinase inhibitors remain. Most importantly, the optimal duration of treatment before surgical intervention and following both complete and incomplete tumor resection remains to be elucidated. Ongoing prospective trials have the potential to provide some of these answers in the near future.

Imaging studies in patients with melanoma.

The incidence of malignant cutaneous melanoma is rising. Imaging studies represent a major component of the staging work-up and follow-up of melanoma patients and are used to facilitate preoperative planning and intraoperative management. Study benefits are not clear, and evidence does not support any particular protocol for their use. The National Comprehensive Cancer Network's updated guidelines for use of imaging studies in melanoma patients represent a consensus based on lower level evidence, including clinical experience. The utility of individual imaging studies in melanoma patients depends on disease stage. Chest radiography, CT, MRI, lymphoscintigraphy, ultrasonography, PET, and PET/CT have specific roles in patient evaluation. Clinicians must use available evidence to guide decisions regarding which imaging modalities are appropriate for a given indication.

Current concepts in multimodality therapy for retroperitoneal sarcoma.

Radical surgical resection currently represents the most effective therapy for patients with retroperitoneal sarcoma. Unfortunately, margin-negative resection often mandates extirpation of multiple retroperitoneal viscera, and such operations are nonetheless fraught with high rates of locoregional recurrence. In an attempt to improve local control and ultimately survival, adjuvant strategies of radiation and chemotherapy have been increasingly employed, with promising results. To date, however, the rarity of the disease has limited large, prospective studies investigating the efficacy of these adjuvant modalities. In this article, we review the current literature pertaining to the diagnosis, staging and treatment of retroperitoneal sarcoma and demonstrate the critical need for future large, multi-institutional studies to advance our knowledge of this uncommon disease.

Synchronous colorectal adenocarcinoma and gastrointestinal stromal tumor (GIST).

BACKGROUND: Little is known about the synchronous occurrence of gastrointestinal stromal tumors (GISTs) and other gastrointestinal tumors. We present two cases of an invasive colon cancer with a synchronous small-bowel GIST; immunohistochemistry studies were performed to evaluate possible genetic similarities. METHODS: This paper reports two cases of synchronous GISTs and colorectal cancer (CRC) with immunohistochemistry analysis of c-Kit expression. This paper is also a review of the existing literature on the association of GISTs and CRC and the role of c-Kit in CRC. RESULTS: In the last 2 years, we observed two patients with synchronous CRCs and GISTs of the small bowel. The GISTs were incidentally discovered during the work-up for CRCs and excised at the time of the colon resection. Immunohistochemistry study did not reveal an expression of c-Kit in CRCs. Clinical implications of the association between these two neoplasms are described in this paper. CONCLUSIONS: Synchronous CRC and GIST has been more frequently reported. Because of the limited number of cases, we cannot exclude an incidental relationship. The genetic pathways of tumorigenesis appear different for the two neoplasms. Further studies are needed to clarify a possible role of c-Kit in the development of colonic adenocarcinomas.

Combined 5-fluorouracil/systemic interferon-beta gene therapy results in long-term survival in mice with established colorectal liver metastases.

Preclinical in vitro and in vivo studies have demonstrated synergistic interactions between 5-fluorouracil (5-FU) and type I and II IFNs against human colorectal cancer cells. Despite these activities, randomized human trials have failed to identify a clinical benefit for this combination treatment. These limited clinical results may be secondary to the short half-life of recombinant IFN protein and the increased systemic toxicities of 5-FU/IFN combinations. We have previously reported an adenoviral-mediated IFN-beta gene therapy strategy, which may circumvent the pitfalls of recombinant IFN therapy. However, a dose-dependent toxicity and acute inflammatory response to systemically administered adenovirus vectors may limit the clinical application of this therapy. The combination of adenoviral-mediated IFN-beta gene therapy and 5-FU resulted in tumor regression, apoptosis, and improved survival in an established liver metastases model. These therapeutic effects were observed at a significantly lower vector dose than we had previously reported and with limited toxicity. This approach may allow for an effective clinical application of this therapy and warrants additional investigation.

Stat1-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand and the cell-surface death signaling pathway by interferon beta in human cancer cells.

Type I IFNs are known to inhibit tumor cell growth and stimulate the immune system. However, little is known of the mechanism of type I IFN-induced apoptosis in human cancer cells. In this study, we have IFN-beta treatment of a human colorectal cell line (KM12L4) and a resistant clone of this cell line, L4RIFN. We demonstrate the induction of apoptosis in the parent cell line. This process was associated with the induction of the Jak-Stat signaling pathway, induction of the proapoptotic mediator tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and activation of procaspase-3, -8, -9, and -10. Additionally, we evaluated the role of Stat1 in mediating IFN-beta induction of these proapoptotic signals in a fibrosarcoma cell line (2ftgh) and a Stat1-deficient clone (U3A). Our results demonstrate that IFN-beta induction of apoptosis and the induction of proapoptotic mediator TRAIL is Stat1 dependent. Evaluation of a stable transfectant of the KM12L4 cell line expressing c-FLIP supports the role of TRAIL and the cell-surface death signaling pathways in IFN-beta induction of apoptosis. Studies evaluating the TRAIL promoter indicate induction of TRAIL promoter activity by IFN-beta. These results may represent a novel pathway by which IFN-beta may induce therapeutic effects.