Retroperitoneal Soft Tissue Sarcoma: Emerging Therapeutic Strategies.

Retroperitoneal soft tissue sarcoma (RPS) is a rare and heterogenous disease for which surgery is the cornerstone of treatment. However, the local recurrence rate is much higher than in soft tissue sarcoma of the extremities since wide resection is usually unfeasible in RPS due to its large size, indistinct tumour borders, anatomical constraints and the thinness of the overlying peritoneum. Local recurrence is the leading cause of death for low-grade RPS, whereas high-grade tumours are prone to distant metastases. In recent decades, the role of emerging therapeutic strategies, such as more extended surgery and (neo)adjuvant treatments to improve oncological outcome in primary localised RPS, has been extensively investigated. In this review, the recent data on the evolving multidisciplinary management of primary localised RPS are comprehensively discussed. The heterogeneity of RPS, with their different histological subtypes and biological behaviour, renders a standard therapeutic 'one-size-fits-all' approach inappropriate, and treatment should be modified according to histological type and malignancy grade. There is sufficient evidence that frontline extended surgery with compartmental resection including all ipsilateral retroperitoneal fat and liberal en bloc resection of adjacent organs and structures, even if they are not macroscopically involved, increases local tumour control in low-grade sarcoma and liposarcoma, but not in leiomyosarcoma for which complete macroscopic resection seems sufficient. Additionally, preoperative radiotherapy is not indicated for all RPSs, but seems to be beneficial in well-differentiated liposarcoma and grade I/II dedifferentiated liposarcoma, and probably in solitary fibrous tumour. Whether neoadjuvant chemotherapy is of benefit in high-grade RPS remains unclear from retrospective data and is subject of the ongoing randomised STRASS 2 trial, from which the results are eagerly awaited. Personalised, histology-tailored multimodality treatment is promising and will likely further evolve as our understanding of the molecular and genetic characteristics within RPS improves.

The impact of sentinel lymph node mapping with hybrid single photon emission computed tomography/computed tomography in patients with melanoma. Comparison to planar radioisotopic lymphoscintigraphy.

We studied the diagnostic value of 16 slices of single photon emission computed tomography (SPECT)/computed tomography (CT) in the anatomical localization, image interpretation and extra-sentinel lymph nodes (SLNs) detection compared to dynamic and static planar radioisotopic lymphoscintigraphy (PLS) in patients with melanoma. Eighty-two patients with melanoma underwent dynamic PLS, static PLS and SPECT/CT. Data were obtained using a dual head SPECT/CT 16 slices γ-camera. We evaluated the number and localization of SLNs detected with each imaging method. SPECT/CT demonstrated 48 additional SLNs in comparison with PLS in 29 patients. In five truncal and seven head-neck lesions, dynamic and static PLS failed to detect the SLNs found on SPECT/CT (false negative). In one case of truncal and one case of lower limb melanoma, the foci of increased activity interpreted on PLS as possible SLNs were confirmed to be non-nodal sites of uptake on SPECT/CT (false positive). PLS underestimated the number of SLNs detected, whereas SPECT/CT revealed higher agreement compared to the respective number from histological reports. SPECT/CT showed a better prediction of the number of SLNs and higher diagnostic parameters in comparison to planar imaging. SPECT/CT is an important complementary diagnostic modality to PLS, that improves detection, preoperative evaluation, anatomical landmarks of SLNs and surgical management of patients with melanoma.

The current role of secondary cytoreductive surgery for recurrent ovarian cancer.

Ovarian cancer represents worldwide the second most frequent and the most fatal gynecological malignancy, with approximately two thirds of the patients presenting with advanced disease. Cytoreductive surgery, primary or after neoadjuvant chemotherapy, in combination with platinum-based chemotherapy is the standard of care for these patients. Despite the improvement in quality of cytoreductive surgery as well as development of novel drugs and chemotherapy regimens, still most women with ovarian cancer will ultimately develop recurrent disease and die of their disease. In contrast to the management of primary disease, the standard treatment of patients with recurrent ovarian cancer remains a topic of debate. While platinum-based or second line systemic chemotherapy, depending on the time after last platinum treatment, is standard of care, the role of secondary cytoreductive surgery has been a controversial issue for the last decades. Potential outcome benefit must be also weighed against the risk of severe surgical morbidity, impairment of quality of life and costs. In platinum-resistant recurrent disease, i.e., relapse after less than 6 months from the last platinum-based chemotherapy for primary disease, secondary cytoreduction seems generally not to be indicated due to its aggressive biological behavior and the absence of effective systemic treatment. In this comprehensive review, the current role of cytoreductive surgery in platinum-sensitive recurrent ovarian cancer is discussed thoroughly in view of the results of most recent randomized trials and a meta-analysis. There seems to be definitely a role for secondary cytoreductive surgery in selected patients with ovarian cancer recurrence in whom complete resection of macroscopic disease is feasible. However, its role should be continuously reviewed due to the changing systemic treatment of patients with ovarian cancer recurrence over time.

Radiotherapy and Breast Reconstruction: What Is the Ideal Timing? A Narrative Review.

INTRODUCTION: Women undergoing mastectomy choose to pursue breast reconstruction (BR) in order to reduce their body image distress.Adjuvant chest wall irradiation is associated with a negative cosmetic outcome. The aim of our review was to identify the optimal timing of BR relating to radiotherapy delivery. MATERIALS AND METHODS: Using Cochrane Library, Embase, PubMed, Springer, Wanfang and CNKI, we performed a non-systematic review of articles published up to August 2021. RESULTS: There is no hard evidence in favor of immediate, delayed or 2-stage BR when post-mastectomy radiation is indicated. Immediate and 2-stage BR seem to be valid alternatives to delayed BR. CONCLUSIONS: Further research is essential in order to assess clinician and patient reported aesthetic outcomes and determine the optimal timing of BR in view of post-mastectomy radiotherapy, in breast cancer survivors.

A feasibility study of circulating melanoma cells in the perioperative context of hyperthermic isolated limb perfusion (HILP) in 20 patients.

INTRODUCTION: Hyperthermic Ιsolated Limb Perfusion using melphalan and TNFα (TM-HILP) is a regional chemotherapy method for advanced melanoma. PURPOSE: To explore the feasibility of the study of Circulating Melanoma Cells (CMCs) in the context of acute physiological changes induced by TM-HILP and their association with oncological outcomes. METHODS: The study included 20 patients undergoing TM-HILP for unresectable in-transit melanoma of the limbs, stage III(B/C/D). CMCs in the peripheral blood were analyzed at 5-time points from the preoperative day until day 7 from surgery using the following biomarkers: MITF, Tyrosinase mRNA, Melan-A and S100b, through quantitative RT-PCR. RESULTS: No CMCs according to Tyrosinase and Melan-A biomarkers were found in any sample. Friedman test showed significant alterations perioperatively for MITF (p < .001) and S100b (p = .001). Pairwise tests showed a significant increase of MITF levels on postoperative day 7 compared with postoperative day 1, intraoperative and preoperative levels (p < .05). Pairwise tests for S100b showed a significant difference between intraoperative sample and postoperative day 7 (p < .0001). Patients who experienced a complete response to TM-HILP (n = 12) had higher mean levels of MITF and the difference was significant at the time point immediately after the operation (0.29 ± 0.27 vs. 0.06 ± 0.06, p = .014) and on postoperative day 1 (1.48 ± 2.24 vs. 0.41 ± 0.65, p = .046). There was no association of MITF or S100b levels with 4-year disease specific survival. CONCLUSION: TM-HILP is associated with increased levels of CMCs, but there was no association of this increase with survival. Patients with complete response to HILP demonstrate higher values of MITF shortly after the operation.

Hyperthermia During Intraperitoneal Chemotherapy With Paclitaxel or Docetaxel for Ovarian Cancer: Is There Any Benefit?

BACKGROUND/AIM: Intraperitoneal chemotherapy with taxanes provides high locoregional drug concentrations. Regarding their synergy with hyperthermia, results have been inconclusive. In this in vitro study, the thermal enhancement of the effect of paclitaxel and docetaxel on ovarian cancer cells under conditions mimicking those during hyperthermic intraperitoneal chemotherapy (HIPEC) is evaluated. MATERIALS AND METHODS: Cisplatin-resistant SKOV-3 and OVCAR-3 ovarian cancer cells were exposed for 2 h to 0.1, 1 and 3 µΜ of paclitaxel and docetaxel at 37°C (normothermia) and 41.5°C (hyperthermia). Cell proliferation and cell-cycle distribution were evaluated after 24 h, 3 days and 7 days. RESULTS: A concentration-dependent cytotoxic effect on cell proliferation was observed. Concurrent hyperthermia caused an increased arrest of cells in the G2/M phase. At 7 days, thermal enhancement of drug effect was shown only for treatment of OVCAR-3 cells with 1 µM paclitaxel. CONCLUSION: The concentration-dependent cytotoxic effect of paclitaxel and docetaxel supports their intraperitoneal use. Due to the lack of or only minimal thermal enhancement, normothermic may be as effective as hyperthermic intraoperative intraperitoneal chemotherapy with taxanes, avoiding, however, potential oncological and treatment-related adverse effects of concurrent hyperthermia.

An overview and update of hyperthermic intraperitoneal chemotherapy in ovarian cancer.

INTRODUCTION: Despite, the strong rationale and evidence of the benefit of postoperative intraperitoneal chemotherapy in advanced ovarian cancer, it has not been widely adopted, mainly due to its high morbidity and logistical difficulties. Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) is a more tolerable and technically feasible method of intraperitoneal chemotherapy, whereas other potential advantages include homogenous drug distribution, application before tumor regrowth and combination with hyperthermia, which is directly cytotoxic and enhances the efficacy of many drugs. AREAS COVERED: In this review, the authors explain the rationale and indications for cytoreductive surgery (CRS) and HIPEC in advanced ovarian cancer. Data of major clinical studies, meta-analyses, and recent randomized trials are discussed. EXPERT OPINION: After many encouraging clinical studies and meta-analyses, a recent randomized study demonstrated survival benefit for HIPEC during interval CRS in primary ovarian cancer, without increased morbidity, whereas another implied its benefit in recurrent ovarian cancer. Results of recently completed and numerous ongoing randomized studies will further determine the benefit of HIPEC in ovarian cancer at different time points. Patient selection and appraisal of the best protocols are crucial. The field of gynecological oncology will most likely evolve to include HIPEC eventually as a routine treatment for ovarian cancer.

Late local, peritoneal and systemic recurrence of renal angiomyolipoma: A case report.

Renal angiomyolipoma (AML) is a relatively rare tumor that is generally considered as merely benign. However, epithelioid AML (EAML), an uncommon subtype, is associated with potentially malignant behavior. We herein present the case of a 60-year old male patient who had undergone left nephrectomy with left adrenalectomy and lymphadenectomy for a renal tumor 12 years earlier, and presented to our hospital with dull abdominal pain. The histology report after the previous surgery had revealed an AML of the left kidney with a maximal diameter of 17 cm. Imaging studies demonstrated a large tumor of 13 cm in diameter in the area of the resected kidney, as well as hepatic and peritoneal metastases. Computed tomography-guided core needle biopsy of the mass and revision of the histology of the nephrectomy revealed an EAML. Four years after a two-stage resection of the recurrences the patient is in excellent condition and free of disease. From this case report and the literature review on EAML, it appears that correct histological diagnosis of this subtype of renal AML is crucial. Erroneous diagnosis of simple renal AML instead of EAML may lead to insufficient postoperative management. Clinicians should be aware of the malignant potential of EAML and the need for long-term follow-up. As effective surgical and emerging medical treatment options are available, timely detection of recurrent disease may lead to improved outcome.

The evolving management of small bowel adenocarcinoma.

BACKGROUND: Small bowel adenocarcinoma (SBA) is rare despite the fact that the small bowel represents the longest part and has the largest surface of all alimentary tract sections. Its incidence is 50-fold lower than that of colorectal carcinoma. It is often diagnosed at an advanced stage due to atypical and late symptoms, its low index of suspicion, difficult endoscopic access and poor detection by radiological imaging, resulting in impaired outcome. Due to its rarity and being molecularly a unique intestinal cancer, data regarding its optimal management are relatively sparse. MATERIAL AND METHODS: A PubMed search was performed to identify relevant manuscripts that were recently published. Emerging data regarding the pathogenesis, the diagnosis and the treatment of SBA that resulted from recent research are discussed in this comprehensive review. RESULTS: Genomic analysis has demonstrated that SBA is a molecularly unique intestinal cancer. Double balloon enteroscopy and capsule endoscopy are novel techniques which may result in earlier diagnosis and consequently in improvement of the generally poor prognosis. For clinically localized disease, the quality of surgery has recently been defined, with removal of at least 8-10 lymph nodes correlating with improved prognosis. Moreover, adjuvant chemotherapy seems to improve outcome of stage III disease. The combination of a fluoropyrimidine and oxaliplatin appears to be the most effective systemic chemotherapy for disseminated disease. Genomic profiling can identify potentially targetable genomic alterations in a significant proportion of SBA patients. The role of administration of targeted agents or immune checkpoint inhibitors is still unknown and subject of ongoing clinical trials. In the common case of peritoneal metastases, recent studies have shown that cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy may be an attractive treatment option in selected patients. CONCLUSIONS: SBA is a rare and unique malignancy, whose diagnostic approach and treatment are evolving, resulting in improved outcome.

Hyperthermic isolated limb perfusion. The switch from Steinmann pins to Omni-tract assisted isolation.

BACKGROUND: Hyperthermic isolated limb perfusion (HILP) represents an alternative to amputation for patients with either in-transit melanoma or unresectable soft tissue sarcoma, entailing delivery of high-dose chemotherapy after isolation of the extremity, under hyperthermic conditions. Stabilization of the Esmarch elastic bandage is so far performed with the use of Steinmann pins. In this study, we presented our experience with HILP and demonstrated an alternative technique for limb isolation using an Omni-tract retractor instead of the traditional Steinmann pin, while comparing the two methods. METHODS: Forty patients, 28 with recurrent in-transit melanoma and 12 with locally advanced/recurrent sarcoma of the limbs, underwent HILP in a single institution and were included in the study. The Steinmann pin was applied in the first 23 cases, whereas the Omni-tract retractor was applied in the latter 17 patients. RESULTS: The median follow-up for the whole study group was 17.5 mo, whereas the overall response rate was 92.9% for melanoma and 75% for sarcoma patients. Both overall survival and local progression-free survival differed significantly between patients with complete response and those with partial response, stable disease or progressive disease. The use of the Omni-tract retractor was advantageous in every examined field, with the overall complication rate, duration of analgesic administration, and total opioid and paracetamol dose, being significantly less in the Omni-tract patient group. CONCLUSIONS: Although this study was not a randomized trial, we consider that the noninvasive application of the Omni-tract retractor will gain significant acceptance, by contributing to the reduction of HILP complications.

Pharmacological principles of intraperitoneal and bidirectional chemotherapy.

Intraperitoneal chemotherapy is associated with a significant pharmacokinetic and pharmacodynamic benefit and can, alone or in combination with systemic chemotherapy (bidirectional chemotherapy), be used for treating primary and secondary peritoneal surface malignancies. Due to the peritoneal-plasma barrier, high intraperitoneal drug concentration can be achieved by intraperitoneal chemotherapy, whereas systemic concentration remains low. Bidirectional chemotherapy may provide in addition adequate drug concentrations from the side of the subperitoneal space to the peritoneal tumour nodules. Major pharmacological problems of intraperitoneal chemotherapy are limited tissue penetration and poor homogeneity of drug distribution to the entire seroperitoneal surface. Significant pharmacological determinants of intraperitoneal chemotherapy are choice of drug, drug dosage, solution volume, carrier solution, intra-abdominal pressure, temperature, duration, mode of administration, extent of peritonectomy and interindividual variability. Drugs most commonly applied for intraperitoneal chemotherapy include mitomycin C, cisplatin, carboplatin, oxaliplatin, irinotecan, 5-fluoruracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, premetrexed and melphalan. The drugs and their doses that are used vary widely among centres. While the adequate drug choice for intraperitoneal and bidirectional chemotherapy is essential, randomized clinical trials to determine the most optimal drug or drug combination are lacking, and only eight retrospective comparative clinical studies are available. Further clinical pharmacological studies are required to determine the most effective drug regimen for intraperitoneal and bidirectional chemotherapy in various indications. In the future, reliable drug sensitivity testing and genetic profiling of peritoneal metastases will be needed for enabling patient-specific therapy.