Outcomes of relapsed/refractory extracranial germ cell tumors treated on conventional salvage chemotherapy without stem cell rescue: Experience from a tertiary cancer center.

BACKGROUND AND AIMS: Data on the outcome and prognostic indicators in extracranial relapsed/refractory germ cell tumors (rel/ref-GCTs) in children are limited to a few studies. This study looks at remission rates and outcomes of rel/ref-GCTs treated with conventional salvage chemotherapy (SC) regimens without stem cell rescue at a single center in the developing world. METHODS: Patients treated at our center from January 2009 to December 2018 were included. Risk at primary presentation was stratified as all completely excised teratomas and stage I gonadal tumors being low risk (LR); stage IV ovarian, stage III-IV extragonadal GCTs as high risk (HR), and the remaining as intermediate risk (IR). SC regimens were: vinblastine-ifosfamide-cisplatin/carboplatin or paclitaxel-ifosfamide-cisplatin/carboplatin, or cisplatin/carboplatin-etoposide-bleomycin. Local therapy was either surgery and/or radiotherapy. RESULTS: The analyzable cohort comprised 50 patients (44 = rel-GCTs; 6 = ref-GCTs) with a median age of 3.8 years and male:female ratio of 1.27:1. Primary location was ovary in 16 (32%), testicular in 10 (20%), and extragonadal in the rest (48%). Local, metastatic, and combined progression was noted in 28 (56%), 14 (28%), and eight (16%) patients, respectively, at a median time of 8.5 months. At a median follow-up of 60 months, the 5-year event-free survival (EFS) and overall survival (OS) of the entire cohort (n = 50) were 42.4% and 50.0%, respectively. In patients previously exposed to platinum analogs (n = 38), 5-year-EFS and OS were 27.7% and 31.7%, respectively. Local relapses did better when compared to metastatic and combined relapses (5-year EFS: 64% vs. 23% vs. 0%; p = .009). LR and IR tumors did better compared to HR (5-year EFS: 81.5% vs. 49.3% vs. 6.5%; p = .002). Patients with normalization of tumor markers after two cycles had a superior EFS (57.6% vs. 0%; p < .001). Relapsed tumors fared better than primary refractory GCTs (5-year EFS: 48.6% vs. 0%; p < .001). CONCLUSIONS: Primary refractory GCTs, extragonadal rel-GCTs, and rel/ref-GCTs with a poor biochemical response did poorly with conventional SC and need alternative treatment strategies. The rel/ref-testicular GCTs had the best chance of salvage despite a second recurrence (5-year EFS and OS: 28.60% and 42.90%, respectively).

Temporal changes in magnetic resonance imaging appearance of adult granulosa cell tumor.

Granulosa cell tumors (GCTs) can have a wide variety of appearances on magnetic resonance imaging (MRI), ranging from entirely solid to multilocular cystic, suggesting that GCTs undergo remarkable morphological changes during growth. These temporal changes in MRI appearance of individual GCTs have not been documented. A 54-year-old asymptomatic postmenopausal woman was referred to our department for a small ovarian mass. This 3-cm solid mass showed high intensity on diffusion-weighted MRI and low intensity on apparent diffusion coefficient mapping. Close clinical follow-up was recommended, but she did not return to our hospital until the age of 63, when she was referred for a large ovarian tumor. MRI showed a 15-cm multilocular cyst containing a solid component with hemorrhaging. Postoperative diagnosis was adult GCT (AGCT). These temporal changes demonstrate a possible reason why GCTs can have such a wide range of MRI appearance. This knowledge might promote accurate preoperative diagnosis of AGCTs.

Prediction of radiosensitivity in primary central nervous system germ cell tumors using dynamic contrast-enhanced magnetic resonance imaging.

OBJECTIVE: To evaluate the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for predicting tumor response to radiotherapy in patients with suspected primary central nervous system (CNS) germ cell tumors (GCTs). METHODS: DCE-MRI parameters of 35 patients with suspected primary CNS GCTs were obtained prior to diagnostic radiation, using the Tofts and Kermode model. Radiosensitivity was determined in tumors diagnosed 2 weeks after radiation by observing changes in tumor size and markers as a response to MRI. Taking radiosensitivity as the gold standard, the cut-off value of DCE-MRI parameters was measured by receiver operating characteristic (ROC) curve. Diagnostic accuracy of DCE-MRI parameters for predicting radiosensitivity was evaluated by ROC curve. RESULTS: A significant elevation in transfer constant (K(trans)) and extravascular extracellular space (Ve) (P=0.000), as well as a significant reduction in rate constant (Kep) (P=0.000) was observed in tumors. K(trans), relative K(trans), and relative Kep of the responsive group were significantly higher than non-responsive groups. No significant difference was found in Kep, Ve, and relative Ve between the two groups. Relative K(trans) showed the best diagnostic value in predicting radiosensitivity with a sensitivity of 100%, specificity of 91.7%, positive predictive value (PPV) of 95.8%, and negative predictive value (NPV) of 100%. CONCLUSIONS: Relative K(trans) appeared promising in predicting tumor response to radiation therapy (RT). It is implied that DCE-MRI pre-treatment is a requisite step in diagnostic procedures and a novel and reliable approach to guide clinical choice of RT.

Final report of the phase II NEXT/CNS-GCT-4 trial: GemPOx followed by marrow-ablative chemotherapy for recurrent intracranial germ cell tumors.

Background: Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx). Methods: A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR. Treatment response was determined based on radiographic tumor assessments and tumor markers. Results: A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease. Conclusions: GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy.

Extragonadal germ cell tumor: A rare case in dorsal region.

Extragonadal germ cell tumors (GCTs) are a rare group of neoplasms that account for 1%-5% of all GCTs. These tumors can present with an unpredictable behavior and clinical manifestations depending on different factors such as histological subtype, anatomical site, and clinical stage. We report the case of a 43-year-old male patient with a primitive extragonadal seminoma located in the paravertebral dorsal region, an extremely rare site. He presented to our emergency department with a 3-month history of back pain and a 1-week history of fever of unknown origin. Imaging techniques revealed a solid tissue arising from the vertebral bodies of D9-D11 and extending in the paravertebral space. After a bone marrow biopsy and exclusion of testicular seminoma, he was diagnosed with primitive extragonadal seminoma. The patient underwent five cycles of chemotherapy, and the follow-up CT examinations showed a reduction of the mass initially till a complete remission with no evidence of recurrence.

Effects of primary granulocyte-colony stimulating factor prophylaxis on the incidence of febrile neutropenia in patients with germ cell tumors.

Testicular germ cell tumors (GCTs) are the most common solid malignancy in males aged 15-35 years. Febrile neutropenia (FN) is a serious complication of chemotherapy that frequently occurs in patients with GCTs. The present retrospective study aimed to evaluate the effect of primary granulocyte-colony stimulating factor (G-CSF) prophylaxis on the incidence of FN in patients with GCTs. The present study included a review of the medical records of patients diagnosed with GCTs treated with first-line/adjuvant chemotherapy between January 2000 and December 2017 at the National Cancer Institute (Bratislava, Slovakia). In January 2006, a decision was made to administer G-CSF prophylaxis (filgrastim or pegfilgrastim) to patients after every cycle of chemotherapy. The present study included 385 patients, and out of these, 264 patients received primary G-CSF prophylaxis, while 121 patients did not. A total of 71 patients (18.4%) suffered from FN events. In the subgroup that did not receive primary prophylaxis, 42 patients exhibited FN, while only 29 patients with primary prophylaxis suffered from FN (34.7 vs. 11.0%; P=0.00000003). According to the subgroup analysis, FN incidence was decreased in all groups that received primary prophylaxis, except for patients with stage I GCT receiving adjuvant chemotherapy, without affecting overall survival. Primary G-CSF prophylaxis was associated with markedly reduced FN incidence in patients treated with first-line chemotherapy for metastatic disease. Therefore, the results of the present study suggested that primary G-CSF prophylaxis should be considered in patients with GCT receiving first-line chemotherapy.

Treatment Outcome of a ß-hCG Secreting Intracranial Germ Cell Tumor in an Adult Filipino Using Definitive Chemotherapy Followed by Radiotherapy: A Case Report.

We report a case of a 24-year-old Filipino male who complained of general weakness, polydipsia, weight loss, bitemporal headaches, loss of libido and behavioral changes. Endocrine work-up revealed neurogenic diabetes insipidus and panhypopituitarism. Brain MRI showed multiple intracranial tumors in the left frontal lobe, pineal and suprasellar region with moderate non-communicating hydrocephalus. Intracranial mass biopsy with ventriculo-peritoneal shunting was done. Histopathology of the mass and CSF revealed a germinoma. He underwent chemoradiotherapy while on maintenance hormone replacement.

Preservation of sexual and reproductive function in the treatment of extragonadal yolk sac tumors in the female genital tract.

Objective: This study aimed to summarize the clinical features, treatment modalities, therapeutic effects, menstruation and fertility outcomes, and prognosis of extragonadal yolk sac tumors (YSTs) of the female genital tract. Methods: We reviewed 32 cases of extragonadal YSTs in the genital tract treated between 1983 and 2021. The medical records, including clinical characteristics, histopathology, treatments, chemo-reduced adverse events, and outcomes on long-term follow-up, were collected. Results: Among the 32 cases, 30 were vaginal YSTs and two were uterine YSTs (endometrial and cervical). Thirty patients (30/32, 93.8%) were <4 years. Abnormal vaginal bleeding (n = 31) and elevated serum alpha-fetoprotein level (n = 32) were the most common presentations. Vaginohysteroscopy and/or pediatric rhinoscopy were used for diagnosis in 17 pediatric patients and evaluation of chemotherapeutic efficacy in 21 pediatric patients. All the patients received combination chemotherapy. Bleomycin/etoposide/cisplatin (BEP) was chosen with prior consideration in 28 cases; 21 patients were treated with BEP alone. Yellow or grayish-yellow tissue with irregular shape was found in 66.7% of the cases during repeat examinations. Five patients underwent surgeries during repeat examinations and follow-ups, and no evidence of malignancy was noted in them. Thirty-one patients achieved complete remission. During a median follow-up of 63 months (2.4-240.3 months), two patients experienced recurrence, three died, and 29 remained disease-free. One patient recovered menstruation and five had undergone menarche. Conclusion: BEP chemotherapy can serve as a preferred treatment modality for vaginal and uterine YSTs. Vaginohysteroscopy and pediatric rhinoscopy can be used for diagnosis and evaluation of chemotherapeutic efficacy in pediatric patients. YSTs possibly appear as yellow or grayish-yellow after chemotherapy.

Spectrum of Germ Cell Tumor (GCT): 5 Years' Experience in a Tertiary Care Center and Utility of OCT4 as a Diagnostic Adjunct.

Germ cell tumors (GCT) are an intriguing group of neoplasm having myriad clinical and morphological presentation. More and more transcription factors are being evaluated for identification of same. To study the spectrum of GCTs in a tertiary care center and the use of a stem cell marker OCT4 as a diagnostic adjunct, a retrospective 5-year (2008-2013) study was carried out. Immunohistochemistry (IHC) with OCT4 was performed on all cases and IHC for α feto protein (AFP), CD30, and epithelial membrane antigen (EMA) as per requirement. Cohort included 73 cases (23 males and 50 females). Testicular and ovarian GCTs accounted for 95.83% and 35.71% respectively. In males, seminoma was the commonest (34.78%) followed by mixed GCT (26%). 17.85% of ovarian GCTs were malignant mostly constituted by dysgerminoma (18%). Benign mature cystic teratoma (MCT) constituted 50% of ovarian GCTs. OCT4 immunoexpression was seen in all cases of seminoma/dysgerminoma, embryonal carcinoma, immature teratoma, and seminomatous/embryomatous component of mixed GCTs. Pure yolk sac tumor (YST) and MCT were consistently negative. OCT4 was especially helpful in identification of mixed GCT. A panel of immunohistochemical markers would be a more ideal way to identify and clarify the components because correct identification of the components is important for therapeutic intervention and prognostication. OCT4 being a primordial germ cell marker predicts aggressive behavior and targeted therapy against this should be investigated.

Challenging presentations of germ cell tumours in routine clinical practice.

Testicular cancer is the most common malignancy in young men. We discuss four cases of germ cell tumours (GCTs) presenting to general practitioners and physicians where there were notable preventable delays in the diagnosis and management. This diagnostic delay is associated with a more advanced stage of disease, and subsequent increased treatment-related morbidity and decreased survival. Our series highlights the variety of ways in which GCTs may present and we discuss the importance of prompt diagnosis through a thorough history and examination, early measurement of serum tumour markers and appropriate multidisciplinary team discussion. GCTs are highly curable cancers in the majority of patients and delays in management can, therefore, have devastating consequences.

Narrative review of developing new biomarkers for decision making in advanced testis cancer.

Management of testicular germ cell tumor (GCT) patients is based on clinical determinants, mainly CT scan and serum tumor markers (alpha-fetoprotein, beta subunit of HCG and LDH). Treatment decisions are usually straightforward for patients with clear evidence of metastatic disease, confirmed either by imaging tests or by unequivocal elevated tumor markers. However, there are several clinical scenarios where the assessment of metastatic disease is complicated by the limited specificity of the current imaging tests and serum tumor markers. These include patients with clinical stage IIA GCT with negative tumor markers and patients with post-chemotherapy residual disease where, in absence of clear indicators of GCT, decision making and patient treatment allocation become challenging. Therefore, more accurate biomarkers are critical to reduce the risk of under-or over-treatment and to always deliver the most optimal therapy. The objectives of this narrative review are to review the available publications about micro-RNAs in GCT s and their potential clinical applications. Two clusters of micro-RNAs, miR-371a-3p and miR-302/367, specifically expressed by both seminoma and non-seminoma GCT and easily detectable in the peripheral blood, have demonstrated to be promising in this endeavor. Large prospective trials are ongoing to define the operating characteristics of these biomarkers and their clinical utility to improve GCT patient management and reduce the error rate deriving from clinical uncertainty, therefore reducing the risk of sub-optimal treatments.

[18F]FDG and [18F]FES positron emission tomography for disease monitoring and assessment of anti-hormonal treatment eligibility in granulosa cell tumors of the ovary.

PURPOSE: Adult granulosa cell tumors (AGCTs) of the ovary represent a rare malignancy in which timing and choice of treatment is a clinical challenge. This study investigates the value of FDG-PET/CT and FES-PET/CT in monitoring recurrent AGCTs and assessing eligibility for anti-hormonal treatment. MATERIALS AND METHODS: We evaluated 22 PET/CTs from recurrent AGCT patients to determine tumor FDG (n = 16) and FES (n = 6) uptake by qualitative and quantitative analysis. We included all consecutive patients from two tertiary hospitals between 2003-2020. Expression of ERα and ERß and mitoses per 2 mm2 were determined by immunohistochemistry and compared to FES and FDG uptake, respectively. RESULTS: Qualitative assessment showed low-to-moderate FDG uptake in most patients (14/16), and intense uptake in 2/16. One patient with intense tumor FDG uptake had a high mitotic rate (18 per 2 mm2) Two out of six patients showed FES uptake on PET/CT at qualitative analysis. Lesion-based quantitative assessment showed a mean SUVmax of 2.4 (± 0.9) on FDG-PET/CT and mean SUVmax of 1.7 (± 0.5) on FES-PET/CT. Within patients, expression of ERα and ERß varied and did not seem to correspond with FES uptake. In one FES positive patient, tumor locations with FES uptake remained stable or decreased in size during anti-hormonal treatment, while all FES negative locations progressed. CONCLUSIONS: This study shows that in AGCTs, FDG uptake is limited and therefore FDG-PET/CT is not advised. FES-PET/CT may be useful to non-invasively capture the estrogen receptor expression of separate tumor lesions and thus assess the potential eligibility for hormone treatment in AGCT patients.

Mixed Germ Cell Tumor of the Endometrium: A Case Report and Literature Review.

Germ cell tumors (GCTs) localized extragonadally are rare, with only 14 reported cases of a yolk sac tumor in the endometrium. Here we report a case of mixed endometrium GCTs in a 65-year-old postmenopausal woman with abnormal vaginal bleeding. An ultrasound examination showed an oval-shaped mass in the patient's uterine cavity. Biochemical examination revealed elevated serum α-fetoprotein (AFP) at 359 ng/mL, whereas the tumor markers CA-125, CA-199, and CEA were all within normal range. Total hysterectomy and bilateral salpingo-oophorectomy were performed;. a histological examination revealed that the malignant components contained a yolk sac tumor, embryonal carcinoma, and focal immature teratoma. Immunohistochemical staining showed that AFPs were diffusively distributed in both the yolk sac tumor and embryonal carcinoma. The stem cell marker OCT3/4 was positive in the embryonal carcinoma component and that the pan-cytokeratin AE1/AE3 staining was positive in glandular areas. GFAPs (Glial Fibrillary Acidic Proteins) were positive in neuroectodermal tubules; the Ki-67 protein was positive in 90% of the tumor cells, whereas CD117 and placental alkaline phosphatase (PLAP) were negative. The cumulative evidence indicated mixed GCTs of endometrium as the final histopathological diagnosis. The patient received three courses of adjunct chemotherapy that provided good therapeutic efficacy as evidenced by the decreased serum AFP level. Our report on this rare case of mixed GCTs of the endometrium, supported by associated histological patterns and immunophenotypes and successful adjunct chemotherapy after surgery, could provide insight on future treatment of this rare but lethal disease.

Estrogen regulates forkhead transcription factor 2 to promote apoptosis of human ovarian granulosa-like tumor cells.

Granulosa cell tumors of the ovary (GCTs) are the predominant form of ovarian stromal tumors and can lead to abnormally secreted estrogen hormones. Studies have reported that forkhead transcription factor 2 (FOXL2) inhibits estrogen synthesis and its gene mutation can lead to GCTs. We unexpected found that estrogen also regulates the expression level of FOXL2. High-dose estrogen increased the expression of FOXL2 in ovarian-like granulosa (KGN) cells at both the mRNA and protein levels. However, no research has reported on the molecular regulatory mechanism and function between estrogen and FOXL2 in the development of GCTs. In this research, FOXL2 was highly expressed in KGN cells and ovarian stromal tumor tissues. Deletion of FOXL2 increased the estrogen secretion in KGN cells. In turn, high-dose estrogen increased the FOXL2 expression levels. FOXL2 was phosphorylated by GPR30 (G protein coupled receptor)-Protein kinase C (PKC) signaling pathway upon estrogen stimulation. Estrogen inhibited cell migration and proliferation, while promoting cell apoptosis. Deletion of FOXL2 inhibited the influence of estrogen on cell proliferation, migration, and apoptosis. Results suggest that estrogen via regulating FOXL2 suppresses cell proliferation and induces cell apoptosis.

Duration analysis on the adoption behavior of green control techniques.

Based on field survey data of 366 traditional households (THs) and 364 family farms (FFs) from Huang-Huai-Hai Plain, a discrete-time cloglog model for parameter estimation was constructed to reveal factors that affect the two types of farms' duration from the awareness to the adoption of green control techniques (GCTs). Differences in the influencing factors affecting the duration of the two types of farmers were also discussed. The research results are as follows. First, the duration from awareness to adoption of GCTs is significantly shorter in FFs than that in THs. Second, a higher degree of education, risk preference, family financial status, perceived ease of use and usefulness of the technique, and extension of media and supervision of agricultural technique extension departments of local governments significantly reduce the duration from awareness to adoption of GCTs by THs and FFs, whereas a male head of household prolongs the duration. Third, the age, farm size, and number of laborers exert different impacts on the duration from awareness to adoption of GCTs by THs and FFs.

Luteinizing hormone elevation in ovarian granulosa cell tumor: a case report and review of the literature.

BACKGROUND: Ovarian granulosa cell tumors (GCTs) are the most common type of potentially malignant ovarian sex cord-stromal tumor. GCTs often produce estrogen and/or progesterone; consequently, symptoms related to hyperestrogenism are common at diagnosis. Nonspecific symptoms or signs associated with this neoplasm include amenorrhea and changes in various sex hormone levels, which can be hard to diagnose or explain. The aims of this report were to describe a case of GCT with rare presentations and to review the pertinent literature. CASE PRESENTATION: A 33-year-old woman presented with secondary amenorrhea and elevated LH with normal FSH and low estradiol levels. Laparoscopy revealed an ovarian GCT, and the patient underwent left adnexectomy and platinum-based chemotherapy. Removal of the ovarian GCT resulted in the normalization of LH levels and a return to spontaneous menses. CONCLUSIONS: The mechanisms responsible for elevations in serum LH due to GCTs require further investigation. However, addressing the patient's clinical problems remains the most important treatment consideration.

Recurrent granular cell tumor: a case report and review of literature.

Granular cell tumors (GCTs) in the spine are uncommon. They are mostly located in the intradural extramedullary space and rarely, in an intramedullary (IM) location. Complete resection is the treatment of choice. Recurrences are rare in intradural-intramedullary (IDEM) GCTs. Recurrent and incompletely excised cases are subjected to adjuvant radiation therapy. We report such a recurrence in a 13-year-old girl who was re-operated and subjected to radiotherapy.