Spermatocytic Tumor: A Review.

Spermatocytic tumor (ST) is a very rare disease, accounting for approximately 1% of testicular cancers. Previously classified as spermatocytic seminoma, it is currently classified within the non-germ neoplasia in-situ-derived tumors and has different clinical-pathologic features when compared with other forms of germ cell tumors (GCTs). A web-based search of MEDLINE/PubMed library data was performed in order to identify pertinent articles. In the vast majority of cases, STs are diagnosed at stage I and carry a very good prognosis. The treatment of choice is orchiectomy alone. Nevertheless, there are two rare variants of STs having very aggressive behavior, namely anaplastic ST and ST with sarcomatous transformation, that are resistant to systemic treatments and their prognosis is very poor. We have summarized all the epidemiological, pathological and clinical features available in the literature regarding STs that have to be considered as a specific entity compared to other germ GCTs, including seminoma. With the aim of improving the knowledge of this rare disease, an international registry is required.

Management of Germ Cell Tumors During the Outbreak of the Novel Coronavirus Disease-19 Pandemic: A Survey of International Expertise Centers.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs). MATERIALS AND METHODS: To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network-Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options. RESULTS: Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19-positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences. CONCLUSION: Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic. IMPLICATIONS FOR PRACTICE: Despite the chaos, disruptions, and fears fomented by the COVID-19 illness, oncology care teams in Italy, other European countries, and Canada are delivering the enormous promise of curative management strategies for patients with testicular cancer and other germ cell tumors. At the same time, these teams are applying safe and innovative solutions and sharing best practices to minimize frequency and intensity of patient contacts with thinly stretched health care capacity.

Providing nutritional care to cancer patients during the COVID-19 pandemic: an Italian perspective.

The COVID-19 outbreak has drastically changed practices inside hospitals, which include oncology routines. In oncology, malnutrition was and certainly still is a frequent problem associated with an increase in treatment-related toxicity, a reduced response to cancer treatment, an impaired quality of life, and a worse overall prognosis. Even in this situation of healthcare crisis, nutritional support in cancer care is an essential element. During the current COVID-19 pandemic, there is a concrete high risk to see a dramatic worsening of cancer patients' nutritional status, who are left without adequate clinical and nutritional support. The consequences are already reasonably foreseeable and will have a severe negative impact after the emergency. Therefore, we believe that it is essential to try to continue, as far as possible, the activity of clinical nutrition in oncology, by revolutionizing the setting and the approach to patients. For this purpose, the Clinical Nutrition and Dietetics Unit and the Medical Oncology Unit of our hospital, one of the largest community hospital in Lombardy that has been involved in the COVID-19 outbreak management since its inception, have reorganized the clinical routine activity in strict collaboration since the very beginning of the emergency, to better face up to the challenge, while preserving cancer patients' needs.

Sharing real-world experiences to optimize the management of olaparib toxicities: a practical guidance from an Italian expert panel.

Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved as maintenance therapy of recurrent ovarian cancer (OC) patients with a BRCA mutation. To achieve the maximum clinical benefit, adherence to olaparib must be persistent. However, in clinical practice, this is challenged by the frequent suboptimal management of toxicities. In view of the expanding use of olaparib also in Italy, physicians must learn how to adequately and promptly manage drug toxicities not to unnecessarily interrupt or reduce the dose. The experts agreed that nausea,vomiting, anemia, and fatigue are the most frequent events experienced by OC patients on olaparib, and that these toxicities usually develop early during treatment, are mainly of grade 1-2 and transient and can be managed with simple non-pharmacological interventions. By sharing their real-world experiences, the panel prepared, for each toxicity, an algorithm organized by grade and besides the procedures indicated in the local label, included supportive care interventions based also on nutritional and lifestyle modifications and psycho-oncology consultation. Moreover, in view of the tablet entry into the Italian market, the full and reduced dosages of capsules and tablets were compared. This practical guidance is intended to be a tool to support especially less-experienced physicians in the management of these complex patients, with the aim to help preventing the worsening of patients' conditions and the unnecessary interruption/reduction of olaparib dosage, which may jeopardize treatment efficacy.

Adjuvant high-dose chemotherapy with autologous hematopoietic stem cell support for high-risk primary breast cancer: results from the Italian national registry.

The efficacy of high-dose chemotherapy (HDC) and autologous hemopoietic progenitor cell transplantation (AHPCT) for breast cancer (BC) patients has been an area of intense controversy among the medical oncology community. The aim of this study was to assess toxicity and efficacy of this procedure in a large cohort of high-risk primary BC patients who underwent AHPCT in Italy. A total of 1183 patients receiving HDC for high-risk BC (HRBC) (>3 positive nodes) were identified in the Italian registry. The median age was 46 years, 62% of patients were premenopausal at treatment, 60.1% had endocrine-responsive tumors, and 20.7% had a human epidermal growth factor receptor 2 (HER2)-positive tumor. The median number of positive lymph nodes (LN) at surgery was 15, with 71.5% of patients having ≥ 10 positive nodes. Seventy-three percent received an alkylating agent-based HDC as a single procedure, whereas 27% received epirubicin or mitoxantrone-containing HDC, usually within a multitransplantation program. The source of stem cells was peripheral blood in the vast majority of patients. Transplantation-related mortality was .8%, whereas late cardiac and secondary tumor-related mortality were around 1%, overall. With a median follow-up of 79 months, median disease-free and overall survival (OS) in the entire population were 101 and 134 months, respectively. Subgroup analysis demonstrated that OS was significantly better in patients with endocrine-responsive tumors and in patients receiving multiple transplantation procedures. HER2 status did not affect survival probability. The size of the primary tumor and number of involved LN negatively affected OS. Adjuvant HDC with AHPCT has a low mortality rate and provides impressive long-term survival rates in patients with high-risk primary BC. Our results suggest that this treatment modality should be proposed in selected HRBC patients and further investigated in clinical trials.

The first real-world study on the role of carbon ion radiotherapy for oligo-metastatic, persistent, or recurrent (MPR) ovarian/fallopian tube cancer.

Introduction: In the multidisciplinary management of oligometastatic, persistent, or recurrent (MPR) ovarian cancer, radiotherapy (RT) is becoming a more and more worthwhile treatment to potentially improve the chronicity of the disease. Particle beam RT has proved to be effective in several gynecological malignancies, but so far no data are available for ovarian cancer. Material and Methods: This is a real-world, retrospective, bi-institutional, single-arm study aimed to assess the effectiveness and the safety of carbon ion RT (CIRT) in this setting. The co-first endpoints are 1-year and 2-year actuarial local control (LC) rates and the objective response rate (ORR) defined on a "per lesion" basis. The secondary endpoint was toxicity. Actuarial outcomes were evaluated using the Kaplan-Meier method while potential predictors were explored using the Log-rank test. Bi-variable logistic regression was employed in the analysis of factors predicting the complete response on a per-lesion basis. Results: 26 patients accounting for a total of 36 lesions underwent CIRT with a total median dose of 52.8 Gy[RBE] (range: 39-64 Gy[RBE]). Five patients received CIRT for re-irradiation. No concomitant systemic therapies were administered during CIRT. Within 12 months after the treatment, 17 lesions (47 %) achieved complete response while 18 (50 %) obtained a partial response with an ORR of 97 %. The achievement of a complete response is related to the dose per fraction (>4.2 Gy[RBE], p = 0.04) and total dose (>52,8 Gy[RBE], p = 0.05). The 1-year LC was 92 % and the 2-year LC was 83 %, according to the achievement of a CR (p = 0.007) and GTV ≤ 14 cm3 (p = 0.024). No grade > 3 toxicities were recorded both in naïve and re-irradiated patients. PARP-i and anti-VEGF seemed not to exacerbate the risk of severe toxicities. Conclusions: CIRT was effective and safe in MPR ovarian cancers, even in the case of re-irradiation. Largest cohort studies and longer follow-up are needed to confirm these data.

Granulosa cell tumors (GCTs) of the ovary: What is the role of radiotherapy?

Granulosa cell tumors of the ovary have an indolent behavior and a good prognosis, but a high incidence of local recurrence after surgery. The best treatment in the recurrent setting is unclear and randomized clinical trials on the management in the recurrent setting are lacking. The role of radiotherapy is controversial in adjuvant settings and unknown in case of relapse after surgery. This review aims to summarize the level of evidence of the role of radiation treatments for granulosa cell tumors of the ovary.

Clinical Trials of Cellular Therapies in Solid Tumors.

In the past years cancer treatments have drastically changed, mainly due to the development of immune checkpoint inhibitors capable of immune modulation in vivo, thus providing major clinical benefit in a number of malignancies. Simultaneously, considerable technical refinements have opened new prospects for the development of immune cell-based medicinal products and unprecedented success with chimeric antigen receptor (CAR)-T cells targeting B-cell hematologic malignancies has been obtained. However, T cell therapies introduced and performed in the field of solid tumors have produced so far only limited responses in selected patient populations. This standstill is attributable to the difficulty in identifying target antigens which are homogeneously expressed by all tumor cells while absent from normal tissues, and the limited T cell persistence and proliferation in a hostile tumor microenvironment that favors immune escape. Replicating the results observed in hematology is a major scientific challenge in solid tumors, and ongoing translational and clinical research is focused on obtaining insight into the mechanisms of tumor recognition and evasion, and how to improve the efficacy of cellular therapies, also combining them with immune checkpoint inhibitors or other agents targeting either the cancer cell or the tumor environment. This paper provides an overview of current adaptive T cell therapy approaches in solid tumors, the research performed to increase their efficacy and safety, and results from ongoing clinical trials.

Long-lasting responses with chemotherapy followed by T-cell therapy in recurrent or metastatic EBV-related nasopharyngeal carcinoma.

Background: Refractory or metastatic nasopharyngeal carcinoma (NPC) patients have a poor prognosis due to the lack of effective salvage treatments and prolonged survival by means of combination chemotherapy being described only for a minority of younger patients with oligometastatic disease. Targeting the Epstein - Barr virus (EBV) proteins expressed in NPC cells has been shown to be a feasible strategy that could help control systemic disease. Patients and Methods: Between 2011 and 2014, 16 patients with recurrent/metastatic EBV-NPC received first-line chemotherapy (CT) followed by 2 doses of autologous cytotoxic EBV specific T-lymphocytes (15-25 x 107 total cells/dose, 2 weeks apart), based on our previous studies showing the feasibility and efficacy of this infusion regimen. Cumulative overall survival (OS) and median OS were analysed in the whole population and according to specific clinical and biological parameters. Results: All patients received the planned T-cell therapy schedule, 9 after reaching partial (n=5) or complete (n=4) disease remission with CT, and 7 after failing to obtain benefit from chemotherapy. No severe adverse events were recorded. Patients who received cytotoxic T-lymphocytes (CTLs) had a cumulative 10-year OS of 44%, with a median OS of 60 months (95% CI 42-62). Patients responding to CT, with oligometastatic disease (<3 disease sites), and plasma EBV-DNA <1000 copies/mL had a better outcome. Conclusions: Autologous EBV-specific CTLs transplanted following conventional first-line CT demonstrated promising efficacy with several patients obtaining long-lasting disease control. The rationale provided by this study, with the crucial role likely played by the timing of CTL administration when trying to induce synergy with conventional treatment needs to be confirmed in a prospective controlled trial.

Feasibility and safety of adoptive immunotherapy with ex vivo-generated autologous, cytotoxic T lymphocytes in patients with solid tumor.

BACKGROUND AIMS: Adoptive T-cell therapy with tumor-specific T cells has emerged as a potentially useful approach for treating patients with advanced malignancies. We have demonstrated previously the feasibility of obtaining large numbers of autologous anti-tumor-specific cytotoxic T lymphocytes (CTL) generated by stimulation of patients' peripheral blood mononuclear cells with dendritic cells pulsed with apoptotic tumor cells. Methods. Six patients with progressing metastatic solid tumors (one renal cell carcinoma, two ovarian cancers, two extraosseous peripheral neuroectodermal tumors, one soft tissue sarcoma) not eligible for conventional therapies were treated with adoptive immunotherapy. Anti-tumor CTL, proven to be reactive in vitro against patient tumor cells, but not against normal cells, were infused following lymphodepleting chemotherapy administered to favor T-cell proliferation in vivo. RESULTS: Patients received a median of nine CTL infusions (range 2-19). The median number of CTL administered per infusion was 11 × 10(8) (range 1-55 × 10(8)). No patient experienced acute or late adverse events related to CTL infusion, even when large numbers of cells were given. Post-infusion laboratory investigations demonstrated an increase in the frequency of circulating anti-tumor T-cells and, in patients with a longer follow-up receiving two CTL infusions/year, a stabilization of these values. CONCLUSIONS: Our study demonstrates that autologous ex vivo-generated anti-tumor CTL can be administered safely in patients with advanced solid tumors and can improve the immunologic reactivity of recipients against tumor. These preliminary results provide a rationale for evaluating the clinical efficacy of this immunotherapeutic approach in phase I/II studies.

Case report: Successful outcome of COVID-19 in the context of autologous hematopoietic stem cell transplantation: The impact of the anti-SARS-CoV-2 vaccine and early remdesivir.

Coronavirus disease (COVID-19) in patients undergoing hematopoietic stem cell transplantation (HSCT) is a major issue. None of the published papers have reported data on the outcome of HSCT patients with COVID-19 according to the vaccination status and the short course of remdesivir (RDV). Therefore, we present the case of a 22-year-old man with relapsed testicular non-seminomatous germ-cell tumor who was diagnosed with COVID-19 during his first auto-HSCT. Our case report is the first one describing the efficacy of early RDV (and its anti-inflammatory effects that might counterbalance the negative effect of the recombinant human granulocyte-colony stimulating factors -rhG-CSF-) in the context of severe neutropenia following HSCT with the concomitant onset of COVID-19.

Testicular tumors in the "elderly" population.

Germ cell tumors arise in childhood but peak at around 30 years of age. They are the most common cancers in males under the age of 35. Over 95% arise in the testes while a minority originate in extragonadal sites such as the anterior mediastinum, or mainly in childhood the pineal gland or the sacrococcygeal area. These tumors show an extraordinary sensitivity to chemotherapy (and for seminoma, also to radiation) and cure rates are relatively high even in second or subsequent relapses. Very few data are present in the literature regarding patients diagnosed after 50 years and no specific trials have been conducted in this setting. Nearly all patients reported in the literature had testicular cancers, with occasional reports of extragonadal tumors. Despite the fact that > 50 years may be considered an "elderly" population, these patients are treated with the same cisplatin containing combinations as their younger counterparts with consequent higher toxicity. In this review we will present epidemiological and clinical data from this rare population of patients with testicular cancer.

Ovarian Cancer Radiosensitivity: What Have We Understood So Far?

Radiotherapy has been increasingly considered as an active treatment to combine with other approaches (i.e., surgery, chemotherapy, and novel target-based drugs) in ovarian cancers to palliate symptoms and/or to prolong chemotherapy-free intervals. This narrative review aimed to summarize the current knowledge of the radiosensitivity/radioresistance of ovarian cancer which remains the most lethal gynecological cancer worldwide. Indeed, considering the high rate of recurrence in and out of the radiotherapy fields, in the era of patient-tailored oncology, elucidating the mechanisms of radiosensitivity and identifying potential radioresistance biomarkers could be crucial in guiding clinical decision-making.

Pathologic Findings at Risk Reducing Surgery in BRCA and Non-BRCA Mutation Carriers: A Single-Center Experience.

Risk-reducing surgery (RRS) is recommended in BRCA-mutated carriers because of their increased risk of developing ovarian cancer, while its role is still discussed for women harboring mutations in non-BRCA homologous repair genes. The aim of this study was to retrospectively evaluate the occurrence of pathological findings in a high-risk population undergoing RRS in San Matteo Hospital, Pavia between 2012 and 2022, and correlate their genetic and clinical outcomes, comparing them with a control group. The final cohort of 190 patients included 85 BRCA1, 63 BRCA2, 11 CHEK2, 7 PALB2, 4 ATM, 1 ERCC5, 1 RAD51C, 1 CDH1, 1 MEN1, 1 MLH1 gene mutation carriers and 15 patients with no known mutation but with strong familial risk. Occult invasive serous carcinoma (HGSC) and serous tubal intraepithelial carcinoma (STIC) were diagnosed in 12 (6.3%) women, all of them BRCA carriers. No neoplastic lesion was diagnosed in the non-BRCA group, in women with familial risk, or in the control group. Oral contraceptive use and age ≤45 at surgery were both found to be favorable factors. While p53 signature and serous tubal intraepithelial lesion (STIL) were also seen in the control group and in non-BRCA carriers, STIC and HGSC were only found in BRCA1/2 mutation carriers.

An Inflammatory Signature to Predict the Clinical Benefit of First-Line Cetuximab Plus Platinum-Based Chemotherapy in Recurrent/Metastatic Head and Neck Cancer.

Epidermal growth factor receptor (EGFR) pathway has been shown to play a crucial role in several inflammatory conditions and host immune-inflammation status is related to tumor prognosis. This study aims to evaluate the prognostic significance of a four-gene inflammatory signature in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients treated with the EGFR inhibitor cetuximab plus chemotherapy. The inflammatory signature was assessed on 123 R/M HNSCC patients, enrolled in the multicenter trial B490 receiving first-line cetuximab plus platinum-based chemotherapy. The primary endpoint of the study was progression free survival (PFS), while secondary endpoints were overall survival (OS) and objective response rate (ORR). The patient population was subdivided into 3 groups according to the signature score groups. The four-genes-signature proved a significant prognostic value, resulting in a median PFS of 9.2 months in patients with high vs. 6.2 months for intermediate vs. 3.9 months for low values (p = 0.0016). The same findings were confirmed for OS, with median time of 18.4, 13.4, and 7.5 months for high, intermediate, and low values of the score, respectively (p = 0.0001). When ORR was considered, the signature was significantly higher in responders than in non-responders (p = 0.0092), reaching an area under the curve (AUC) of 0.65 (95% CI: 0.55-0.75). Our findings highlight the role of inflammation in the response to cetuximab and chemotherapy in R/M-HNSCC and may have translational implications for improving treatment selection.

Retroperitoneal sarcoma: is it time to change the surgical policy?

BACKGROUND: Complete tumor resection is the mainstay of treatment for retroperitoneal sarcoma (RPS), but the size and quality of surgical margins for radical resection in RPS are unknown. They are believed to be pushing tumors, but recently, aggressive surgical policies leading to multivisceral resection have seemed to suggest better local control compared with simple tumor resection. We analyzed a single-institution series of RPS to provide information useful to surgical decision-making. METHODS: From 1996 to 2008, 77 patients referred to our institution underwent surgery for primary RPS. Thirty tumors were classified as liposarcoma, and 20 as leiomyosarcoma. Potential prognostic factors were tested retrospectively. Number and pathologic status of resected organs were assessed. RESULTS: 151 organs were resected. Ninety-two were involved by the tumor (60.9%). Liposarcoma involved 48 of 77 organs resected for this histotype (62.3%). Infiltrative pattern was observed in 39/92 organs, and expansive pattern in 53/92 viscera. The infiltrative pattern was more often observed in leiomyosarcoma and non-lipogenic tumors. The expansive pattern was more often observed in liposarcoma. Psoas was the organ most often involved by infiltrative pattern (12/14); the kidney was the organ most often involved by expansive pattern (19/28). 80% of patients had at least one viscera infiltrated by the tumor. CONCLUSIONS: This series, in which an aggressive surgical policy was adopted along with extensive pathologic sampling, shows that RPS has a high rate of viscera infiltration. This growth pattern is characteristic of well-differentiated liposarcoma too. These pathologic data should be considered when planning surgical strategy.

Serum tumour markers in germ cell tumours: From diagnosis to cure.

Germ cell tumors (GCTs) represent the best and the only example of solid tumors curable in the large majority of patients. GCTs are one of the few malignancies for which specific biochemical markers have been identified: human chorionic gonadotropin (HCG) and alfa-fetoprotein (AFP). Due to their specificity and sensitivity they constitute formidable tools in the diagnosis and monitoring of treatment for GCTs. As a tumor mass marker, lactate dehydrogenase (LDH) is also considered. Tumor markers are expressed in 15-20% of seminoma and 60-80% of non-seminoma. With the aim to increase sensitivity and specificity, recent studies have proposed miRNAs as serum biomarkers. This review will focus on role of serum tumor markers in diagnosis, staging, prognosis, monitoring of response, and finally follow-up of GCTs.

The Role of Nutritional Support in Cured/Chronic Patients.

Improvements in Clinical Oncology, due to earlier diagnoses and more efficient therapeutic strategies, have led to increased numbers of long-term survivors, albeit many with chronic diseases. Dealing with the complex care needs of these survivors is now an important part of Medical Oncology. Suitable diet and physical activity regimes will be important in maintaining their health. This paper will review what we know and what we can do in the near future for these patients.

Is Proton Beam Radiotherapy Worthwhile in the Management of Angiosarcoma of the Scalp?

In inoperable patients, the management of angiosarcoma of the scalp is challenging. Due to intrinsic, dosimetric and radiobiological properties, proton beam radiotherapy may be an effective and safe option to offer to these difficult-to-cure patients. Here, we report a case of angiosarcoma of the scalp treated successfully with proton beam radiotherapy. Angiosarcoma is a rare malignancy concerning around 2% of soft-tissue sarcomas and 5% of cutaneous soft-tissue sarcomas. Cutaneous angiosarcomas can occur in any part of the body, but the head and neck region is a common primary site and the scalp is a frequent site in elderly patients.